Estrogen induction of glial heat shock proteins: implications for hypothalamic aging.
In the aging mammalian hypothalamus, a unique subpopulation of glial cells accumulates peroxidase-positive cytoplasmic inclusions distinct from lipofuscin. In adult rodents, this senescence-dependent glial granulation is accelerated by administration of estradiol valerate. In the present study, brain sections derived from male rats given 3 monthly intramuscular injections of estradiol valerate (0.2 mg or 2.0 mg) were immunostained for heat shock proteins and glial fibrillary acidic protein to determine whether a glial stress response is implicated in estrogen-induced granulation. Our findings indicate that estrogen elicits a heat shock response and subsequent granulation in astrocytes residing in estradiol receptor-rich brain regions including the arcuate nucleus and the wall surrounding the third ventricle but not in estradiol receptor-deficient regions such as the striatum and corpus callosum. The heat shock proteins induced by estrogen, namely, the 27, 72, and 90 kDa stress proteins, are upregulated in astrocytes in response to oxidative challenge supporting our hypothesis that estrogen mediates senescent changes in the rodent hypothalamus through oxidative mechanisms.


Vapocoolant Spray Versus Lidocaine Infiltration for Radial Artery Cannulation: A Prospective, Randomized, Controlled Clinical Trial.
Local infiltration with lidocaine is a frequently used measure to prevent pain during arterial cannulation. Its administration is associated with pain. Vapocoolants like ethyl chloride or alkanes also affect rapid-onset anesthesia. However, their administration causes less discomfort compared with administration of lidocaine. The effectiveness of vapocoolants in mitigating discomfort associated with arterial cannulation never has been studied. The authors therefore compared vapocoolant with lidocaine for reducing discomfort caused by arterial cannulation. Prospective, randomized, controlled study. University hospital, single center. One hundred sixty adult patients requiring arterial cannulation before induction of general anesthesia for cardiac surgery or carotid endarterectomy. Patients received either lidocaine infiltration or vapocoolant spray prior to arterial cannulation. Overall discomfort resulting from the whole procedure (applying local/topical anesthesia followed by arterial puncture) was rated on a 0 to 10 numerical rating scale. Puncture failure rate and time required for the intervention also were recorded. One hundred forty-three patients were included in the per-protocol analysis. Mean pain scores in the vapocoolant group were 3.4 (±1.58) compared with 4.5 (±2.29) in the lidocaine group (difference 1.1±0.33; p = 0.032; Mann-Whitney U-test). The higher puncture failure rate in the lidocaine group (n = 11 v 4) was not significant (p = 0.06; Fisher's exact test). The time required for the intervention was longer in the lidocaine group (138±44 s v 128±44 s; p = 0.019; Mann-Whitney U-test). Vapocoolant spray is an alternative to lidocaine infiltration to mitigate discomfort associated with arterial cannulation.


Design of a peptibody consisting of the antimicrobial peptide dhvar5 and a llama variable heavy-chain antibody fragment.
Immunoconjugates have been widely studied as potential therapeutics for infectious diseases to direct unspecific antimicrobials to pathogens. In this study, the recombinant approach was used for expression of the immunoconjugate composed of the variable domain of a llama heavy-chain antibody (VHH) against Streptococcus mutans and dhvar5, a synthetic antimicrobial peptide. Before cloning, the impact of the elongation of the peptide termini on its biological activity was evaluated by chemical synthesis of the N- or C-termini extended dhvar5 peptides. As the elongation of the C-terminus had a greater influence on decline of the antimicrobial activity, the N-terminal fusion was designed. To promote in vivo release of the active peptide, a factor Xa cleavage site was inserted between VHH and dhvar5. Propagation of transformed Escherichia coli with the constructed plasmid was only possible in the absence of isopropyl beta-D-thiogalactoside (IPTG). Although these data demonstrate that the diminished antimicrobial activity of dhvar5 by the N-terminal fusion to VHH was not sufficient for the protection of the bacterial host cells against the peptide lethal effect, an insight into propeptides biological activities may be beneficial not only for new and more successful rearrangement of the VHH-dhvar5 immunoconjugate construct, but also design of the other recombinant molecules composed of peptides toxic to host cells.


Prognostic role of subsequent atrial tachycardias occurring during ablation of persistent atrial fibrillation: a prospective randomized trial.
The role of subsequent atrial tachycardias (AT) in the context of persistent atrial fibrillation (AF) remains undetermined. This study evaluated the prognostic role of subsequent ATs for arrhythmia recurrences after catheter ablation of persistent AF. A total of 110 patients with persistent AF (63±9 years; 22 women; 61 long-lasting persistent AF) underwent pulmonary vein isolation followed by electrogram-guided ablation. After AF terminated to AT, patients were separated by the randomization protocol to receive either direct cardioversion (group A) or further ablation of subsequent ATs to sinus rhythm (group B). After a mean follow-up of 20.1±13.3 months after the first procedure, significantly more group B patients were in sinus rhythm as compared with patients in group A (30 [57%] versus 18 [34%]; P=0.02). Moreover, recurrences of AF were significantly less frequent of group B than in group A patients (10 [19%] versus 26 [49%]; P=0.001). After the last procedure (follow-up, 34.0±6.4 months), significantly more group B patients were free of AF as compared with patients of group A (49 [92%] versus 39 [74%]; P=0.01). The proportion of AT recurrences did not differ between the 2 groups after the first and final procedures. The strongest predictor for an arrhythmia-free survival after a single procedure was randomization to the procedural end point of termination to sinus rhythm by elimination of subsequent ATs (P=0.004). Catheter ablation of subsequent ATs increases freedom from AF but not AT, suggesting a contributing role of subsequent ATs in the mechanisms of persistent AF. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01896570.


[Macrophage depletion inhibits leukocyte recruitment in experimental melanin-induced uveitis (EMIU)].
To study the role of macrophages in experimental melanin-induced uveitis (EMIU), we used the method of intravital microscopy to analyse changes in leukocyte adhesion to iris venules of live rats with EMIU after pretreatment with liposomal clodronate. EMIU was induced in Lewis rats (n = 48) by intraperitoneal immunisation with bovine crude melanosomes emulsified in complete Freund's adjuvant (CFA) and pertussis toxin (PTX). Control animals received CFA and PTX only (n = 12) or no injection (n = 6). Animals were treated with liposomal clodronate (DMDP-lip) or empty liposomes on days -2, +1, 4, 6 and 8. Using IVM, postcapillary iris venules of rats were examined to quantify leukocyte rolling and firm adhesion to the vascular endothelium. Depletion of macrophages caused a decreased percentage of rolling leukocytes on day 8 (2 +/- 1.1% vs 15.2 +/- 1.6%, DMDP-lip vs EMIU, mean +/- SEM, ANOVA, p < 0.05) and day 10 (2.6 +/- 0.3% vs 14.2 +/- 1.6%). A significant decline in the number of firmly adherent leukocytes was detected on days 8 and 10 (88 +/- 13/mm2 vs 175 +/- 18/mm2 and 129 +/- 13/mm2 vs 372 +/- 31/mm2, DMDP-lip vs EMIU). Treatment with empty liposomes showed no changes in leukocyte firm adhesion. Elimination of macrophages prevents the induction of EMIU. In autoimmune-mediated uveitis, macrophages play a crucial role in the initiation of leukocyte-endothelium interaction.


Modification of the titmus fly test to improve accuracy.
In spite of its well-known flaws, the Titmus test is still the most commonly available and frequently utilized stereotest worldwide. Detecting stereopsis in the patient with small-angle strabismus is an important part of the sensorimotor exam. Because these patients often have only gross stereopsis, stereoacuity may have to be evaluated with the House Fly plate alone. This study evaluates an alternative method of presentation designed to decrease the false positive rate of the Titmus Fly test. A group of orthotropic volunteers with normal binocular vision, a group of patients with small angle strabismus, and a group of patients whose angle of strabismus was large enough to preclude stereopsis were tested with the Titmus Fly using two different presentations and compared. The sensitivity of the Titmus Fly test was 79%, but specificity was only 26% due to the large number of false positive responses detected with the modified presentation. Patients with childhood-onset strabismus who have been repeatedly exposed to this test over many visits were particularly vulnerable to overestimation of stereoacuity. If the Titmus fly test is the only stereoacuity measure that can be used due to the presence of manifest strabismus, modifying the presentation of the test plate with this method will improve accuracy and precision of results.


Critical illness is associated with low circulating concentrations of insulin-like growth factors-I and -II, alterations in insulin-like growth factor binding proteins, and induction of an insulin-like growth factor binding protein 3 protease.
To describe the sequential changes in the circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins in critically ill patients. To determine whether critical illness is associated with induction of a specific protease directed against insulin-like growth factor binding protein 3 and to relate these changes to outcome. Prospective, descriptive study. Intensive care unit (ICU) of a university hospital. Eighteen heterogeneous critically ill patients, requiring ventilatory support. Serial daily blood samples were collected until death or discharge from the ICU. In five patients, samples were also obtained on the ward before discharge from the hospital. Serum concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins 1, 2, and 3 were measured by radioimmunoassay. After 5 days, insulin-like growth factor binding protein 3 concentrations were measured on alternate days. Alterations in binding of insulin-like growth factor-I to insulin-like growth factor binding protein 3 and the presence of protease activity directed against insulin-like growth factor binding protein 3 were investigated by Western ligand blotting. Circulating concentrations of insulin-like growth factor-I and insulin-like growth factor-II were low and remained low throughout the 7-day study period. Insulin-like growth factor binding protein 1 concentrations were initially increased to within the fasting range, but subsequently decreased. There was considerable variability in insulin-like growth factor binding protein 2 concentrations, but generally, concentrations were at the upper end of the normal range throughout. Insulin-like growth factor binding protein 3 concentrations were consistently low and Western ligand blotting at the nadir of the insulin-like growth factor-I concentration demonstrated the presence of a protease directed against insulin-like growth factor binding protein 3. The last recorded concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein 3 were higher in survivors than in nonsurvivors (p < .05). Two patients were also studied for a prolonged period. In one patient, a survivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 were low initially, but later increased in association with recovery and cessation of protease activity over a period of 33 days. In another patient, a nonsurvivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 remained low and protease activity persisted until the patient died 38 days after admission to the ICU. Critical illness is associated with low circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein 3 and these low values are associated with induction of protease activity specifically directed against insulin-like growth factor binding protein 3. In survivors, recovery is associated with increasing insulin-like growth factor-I and insulin-like growth factor binding protein 3 concentrations and cessation of protease activity. The therapeutic effects of exogenous growth factors are likely to be influenced by these changes.


Aerobic anoxygenic photosynthesis genes and operons in uncultured bacteria in the Delaware River.
Photosynthesis genes and operons of aerobic anoxygenic photosynthetic (AAP) bacteria have been examined in a variety of marine habitats, but genomic information about freshwater AAP bacteria is lacking. The goal of this study was to examine photosynthesis genes of AAP bacteria in the Delaware River. In a fosmid library, we found two clones bearing photosynthesis gene clusters with unique gene content and organization. Both clones contained 37 open reading frames, with most of those genes encoding known AAP bacterial proteins. The genes in one fosmid were most closely related to those of AAP bacteria in the Rhodobacter genus. The genes of the other clone were related to those of freshwater beta-proteobacteria. Both clones contained the acsF gene, which is required for aerobic bacteriochlorophyll synthesis, suggesting that these bacteria are not anaerobes. The beta-proteobacterial fosmid has the puf operon B-A-L-M-C and is the first example of an uncultured bacterium with this operon structure. The alpha-3-proteobacterial fosmid has a rare gene order (Q-B-A-L-M-X), previously observed only in the Rhodobacter genus. Phylogenetic analyses of photosynthesis genes revealed a possible freshwater cluster of AAP beta-proteobacteria. The data from both Delaware River clones suggest there are groups of freshwater or estuarine AAP bacteria distinct from those found in marine environments.


The effect of chitosan and PVDF substrates on the behavior of embryonic rat cerebral cortical stem cells.
In this study, the behavior of neural stem cells from embryonic rat cerebral cortex were compared on the chitosan and poly(vinylidene fluoride) (PVDF) substrates at single-cell and neurosphere level. It was found that chitosan and PVDF substrates inhibited the proliferation and differentiation of single neural stem cells. It seemed that single-cell cultures on both substrates show cells remained dormant. However, neurospheres could exhibit different or similar behavior on these two substrates, which is dependent on the presence or absence of serum. More cells migrated outside from the neurospheres and longer processes extended from differentiated cells on chitosan than on PVDF when neurospheres were cultured in the serum-free medium. On the contrary, when serum was added to the culture system, chitosan and PVDF could induce the neurosphere-forming cells into an extensive cellular substratum of protoplasmic cells upon which process-bearing cells spread. In addition, based on the immunocytochemical analysis, the percentages of differentiated cell phenotypes of neurospheres cultured on chitosan and PVDF substrates became similar in the presence of serum. Therefore, it is reasonable to suggest that biomaterials may stimulate or inhibit the proliferation and differentiation of neural stem cells according to the complex environmental conditions. The information presented here should be useful for the development of biomaterials to regulate the preservation, proliferation, and differentiation of neural stem cells.


Investigations on the Mechanism of the Brassinosteroid Response: I. Indole-3-acetic Acid Metabolism and Transport.
A brassinosteroid treatment of light-grown first internode sections of Phaseolus vulgaris results in an increased bending response following unilateral indole-3-acetic acid (IAA) application. Reverse isotope dilution analysis shows that this increased response is not due to an increase in the concentration of applied IAA in the tissue or a change in the amount of IAA conjugated. Treatment with the brassinosteroid also does not affect the rate of IAA transport as measured using the agar block method. These results indicate that even though brassinosteroid potentiates auxin action, it does not have a direct effect on IAA uptake, metabolism, or cell to cell transport.


Plasmid-mediated multiple antibiotic resistance in Proteus mirabilis isolated from patients with urinary tract infection.
Worldwide surveillance of antimicrobial resistance among urinary tract pathogens is useful to determine important trends and geographical variation for common Gram negative and positive species. We initiated this study to learn the drug resistance pattern and its location (genomic or plasmid-borne) among the strains of Proteus mirabilis, one of the most common causative agents of urinary tract infection (UTI). A total of 200 urine samples were collected from UTI patients, followed by isolation and identification of Proteus milabilis strains. Antibiotic sensitivity and resistance analysis was performed by the disc diffusion method, employing multiple antibiotic discs. The sensitivity was monitored by visualizing the zone of inhibition around the disc. Plasmid isolation was performed by the method of Kado and Liu. Transfer of the R-Plasmid to recipient E.coli C600 cells was achieved using the method of Lederberg and Cohen. Clinical study revealed that this infection is more common in young pregnant women. Various strains of Proteus mirabilis isolated during the course of the study were found to show multiple antibiotic resistance, which was further characterized as plasmid-borne drug resistance. Proteus mirabilis is one of the important causative agents of urinary tract infection in young women especially during the state of pregnancy. Multiple antibiotic resistance markers of Proteus strains were identified as plasmid mediated.


Functionalized Nickel Oxide Hole Contact Layers: Work Function versus Conductivity.
Nickel oxide (NiO) is a widely used material for efficient hole extraction in optoelectronic devices. However, its surface characteristics strongly depend on the processing history and exposure to adsorbates. To achieve controllability of the electronic and chemical properties of solution-processed nickel oxide (sNiO), we functionalize its surface with a self-assembled monolayer (SAM) of 4-cyanophenylphosphonic acid. A detailed analysis of infrared and photoelectron spectroscopy shows the chemisorption of the molecules with a nominal layer thickness of around one monolayer and gives an insight into the chemical composition of the SAM. Density functional theory calculations reveal the possible binding configurations. By the application of the SAM, we increase the sNiO work function by up to 0.8 eV. When incorporated in organic solar cells, the increase in work function and improved energy level alignment to the donor does not lead to a higher fill factor of these cells. Instead, we observe the formation of a transport barrier, which can be reduced by increasing the conductivity of the sNiO through doping with copper oxide. We conclude that the widespread assumption of maximizing the fill factor by only matching the work function of the oxide charge extraction layer with the energy levels in the active material is a too narrow approach. Successful implementation of interface modifiers is only possible with a sufficiently high charge carrier concentration in the oxide interlayer to support efficient charge transfer across the interface.


Evaluation of Biofilms on Explanted Shoulder Prostheses Using Functional Biofilm Assay and Scanning Electron Microscopy.
Successfully treating shoulder arthroplasty infection requires diagnosis and bacterial identification. Higher incidence of infection with low-virulence bacteria makes this challenging. This study evaluates shoulder prostheses for infection using sonication and a functional biofilm assay. Nineteen patients undergoing revision shoulder arthroplasty were followed prospectively. Periprosthetic tissue and prosthetic components were obtained during the revision and evaluated with a functional biofilm assay. Results were compared with conventional cultures and laboratory results. Hardware samples were analyzed with scanning electron microscopy. Six of the 19 cases demonstrated growth on the biofilm assay. Three of these had positive conventional culture results and met Musculoskeletal Infection Society (MSIS) criteria for infection. Two other cases met MSIS criteria but demonstrated negative assay and conventional culture results. Of the six cases with positive assay results, three demonstrated evidence of biofilm on scanning electron microscopy. The biofilm assay identifies infections not recognized by traditional culture or MSIS criteria. (Journal of Surgical Orthopaedic Advances 27(3):171-177, 2018).


Transplacement mutagenesis: a novel in situ mutagenesis system using phage-plasmid recombination.
Site-specific mutagenesis provides the ability to alter DNA with precision so that the function of any given gene can be more fully understood. Several methods of in vitro mutagenesis are time-consuming and imprecise, requiring the subcloning and sequencing of products. Here we describe a rapid, high fidelity method of in situ mutagenesis in bacteriophage lambda using transplacement. Using this method, mutations are transferred from oligonucleotides to target phages using a plasmid interface. A small (50 bp) homology region bearing a centred point mutation is generated from oligonucleotides and subcloned into a transplacement plasmid bearing positive and negative phage selectable markers. Following a positive/negative selection cycle of integrative recombination and excision, the point mutation is transferred precisely from plasmid to phage in a subset ( approximately 25-50%) of recombinants. As the fidelity of both oligonucleotide synthesis and phage-plasmid recombination is great, this approach is extremely reliable. Using transplacement, point mutations can be accurately deposited within large phage clones and we demonstrate the utility of this technique in the construction of gene targeting vectors in bacteriophages.


Two-Dimensional Crowding Uncovers a Hidden Conformation of α-Synuclein.
The intrinsically disordered protein (IDP), α-synuclein (αS), is well-known for phospholipid membrane binding-coupled folding into tunable helical conformers. Here, using single-molecule experiments in conjunction with ensemble assays and a theoretical model, we present a unique case demonstrating that the interaction-folding landscape of αS can be tuned by two-dimensional (2D) crowding through simultaneous binding of a second protein on the bilayer surface. Unexpectedly, the experimental data show a clear deviation from a simple competitive inhibition model, but are consistent with a bimodal inhibition mechanism wherein membrane binding of a second protein (a membrane interacting chaperone, Hsp27, in this case) differentially inhibits two distinct modules of αS-membrane interaction. As a consequence, αS molecules are forced to access a hidden conformational state on the phospholipid bilayer in which only the higher-affinity module remains membrane-bound. Our results demonstrate that macromolecular crowding in two dimensions can play a significant role in shaping the conformational landscape of membrane-binding IDPs with multiple binding modes.


Construction of an intravascular ultrasound catheter with a micropiezoelectric motor internally installed.
Intravascular ultrasound (IVUS) has become a useful tool in the detection of coronary artery disease. However, non-uniform rotation distortion (NURD) reduces the image quality. In order to suppress the influence of NURD, a piezoelectric motor that can meet the requirements of IVUS catheters has been proposed. The motor has a diameter of 1 mm and a length of 10 mm using the new polarization direction proposed in the paper. A 45° mirror is fixed on the top of the motor to reflect the ultrasound transmitted from the transducer. The manufacture and drive of the piezoelectric motor is simple, and the maximum speed of the piezoelectric motor can reach 6450 rpm under the voltage of 20Vp-p. The minimum power required by the rotating motor is only 0.038 W, which can be directly driven by the signal generator without a power amplifier. The motor can operate at a low voltage and still has a high and stable speed. Meanwhile, the speed of the motor is controllable and has a satisfactory stability with a maximum angular error of 8°. The images detected by the cooperation of the motor and the ultrasonic transducer are also shown, which indicates that the motor has the rotational stability that meets the imaging requirements and the potential for application in the IVUS catheter to help improve the image quality of the coronary arteries and prevent and help treat potential diseases.


The Prevalence of Persistent Petrosquamosal Sinus and Other Temporal Bone Anatomical Variations on High-Resolution Temporal Bone Computed Tomography.
BACKGROUND The aim of the study was to determine the prevalence of petrosquamosal sinus (PSS) and other temporal bone (TB) anatomical variations in various patients using high-resolution computed tomography (CT). MATERIAL AND METHODS We reviewed clinical and consecutively obtained CT data for 276 TBs of 138 patients. The incidence of TB anatomical variations was compared among patients with radiological markers of chronic otitis media (RCOM) and non-RCOM. RESULTS The PSS incidence in our sample was 6.9%, and it was significantly higher in TBs with RCOM (14.6%). Selected anatomical variations of RCOM TBs were observed: lateral sigmoid sinus (14.5%), prominent sigmoid sinus (23.6%), PSS (14.6%), and high jugular bulb (17.3%). Lateral sigmoid sinus and prominent sigmoid sinus (p<0.01), high jugular bulb (p<0.05), and PSS (p<0.01) were observed more often in RCOM than in non-RCOM TBs. CONCLUSIONS The TB vascular and anatomical variations, including PSS, a high jugular bulb, and a laterally and prominent placed sigmoid sinus, were more often observed in TBs with RCOM. Presurgical imaging and CT-based navigation techniques for TB surgery can offer remarkable value for understanding the altered anatomy of this complex structure and can localize rare anatomical variations.


Growth of bilayer graphene on insulating substrates.
Here we demonstrate a general transfer-free method to directly grow large areas of uniform bilayer graphene on insulating substrates (SiO(2), h-BN, Si(3)N(4), and Al(2)O(3)) from solid carbon sources such as films of poly(2-phenylpropyl)methysiloxane, poly(methyl methacrylate), polystyrene, and poly(acrylonitrile-co-butadiene-co-styrene), the latter leading to N-doped bilayer graphene due to its inherent nitrogen content. Alternatively, the carbon feeds can be prepared from a self-assembled monolayer of butyltriethoxysilane atop a SiO(2) layer. The carbon feedstocks were deposited on the insulating substrates and then caped with a layer of nickel. At 1000 °C, under low pressure and a reducing atmosphere, the carbon source was transformed into a bilayer graphene film on the insulating substrates. The Ni layer was removed by dissolution, affording the bilayer graphene directly on the insulator with no traces of polymer left from a transfer step. The bilayer nature of as-grown samples was demonstrated by I(G)/I(2D) Raman mapping, the statistics of the full-width at half-maximum of the Raman 2D peak, the selected area electron diffraction patterns over a large area, and randomly imaged graphene edges by high-resolution transmission electron microscopy.


Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis.
Interactions between RNA binding proteins (RBPs) and genes are not well understood, especially in regulation of angiogenesis. The RBP HuR binds to the AU-rich (ARE) regions of labile mRNAs, facilitating their translation into protein and has been hypothesized to be a tumor-maintenance gene. Elevated levels of cytoplasmic HuR directly correlate with increased invasiveness and poor prognosis for many cancers, including those of the breast. HuR controls the expression of multiple genes involved in angiogenesis including VEGFα, HIF1α and thrombospondin 1 (TSP1). We investigated the role of HuR in estrogen receptor negative (ER(-)) breast cancer. MDA-MB-231 cells with higher levels of HuR have alterations in cell cycle kinetics and faster growth. Unexpectedly, HuR overexpression significantly interfered with tumor growth in orthotopic mouse models. The putative mechanism seems to be an anti-angiogenetic effect by increasing expression of TSP1 but also surprisingly, downregulating VEGF, a target which HuR normally increases. Our findings reveal that HuR may be regulating a cluster of genes involved in blood vessel formation which controls tumor angiogenesis. An approach of modulating HuR levels may overcome limitations associated with monotherapies targeting tumor vessel formation.


Laws for pauses.
It is shown that a particular class of pauses taken in both read and composed speech obey allometric laws such that mean pause length predicts body size. The pauses in this class have durations that roughly span 250 ms to 1,000 ms and are taken to mark grammatical and prosodic boundaries. A theory of pause allometry is developed based on the observation that these pauses are expressive, they give speech momentum and rhythm, and most importantly, their durations reflect temporal discrimination-they are not produced by articulatory constraints. The theory is formulated in terms of a leaky integrator differential equation that is intended to model the sense of time passage that occurs during relatively brief pauses. The theory predicts that if the decay time scale associated with the leakage term includes body size as a parameter, then allometry will be observed generally in the amount of silence people deploy in pause behavior. A second study tested the theory on a class of long pauses defined by being terminated by a speech gesture indicating speaker recognition that the pause was indeed long. These long pauses were also found to obey allometry. The exponents derived from power law models of mean pause duration in both studies were found to be significantly larger than those associated with allometries of body energy expenditure. These findings provide a new meaning to the embodiment of cognition. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


[The effective time of HX solution for rat liver preservation].
The effects of HX solution and UW solution for rat liver preservation were studied with non-circulated isolated perfused rat liver model. Sixty-six inbred Wistar rat livers were randomly preserved for 12, 18, 24, and 30h with HX solution or UW solution. The effects were assessed by measuring hepatic tissue water content, sinusoidal lining cell mortality, Krebs-Henseleit's perfusate aspartate aminotransferase, the number of livers secreting bile during isolated perfusion, and by observing the morphological changes in liver. The experimental results suggest that the effects of HX solution for rat liver preservation be similar to those of UW solution within 24h storage.


Two-Dimensional Halide Perovskites: Tuning Electronic Activities of Defects.
Two-dimensional (2D) halide perovskites are emerging as promising candidates for nanoelectronics and optoelectronics. To realize their full potential, it is important to understand the role of those defects that can strongly impact material properties. In contrast to other popular 2D semiconductors (e.g., transition metal dichalcogenides MX2) for which defects typically induce harmful traps, we show that the electronic activities of defects in 2D perovskites are significantly tunable. For example, even with a fixed lattice orientation one can change the synthesis conditions to convert a line defect (edge or grain boundary) from electron acceptor to inactive site without deep gap states. We show that this difference originates from the enhanced ionic bonding in these perovskites compared with MX2. The donors tend to have high formation energies and the harmful defects are difficult to form at a low halide chemical potential. Thus, we unveil unique properties of defects in 2D perovskites and suggest practical routes to improve them.


Renal Calyceal Rupture following Ureteral Injury after Total Laparoscopic Hysterectomy.
Ureteral injury (UI) complicates 0.1%-2.5% of total laparoscopic hysterectomies (TLHs). Renal calyceal rupture (RCR) is predominantly seen in patients with ureteral stones causing ureteral obstruction. Iatrogenic (surgical and nonsurgical) causes are responsible for only 3.5% of RCR. A 45-year-old gravida 4, para 2 female with a body mass index of 20 and no previous abdominal surgeries underwent a TLH due to hypermenorrhea and secondary anemia in the presence of a myomatous uterus. Intraoperatively, pelvic endometriosis and an isthmic myoma, 4 cm in diameter, were documented. On the 2nd postoperative day, the patient reported right-sided loin pain. The computed tomography scan revealed a right-sided RCR with urine extravasation and a retroperitoneal and intra-abdominal urinoma. The patient was treated with a transitory nephrostomy for 6 months, and subsequently finally with ureteroneocystostomy (psoas hitch). This case extends the spectrum of iatrogenic RCR causes as well as UI manifestations after TLH.


Cross-validation and modifications of the perceived mattering questionnaire-Physical education in Chinese inservice physical education teachers.
This study aimed to provide evidence of validity and reliability for the Perceived Mattering Questionnaire-Physical Education (PMQ-PE) developed by Richards et al. (2017) for the Chinese physical education (PE) teachers. The PMQ-PE consisted of two factors (i.e., PE matters and PE teacher matters) with four items in each, measuring four dimensions (attention, importance, dependence, and ego-extension). PMQ-PE in Chinese (PMQ-PEC) was validated among 1,278 elementary and secondary school PE teachers in China, of whom 59.0% were secondary PE teachers and 70.2% were males. Confirmatory factor analysis (CFA) with the entire sample found a poor model fit. Then exploratory factor analysis (EFA) using half of the sample indicated there was only one factor in PMQ-PEC. CFA of the other half of the sample suggested a one-factor model with the elimination of three unfitted items showed a better fitness to the data. Cronbach's alpha value was also acceptable. The final version of PMQ-PEC included five items with one factor that demonstrated acceptable validity and reliability and was deemed acceptable among Chinese PE teachers after the above modifications were made.


Inhibitory effect of nicotine on chemiluminescence response of human polymorphonuclear leukocytes stimulated by opsonized zymosan in vitro.
Effect of nicotine on chemiluminescence (CL) responses of human polymorphonuclear leukocytes (PMN) in vitro was investigated. Nicotine, ranging from 10(-5) to 5 X 10(-4)M, showed a concentration-dependent inhibition of the CL induced by 2.5 mg of opsonized zymosan. This inhibitory effect of nicotine (10(-4)M) on CL was not affected by atropine (10(-4)M), hexamethonium (10(-4)M) or acetyl beta-methylcholine (10(-4)M). These results indicate that nicotine directly acts to PMN with no relation of cholinergic affecting receptors. As to cytotoxic effects on PMN, assessed by the methods of trypan blue exclusion and of lactate dehydrogenase leakage from the cells, nicotine showed no cytotoxic effect on PMN in its range of 10(-5) to 5 X 10(-4)M. It is concluded that tobacco alkaloid nicotine could directly inhibit phagocytizing function of PMN. Furthermore, it is presumed that PMN circulating in the respiratory organs in tobacco smoking would be exposed to high concentrations of nicotine, and that the nicotine incorporated into the circulating system could suppress PMN functions resulting in harmful influences on the host defense mechanisms.


Dissecting the link between stress fibres and focal adhesions by CALI with EGFP fusion proteins.
Chromophore-assisted laser inactivation (CALI) is a light-mediated technique used to selectively inactivate proteins within cells. Here, we demonstrate that GFP can be used as a CALI reagent to locally inactivate proteins in living cells. We show that focused laser irradiation of EGFP-alpha-actinin expressed in Swiss 3T3 fibroblasts results in the detachment of stress fibres from focal adhesions (FAs), whereas the integrity of FAs, as determined by interference reflection microscopy (IRM), is preserved. Moreover, consistent with a function for focal adhesion kinase (FAK) in FA signalling and not FA structure, laser irradiation of EGFP-FAK did not cause either visible FA damage or stress fibre detachment, although in vitro CALI of isolated EGFP-FAK decreased its kinase activity, but not its binding to paxillin. These data indicate that CALI of specific FA components may be used to precisely dissect the functional significance of individual proteins required for the maintenance of this cytoskeletal structure. In vitro CALI experiments also demonstrated a reduction of EGFP-alpha-actinin binding to the cytoplasmic domain of the beta(1) integrin subunit, but not to actin. Thus, alpha-actinin is essential for the binding of microfilaments to integrins in the FA. CALI-induced changes in alpha-actinin result in the breakage of that link and the subsequent retraction of the stress fibre.


Hyperglycemia During Childhood Cancer Therapy: Incidence, Implications, and Impact on Outcomes.
Hyperglycemia is a known complication of therapies used in the treatment of childhood cancer, particularly glucocorticoids and asparaginase. It has been linked to increased infection and reduced survival. With more limited data on hyperglycemia during childhood cancer treatment compared with adult cancer, impact on outcomes is less clear in this population. As additional glycemic-altering cancer agents including immune checkpoint inhibitors and targeted therapies make their way into pediatric cancer treatment, there is a more pressing need to better understand the mechanisms, risk factors, and adverse effects of hyperglycemia on the child with cancer. Thus, we utilized a systematic approach to review the current understanding of the incidence, implications, and outcomes of hyperglycemia during childhood cancer therapy.


Spurious sulfamethoxazole-trimethoprim resistance of Salmonella typhi.
Several studies have identified thymidine excess in susceptibility test media as the cause of spurious resistance of various bacteria to sulfamethoxazole-trimethoprim. We document the phenomenon in Salmonella typhi and Salmonella paratyphi-A and demonstrate its occurrence in 3 of 17 (18%) lots of Mueller-Hinton agars now in use in major medical laboratories in Lima, Peru. The findings are particularly significant because sulfamethoxazole-trimethoprim is an important alternative to chloramphenicol or ampicillin for the treatment of typhoid and paratyphoid fevers.


Passive cavitation imaging with ultrasound arrays.
A method is presented for passive imaging of cavitational acoustic emissions using an ultrasound array, with potential application in real-time monitoring of ultrasound ablation. To create such images, microbubble emissions were passively sensed by an imaging array and dynamically focused at multiple depths. In this paper, an analytic expression for a passive image is obtained by solving the Rayleigh-Sommerfield integral, under the Fresnel approximation, and passive images were simulated. A 192-element array was used to create passive images, in real time, from 520-kHz ultrasound scattered by a 1-mm steel wire. Azimuthal positions of this target were accurately estimated from the passive images. Next, stable and inertial cavitation was passively imaged in saline solution sonicated at 520 kHz. Bubble clusters formed in the saline samples were consistently located on both passive images and B-scans. Passive images were also created using broadband emissions from bovine liver sonicated at 2.2 MHz. Agreement was found between the images and source beam shape, indicating an ability to map therapeutic ultrasound beams in situ. The relation between these broadband emissions, sonication amplitude, and exposure conditions are discussed.


Tetra-kis(3-cyano-pyridine-κN)bis-(thio-cyanato-κN)cobalt(II) 1,4-dioxane disolvate.
In the crystal structure of the title compound, {[Co(NCS)(2)(C(6)H(4)N(2))(4)]·2C(4)H(8)O(2)}, the Co(II) cations are octa-hedrally coordinated by two terminal N-bonded thio-cyanate anions and four N-bonded 3-cyano-pyridine ligands. The asymmetric unit consists of one Co(II) cation, which is located on a special position with site symmetry 2/m, one thio-cyanate anion and one dioxane mol-ecule, located on a crystallographic mirror plane, as well as one 3-cyano-pyridine ligand in a general position. The crystal structure consists of discrete complexes of [Co(NCS)(2)(3-cyano-pyridine)(4)], as well as two non-coordinating 1,4-dioxane solvent mol-ecules which are disordered due to symmetry.


Tyrosine kinase activity of discoidin domain receptor 1 is necessary for smooth muscle cell migration and matrix metalloproteinase expression.
Smooth muscle cell (SMC) interactions with collagen mediate cell migration during the pathogenesis of atherosclerosis and restenosis. Discoidin domain receptors (DDRs) have been identified as novel collagen receptors. We used aortic SMCs from wild-type and DDR1(-/-) mice to evaluate the function of the DDR1 in regulating migration. DDR1(-/-) SMCs exhibited impaired attachment to and migration toward a type I collagen substrate. Matrix metalloproteinase-2 (MMP-2) and MMP-9 activities were concomitantly reduced in these cells. Transfection of a full-length cDNA for DDR1b rescued these deficits, whereas kinase-dead mutants of DDR1 restored attachment but not migration and MMP production. These results suggest that active DDR1 kinase is a central mediator of SMC migration.


A protocol for metal triflate catalyzed direct glycosylations with GalNAc 1-OPiv donors.
Herein we report on the development of novel glycosylation methodology for the concise synthesis of naturally occurring glycoconjugate motifs containing N-acetylgalactosamine (GalNAc) from the cheaper and commercially available N-acetylglucosamine (GlcNAc). The stereoselective glycosylations proceed with catalytic amounts of a promoter and without the need for N-protection other than the biologically relevant N-acetyl group. Among the catalysts explored, both Bi(OTf)3 and Fe(OTf)3 were found to be highly active Lewis acids for this reaction. It was also found that other less reactive metal triflates such as those of Cu(II) and Yb(III) can be beneficial in glycosylation reactions on more demanding glycosyl acceptors. We have furthermore demonstrated that it is possible to control the anomeric stereoselectivity in the glycosylation via postglycosylation in situ anomerization to obtain good yields of α-galactosides. The present protocol was used to prepare important naturally occurring carbohydrate motifs, including a trisaccharide fragment of the naturally occurring marine sponge clarhamnoside.


Synergistic effect of repulsive inhibition in synchronization of excitatory networks.
We show that the addition of pairwise repulsive inhibition to excitatory networks of bursting neurons induces synchrony, in contrast to one's expectations. Through stability analysis, we reveal the mechanism underlying this purely synergistic phenomenon and demonstrate that it originates from the transition between different types of bursting, caused by excitatory-inhibitory synaptic coupling. This effect is generic and observed in different models of bursting neurons and fast synaptic interactions. We also find a universal scaling law for the synchronization stability condition for large networks in terms of the number of excitatory and inhibitory inputs each neuron receives, regardless of the network size and topology. This general law is in sharp contrast with linearly coupled networks with positive (attractive) and negative (repulsive) coupling where the placement and structure of negative connections heavily affect synchronization.


Physical activity and dietary fat as determinants of body mass index in a cross-sectional corelational design.
Overweight/obesity and related disease conditions will constitute a major threat to the economically productive adults and subsequently, will present a huge health-care burden on developing countries in the near future. Suspected determinants include physical activity and dietary fat. The main indicator of overweight/obesity is Body Mass Index (BMI . The purpose of this article is to present the prediction power of physical activity and dietary fat intake on BMI of lecturers within a higher learning institutionalized setting. The studyadopted a cross-sectional correlational design. Proportionate and simple random sampling techniques were used to select a sample of 120 lecturers who participated in the study. Data collection was conducted through questionnaires, which had sections including physical activity checklist, 24-hour food recall, anthropometrics measurements mainly weight and height. Analysis of data involved the use of bivariate correlation and linear regression. A significant inverse association occurred between BMI and minutes spent in moderate intense physical activity per day (r=-0322, p<0.01). Physical activity also predicted BMI (R2=0.096, F=13.616, beta=-3.22, t=-3.69, N=120, P<0.01). However, the association between Body Mass Index and dietary fat was not significant (r=0.038, p>0.05). In conclusion, physical activity was a significant predictor to BMI and on the contrary no significant impact was caused by dietary fat intake. Therefore, we still need further investigations on the effect of physical activity and dietary fat on BMI and risk factors associated poor diet should take priority.


[Pharmacological Treatments of Esophageal Dysphagia].
Patients with esophageal dysphagia need a step-by-step approach for diagnosis and treatment. Endoscopic with biopsy and barium esophagogram are the essential tests evaluating anatomical abnormality and esophageal bolus stasis. Further imaging or esophageal function tests such as high-resolution esophageal manometry, functional endoluminal imaging probe, CT or endoscopic ultrasound are required. In the case of dysphagia due to esophageal motility disorder, whether it is the major motility disorder or minor motility disorder should be identified in high resolution manometry. Major motility disorders show esophagogastric junction obstruction or major peristaltic defects. In this case, the severity of the symptoms should be assessed and patients who need endoscopic or surgical treatment targeting lower esophageal sphincter should be screened. Impaired lower esophageal sphincter relaxation (achalasia, esophagogastric junction outflow obstruction, esophageal spasm or abnormal hypercontraction (jackhammer esophagus), hypotensive contraction (ineffective esophageal motility, failed peristalsis), esophageal hypersensitivity (noncardiac chest pain), gastroesophageal reflux disease and esophageal bolus stasis are the possible mechanisms causing dysphagia symptoms. The proper medical treatment depends on underlying mechanisms.


Effect of catheter positions on hemodynamics and coil formation after coil embolization.
Coil embolization using a micro catheter and coils is one of the most popular surgical methods used for treating intracranial aneurysms. Surgeons need to better understand the effects of changing catheter position because this is under their control during operations. In this study, we simulate coil embolization for a basic bifurcation-type aneurysm using finite element method and computational fluid dynamics. We evaluated the reduction in velocity after embolization and the distance of the embolized coil's center of gravity from the center of the aneurysm (rCG) while changing the catheter tip position. The results show there is a high correlation between velocity reduction and neck volume embolization ratio (NVER) with a correlation coefficient of 0.955, and between the catheter tip position and rCG with a correlation coefficient of 0.866. These results indicate the NVER is also important for effective velocity reduction in both bifurcation-type and sidewall-type aneurysms. In addition, it is useful to set the catheter tip at the bottom of the aneurysms to deploy the first coil as a framing coil.


A case of herniated gravid uterus through a laparotomy scar.
A 36-year-old manual worker presented in her second pregnancy at 34 weeks of gestation with an unusual bulge of her abdomen. The lower abdominal bulge turned out to be her gravid uterus herniated through an anterior abdominal wall incisional hernia which is a rare but serious obstetric situation with complications such as premature labour, intrauterine growth retardation, strangulation, intrauterine death and rupture of the lower uterine segment been reported. We had a successful outcome by conservative treatment till 38 weeks of gestation followed by an elective lower segment Caesarean section with hernia repair. Incisional hernia is a frequent complication of abdominal wall closure and the management of pregnancy with a large incisional hernia with gravid uterus in its sac is challenging.


Estradiol attenuates hypoxia-induced pulmonary endothelin-1 gene expression.
The ovarian hormone 17beta-estradiol (E2beta) attenuates chronic hypoxia-induced pulmonary hypertension. We hypothesized that E2beta attenuates this response to hypoxia by decreasing pulmonary expression of the vasoactive and mitogenic peptide endothelin-1 (ET-1). To test this hypothesis, we measured preproET-1 mRNA and ET-1 peptide levels in the lungs of adult female normoxic and hypoxic (24 h or 4 wk at barometric pressure = 380 mmHg) rats with intact ovaries and in hypoxic ovariectomized (OVX) rats administered E2beta or vehicle via subcutaneous osmotic pumps. Hypoxic exposure increased lung preproET-1 mRNA levels in OVX vehicle-treated rats, but not in rats with intact ovaries. In addition, E2beta replacement prevented hypoxia-mediated increases in preproET-1 mRNA and ET-1 peptide expression. Considering that hypoxic induction of ET-1 gene expression is mediated by a hypoxia-inducible transcription factor(s) (HIF), we further hypothesized that E2beta-induced attenuation of pulmonary ET-1 expression during hypoxia results from decreased HIF activity. We found that E2beta abolished HIF-dependent increases in reporter gene activity. Further experiments demonstrated that overexpression of the transcriptional coactivator cAMP response element binding protein (CREB) binding protein (CBP)/p300, a factor common to both the estrogen receptor and HIF pathways, eliminated E2beta-mediated attenuation of hypoxia-induced ET-1 promoter activity. We conclude that E2beta inhibits hypoxic induction of ET-1 gene expression by interfering with HIF activity, possibly through competition for limiting quantities of CBP/p300.


A chlorine isotope effect for enzyme-catalyzed chlorination.
Several chlorinated organic compounds (COCs) that have been detected in a wide range of human, animal, and environmental samples may be derived from natural or anthropogenic sources. To determine whether the Cl isotope ratios of these compounds could be used to differentiate sources, we investigated the chlorine isotope effect for enzyme-catalyzed chlorination. Two aromatic substrates, 1,3,5-trimethylbenzene (TMB) and 3,5-dimethylphenol (DMP), were treated with a chloroperoxidase isolated from the fungus Caldariomyces fumago. A kinetic isotope effect (KIE) (in terms of k35/k37) was calculated to be 1.012 for TMB and 1.011 for DMP. A similar reaction, but not catalyzed, with hypochlorite yielded a much smaller KIE. These results indicate that a substantial KIE exists for this process. Furthermore, natural COCs synthesized by this enzymatic pathway may have Cl isotope ratios that will be easily distinguished from anthropogenic COCs.


Backbone flexibility, conformational change, and catalysis in a phosphohexomutase from Pseudomonas aeruginosa.
The enzyme phosphomannomutase/phosphoglucomutase (PMM/PGM) from the bacterium Pseudomonas aeruginosa is involved in the biosynthesis of several complex carbohydrates, including alginate, lipopolysaccharide, and rhamnolipid. Previous structural studies of this protein have shown that binding of substrates produces a rotation of the C-terminal domain, changing the active site from an open cleft in the apoenzyme into a deep, solvent inaccessible pocket where phosphoryl transfer takes place. We report herein site-directed mutagenesis, kinetic, and structural studies in examining the role of residues in the hinge between domains 3 and 4, as well as residues that participate in enzyme-substrate contacts and help form the multidomain "lid" of the active site. We find that the backbone flexibility of residues in the hinge region (e.g., mutation of proline to glycine/alanine) affects the efficiency of the reaction, decreasing k cat by approximately 10-fold and increasing K m by approximately 2-fold. Moreover, thermodynamic analyses show that these changes are due primarily to entropic effects, consistent with an increase in the flexibility of the polypeptide backbone leading to a decreased probability of forming a catalytically productive active site. These results for the hinge residues contrast with those for mutants in the active site of the enzyme, which have profound effects on enzyme kinetics (10 (2)-10 (3)-fold decrease in k cat/ K m) and also show substantial differences in their thermodynamic parameters relative to those of the wild-type (WT) enzyme. These studies support the concept that polypeptide flexibility in protein hinges may evolve to optimize and tune reaction rates.


Chronic Myeloid Leukemia in 2020.
New insights have emerged from maturing long-term academic and commercial clinical trials regarding optimum management of chronic myeloid leukemia (CML). Velocity of response has unexpectedly proved less important than hitherto thought, does not predict survival, and is of unclear relevance for treatment-free remission (TFR). Serious and cumulative toxicity has been observed with tyrosine kinase inhibitors that had been expected to replace imatinib. Generic imatinib has become cost-effective first-line treatment in chronic phase despite chronic low-grade side-effects in many patients. Earlier recognition of end-phase by genetic assessment might improve prospects for blast crisis (BC). TFR has become an important new treatment goal of CML. To reflect this new situation ELN has recently revised and updated its recommendations for treating CML. After a brief review of 175 years of CML history this review will focus on recent developments and on current evidence for treating CML in 2020.


[Animal and human bites : what to do and what to know ?]
Animal and human bites are a common cause of admission to the emergency room and the infections are common, although they are often trivialized. Complications can range from simple cellulitis to septic shock especially in asplenic patients with Capnoyctophaga canimorsus infection. Other less common infections are possible such as rat-bite fever, leptospirosis, tularemia, and evaluation of post-exposure prophylaxis (anti-tetanus, anti-rabies, HIV, HBV) is essential. Antibiotic prophylaxis remains controversial but is recommended for certain groups of patients and must cover common bite pathogens.


5-Year Outcomes of PCI Guided by Measurement of Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve.
Instantaneous wave-free ratio (iFR) is a coronary physiology index used to assess the severity of coronary artery stenosis to guide revascularization. iFR has previously demonstrated noninferior short-term outcome compared to fractional flow reserve (FFR), but data on longer-term outcome have been lacking. The purpose of this study was to investigate the prespecified 5-year follow-up of the primary composite outcome of all-cause mortality, myocardial infarction, and unplanned revascularization of the iFR-SWEDEHEART trial comparing iFR vs FFR in patients with chronic and acute coronary syndromes. iFR-SWEDEHEART was a multicenter, controlled, open-label, registry-based randomized clinical trial using the Swedish Coronary Angiography and Angioplasty Registry for enrollment. A total of 2,037 patients were randomized to undergo revascularization guided by iFR or FFR. No patients were lost to follow-up. At 5 years, the rate of the primary composite endpoint was 21.5% in the iFR group and 19.9% in the FFR group (HR: 1.09; 95% CI: 0.90-1.33). The rates of all-cause death (9.4% vs 7.9%; HR: 1.20; 95% CI: 0.89-1.62), nonfatal myocardial infarction (5.7% vs 5.8%; HR: 1.00; 95% CI: 0.70-1.44), and unplanned revascularization (11.6% vs 11.3%; HR: 1.02; 95% CI: 0.79-1.32) were also not different between the 2 groups. The outcomes were consistent across prespecified subgroups. In patients with chronic or acute coronary syndromes, an iFR-guided revascularization strategy was associated with no difference in the 5-year composite outcome of death, myocardial infarction, and unplanned revascularization compared with an FFR-guided revascularization strategy. (Evaluation of iFR vs FFR in Stable Angina or Acute Coronary Syndrome [iFR SWEDEHEART]; NCT02166736).


Neonatal Teratoma: Craniofacial Treatment.
Teratomas are rare congenital neoplasms. Head and neck locations of the tumor are uncommon with combined intracranial and extracranial extensions being even more rare. The authors present a case of teratoma involving the temporal, buccal, maxillary, orbital and extending to the intracranial regions, which was successfully managed by surgical resection.


A fourth dimension in decision making in hepatology.
Today, the assessment of liver function in patients suffering from acute or chronic liver disease is based on liver biopsy and blood tests including synthetic function, liver enzymes and viral load, most of which provide only circumstantial evidence as to the degree of hepatic impairment. Most of these tests lack the degree of sensitivity to be useful for follow-up of these patients at the frequency that is needed for decision making in clinical hepatology. Accurate assessment of liver function is essential to determine both short- and long-term prognosis, and for making decisions about liver and non-liver surgery, TIPS, chemoembolization or radiofrequency ablation in patients with chronic liver disease. Liver function tests can serve as the basis for accurate decision-making regarding the need for liver transplantation in the setting of acute failure or in patients with chronic liver disease. The liver metabolic breath test relies on measuring exhaled (13) C tagged methacetin, which is metabolized only by the liver. Measuring this liver-specific substrate by means of molecular correlation spectroscopy is a rapid, non-invasive method for assessing liver function at the point-of-care. The (13) C methacetin breath test (MBT) is a powerful tool to aid clinical hepatologists in bedside decision-making. Our recent findings regarding the ability of point-of-care (13) C MBT to assess the hepatic functional reserve in patients with acute and chronic liver disease are reviewed along with suggested treatment algorithms for common liver disorders.


[Post-tracheal extubation pulmonary oedema - case report].
Negative pressure pulmonary oedema is an uncommon complication of traqueal extubation (approximately 0,1%) mostly caused by acute upper airway obstruction. Upper airway obstruction from glottis closure leads to marked inspiratory effort, which generates negative intrathoracic pressure transmitting to pulmonary interstitium, and inducing fluid transudation from pulmonary capillary bed(1-5). We report a case of post-extubation pulmonary oedema in a fifteen years old patient, submitted to surgery following traumatic amputation of his left leg. We review the pathophysiology, radiological findings, potential risk factors and preventive measures of this post-anaesthetic respiratory complication.


The illnesses of Carlo di Ferdinando I de' Medici: a second opinion.
To offer a second opinion on the recently published retrospective diagnosis of Cardinal Carlo de' Medici (1596-1666), a prominent member of the grand ducal family then ruling Tuscany. Retrospective diagnosis of historical figures is difficult and at times controversial, even with modern technology. It is based on contemporaneous medical descriptions and historical reviews, inherited iconography, and rarely - as in the case of the Medici of Florence - skeletal assessment, completed with radiological, histological and even immunological studies. Modern clinical work is often complemented with a second opinion obtained from specialists in the relevant fields. It is this type of second opinion that our collaborative Australian and Italian team, comprised of an orthopaedic/spinal surgeon, a rheumatologist and two medical historians, now offers. The authors concur with the first opinion's diagnosis of Klippel-Feil syndrome in Carlo de' Medici, but disagree with the diagnoses of tuberculosis (Pott's disease) and rheumatoid arthritis. We find evidence, instead, for a psoriatic-DISH arthropathy with involvement of Klippel-Feil syndrome. A psoriatic-DISH arthropathy, previously described by the present authors as the 'Medici syndrome', was commonly found in the males of the primary branch of the family. The diagnosis of this condition in Cardinal Carlo de' Medici represents its first identification in a male of the secondary (grand ducal) branch of the family.


Dermatomyositis associated with adenocarcinoma of the lung: A case report.
The association of dermatomyositis and underlying malignancies, especially small cell and squamous cell carcinoma of the lung, has been recognized a long time ago. We report the case of a 63-year-old male chronic smoker with adenocarcinoma lung associated with dermatomyositis. The occurrence of dermatomyositis should be considered as a potential presentation of paraneoplastic syndromes and physicians encountering similar clinical situations should perform extensive diagnostic work-up to exclude underlying neoplastic lesions.


[The relationship of plasmids from environmental Yersinia isolates and the virulence plasmid of enteropathogenic Yersinia strains].
The human pathogenic strains of Yersinia harbour a conserved plasmid carrying the Yop virulon. The virulence plasmid of Yersinia enterocolitica strains belonging to the serogroups O:3 and O:9 were used as probes to detect homologous sequences in plasmids of "avirulent" Yersinia strains. "Avirulent" Yersinia strains (Y. enterocolitica biogroup 1A, Y. intermedia, Y. kristensenii and Y. frederiksenii) lack the virulence plasmid. They are widely distributed in the environment and can frequently be isolated from clinical samples. Hybridisation experiments revealed a number of common genetic elements of the virulence plasmid and the plasmids of "avirulent" Yersinia strains. These elements were identified as genes involved in plasmid replication, as an endonuclease gene and as mobile genetic elements. However, none of the plasmid encoded virulence genes was present in the plasmids of "avirulent" Yersinia strains. The frequent occurrence and the possible etiological relevance of "avirulent" isolates will be discussed.


Demographic pressure and the Irish famine: Malthus after Mokyr.
"This paper presents a fresh analysis of demographic pressure in pre-Famine Ireland. The crucial issue is one of measurement. Population pressure is taken as the ratio of population to non-reproducible natural resources, that is, land." The author develops a measure of land quality that is used to test the Malthusian hypothesis. "The central finding of this paper may be stated quite simply: when proper account is given to the measurement of land quality and demographic pressure, then the Malthusian hypothesis that income per capita decreases with population pressure is not rejected by the evidence of pre-Famine Ireland."


Cytokine synthesis by intestinal intraepithelial lymphocytes. Both gamma/delta T cell receptor-positive and alpha/beta T cell receptor-positive T cells in the G1 phase of cell cycle produce IFN-gamma and IL-5.
Murine intestinal intraepithelial lymphocytes (IEL) have been shown to contain subsets of alpha/beta TCR+ and gamma/delta TCR+ T cells that spontaneously produce cytokines such as IFN-gamma and IL-5. We have now determined the nature and cell cycle stage of these cytokine-producing T lymphocytes in EIL by using IFN-gamma- and IL-5-specific ELISPOT assay, cytokine-specific mRNA-cDNA dot-blot hybridization and polymerase chain reaction, and flow cytometry (FACS) for DNA analysis. When CD3+ T cells from IEL of normal C3H/HeN mice were separated into low and high density fractions by discontinuous Percoll gradients, IFN-gamma and IL-5 spot-forming cells were only found in the former population. Analysis of mRNA for these cytokines by both IFN-gamma- and IL-5-specific dot-blot hybridization and polymerase chain reaction revealed that higher levels of message for IFN-gamma and IL-5 were also seen in the low density fraction. However, cell cycle analysis of these two fractions by FACS using propidium iodide showed a similar pattern of cell cycle stages in both low and high density populations (G0 + G1 approximately 96 to 98% and S/G2 + M approximately 2 to 4%). Finally, mRNA from gamma/delta TCR+ and alpha/beta TCR+ T cells in both low and high density fractions of IEL were analyzed for IFN-gamma and IL-5 message by polymerase chain reaction. After 35 cycles of amplification, both gamma/delta TCR+ and alpha/beta TCR+ T cells in the low density fraction expressed higher levels of message for these two cytokines when compared with the high density population. These results have now shown that both gamma/delta and alpha/beta TCR+ IEL can be separated into low and high density subsets and both fractions possess a similar stage of cell cycle. However, only the low density cells (in G1 phase) of both gamma/delta and alpha/beta TCR types possess increased cytokine-specific mRNA and produce the cytokines IFN-gamma and IL-5. Our results suggest that alpha/beta TCR+ and gamma/delta TCR+ IEL can produce cytokines without cell proliferation.


Nasal and frontal sinus mucosa of the adult dog contain numerous olfactory sensory neurons and ensheathing glia.
Olfactory glial cells have been the focus of much recent research interest because of their possible future use as cellular transplants in repair of spinal cord injury. Although olfactory glial cells can be collected from the olfactory bulb for in vitro culture, alternative sites would be preferable for safer surgical access. This study was designed to investigate the distribution of olfactory sensory neurons and olfactory glial cells within the canine peripheral olfactory system. Using immunohistochemistry and electron microscopy on perfused tissue we demonstrate that olfactory sensory neurons are found in both the caudal nasal and the frontal sinus epithelia. Olfactory ensheathing glia were found in the mucosa at both these sites implying that surgical access for harvesting cells for transplantation would be straightforward.


Simultaneous color-coded imaging to distinguish cancer "stem-like" and non-stem cells in the same tumor.
In this study, we demonstrate that the differential behavior, including malignancy and chemosensitivity, of cancer stem-like and non-stem cells can be simultaneously distinguished in the same tumor in real time by color-coded imaging. CD133(+) Huh-7 human hepatocellular carcinoma (HCC) cells were considered as cancer stem-like cells (CSCs), and CD133(-) Huh-7 cells were considered as non-stem cancer cells (NSCCs). CD133(+) cells were isolated by magnetic bead sorting after Huh-7 cells were genetically labeled with green fluorescent protein (GFP) or red fluorescent protein (RFP). In this scheme, CD133(+) cells were labeled with GFP and CD133(-) cells were labeled with RFP. CSCs had higher proliferative potential compared to NSCCs in vitro. The same number of GFP CSCs and the RFP NSCCs were mixed and injected subcutaneously or in the spleen of nude mice. CSCs were highly tumorigenic and metastatic as well as highly resistant to chemotherapy in vivo compared to NSCCs. The ability to specifically distinguish stem-like cancer cells in vivo in real time provides a visual target for prevention of metastasis and drug resistance.


Light-Responsive Nanocapsule-Coated Polymer Films for Antimicrobial Active Packaging.
The development of antimicrobial active packaging constitutes a powerful tool to reduce waste and increase quality standards of perishable goods. Among numerous available antimicrobial agents, essential oils stand out for their renowned efficiency, and their use is beneficial due to their sustainability compared to other oil-based antimicrobials. In this work, we report on the use of photo-responsive nanocapsules containing thyme essential oil as functional coatings for polyethylene and polylactic acid films to obtain antimicrobial active packaging. Polymer surface activation treatment enhanced compatibility with nanocapsules solution. The films were analyzed to assess the structural and functional properties of the coating, evaluate morphological changes due to their photo-responsive behavior, and monitor the light-induced release of volatile thyme oil. It was found that 24 h after a 15-min UV exposure of the coated films, the concentration of thyme oil in the headspace was eight times higher with respect to un-irradiated films, thus confirming the efficiency of the light-triggered release system. Therefore, the manufactured films are proposed as on-demand release devices for application in non-contact antimicrobial active packaging.


Association Between eNOS, MMP-9, BAG-6 Gene Polymorphisms and Risk of Hypertensive Disorders of Pregnancy in the Northern Chinese Population.
The objective of this study was to investigate the role of endothelial nitric oxide synthase (eNOS), matrix metalloproteinases (MMP)-9, and Bcl2-associated oncogene 6 (BAG-6) gene polymorphisms, as well as the combined role of single nucleotide polymorphisms (SNPs) in hypertensive disorders of pregnancy (HDP) patients. This case-control study consisted of women with 326 HDP and 312 healthy pregnant controls. Multiplex PCR combined with next-generation sequencing method was used for determination of gene polymorphisms. Nine SNPs were analyzed, and we classified these case samples in depth by preeclampsia (PE) non-PE or blood pressure stages. We undertook allele and genotype haplotype association studies in all the cases and in the subgroups, as well as adjust age by binary logistic regression. Furthermore, the distribution of the haplotypes formed by the nine SNPs mentioned between the HDP patients and healthy pregnant controls were analyzed. There were no statistically significant differences in the nine SNPs of eNOS, MMP-9, and BAG-6 gene allele and genotype frequencies between HDP or subtypes and controls. However, for haplotype analyses, we found that the frequencies of AGACGCCGA (p = 3.67e-005), AGACGCGCA (p = 0.03127), and GAACACCGA (p = 0.02449) were significantly lower in the cases than in the controls. However, the haplotype of GGACGCCGA (p = 0.000686) was higher in the cases than in the controls. Our results suggested protective effect of the haplotypes AGACGCCGA, AGACGCGCA, and GAACACCGA against the development of HDP, and the haplotype GGACGCCGA was the risk factor of HDP.


GnRH analogues may increase endometrial Hoxa10 promoter methylation and affect endometrial receptivity.
The present study aimed to investigate whether gonadotropin-releasing hormone analogues (GnRH-as), including GnRH agonists and antagonists, affect endometrial homeobox (Hox) a10 DNA methylation during the implantation window in mice. GnRH analogue mouse models were used and were treated with either human menopausal gonadotropin (HMG) and a GnRH agonist or HMG and a GnRH antagonist. Uterus samples were collected 48 h after GnRH analogue treatment or ovulation. Bisulfite sequencing polymerase chain reaction (PCR), quantitative-PCR and western blot analysis were performed to assess Hoxa10 and integrin β3 expression. Scanning electron microscope analyses were conducted to analyze pinopode development. Compared with the natural cycle control mice, mice in the GnRH analogue groups were found to exhibit increased levels of methylation at the Hoxa10 promoter, decreased Hoxa10 mRNA and protein expression and disrupted pinopode development. These findings suggest that GnRH-as may be associated with altered Hoxa10 DNA methylation, thus GnRH-as may affect uterine Hoxa10 expression and endometrial receptivity.


Addressing the Global Burden of Cardiovascular Diseases; Need for Scalable and Sustainable Frameworks.
Only 14 countries are on track to attain the Sustainable Development Goal (SDG) target of reducing premature mortality from Noncommunicable Diseases (NCDs) by one-third by 2030. This target cannot be reached without reducing the burden of cardiovascular diseases (CVDs) which is the major contributor to premature mortality from NCDs. Sustainable and scalable national responses to address both CVDs and their risk factors are urgently needed. Although smoking rates have decreased globally, consumption of alcohol and physical inactivity are on the rise. No country is on course to achieve the target to halt the rise in obesity or to reduce salt intake: targets critical for reducing the diabetes related cardiovascular burden and for hypertension control. Although very cost-effective scalable interventions are available, they are underutilized. Unless pathways selected to tackle CVDs prioritize prevention, primary health care and universal health coverage, countries will fall further behind in the attainment of the SDG target.


Swedish Council on Technology Assessment in Health Care (SBU). Chapter 6. Sickness absence due to back and neck disorders.
The scientific evidence on the causes for sick leave attributed to back and neck disorders was reviewed. Categories were established for acute, recurring, and chronic problems based on the duration of the sick leave period. Forty-eight articles were found to be relevant, whereof two were of high quality and 26 were of medium or low quality. Quality was assessed exclusively in relation to the aim of this systematic review. The results reveal limited published research on causes for sick leave from back and neck disorders. The generalisability of the findings is also limited since most of the subjects were men and employees in manufacturing industries. Women, white-collar workers, employees in the public sector (care, social services, schools, etc) were underrepresented in the studies. Hence, these groups and areas should be studied further to verify conclusions and enhance knowledge about the causes for sick leave from back and neck disorders. The following factors were found to have consistent, but limited, support as regards their influence on the risk for sick leave due to back and neck disorders: (a) heavy physical workload, bent or twisted working position, and low work satisfaction increases the risk for short-term and long-term sick leave; (b) specific back diagnoses and previous sick leave due to back disorders increases the risk for short-term and long-term sick leave; (c) female gender, smoking, exposure to vibration, and deficient social support were not found to significantly increase the risk for short-term and long-term sick leave; (d) self-reported pain and functional impairments were associated with a high risk for long-term sick leave; (e) longer employment periods reduced the risk for short-term sick leave; (f) perceived demands at work did not influence short-term sick leave; (g) female gender and higher age increases the risk for disability pension.


Outcomes and prognostic factors for squamous-cell carcinoma of the anal canal: analysis of patients from the National Cancer Data Base.
The objective of this study was to assess survival and prognostic factors for anal carcinoma in the population. Patients with squamous-cell carcinoma of the anal canal were identified from the National Cancer Data Base (1985-2000). Univariate and multivariable methods were used to assess factors associated with survival. Concordance was calculated to assess agreement between American Joint Committee on Cancer stage and actual outcome. Nineteen thousand one hundred ninety-nine patients with anal carcinoma were identified (Stage I, 25.3 percent; Stage II, 51.8 percent; Stage III, 17.1 percent; Stage IV, 5.7 percent). Overall five-year survival was 58.0 percent. The American Joint Committee on Cancer (6th edition) staging system provided good survival discrimination by stage: I, 69.5 percent; II, 59.0 percent; III, 40.6 percent; and IV, 18.7 percent (concordance index, 0.663). On multivariable analysis, patients with anal carcinoma had a higher risk of death if they were male, >or=65 years old, black, living in lower median incomes areas, and had more advanced T stage tumors, nodal or distant metastases, or poorly differentiated cancers (P < 0.0001). There was not a significant difference in survival by hospital type or year of diagnosis. Although tumor characteristics and staging affect prognosis, patient factors, such as gender, race, and socioeconomic status, are also important prognostic factors for squamous-cell carcinoma of the anal canal.


Measuring the pain impact in adults with a chronic pain condition: adaptation and validation of the Pain Impact Questionnaire (PIQ-6) to the Portuguese culture.
The aim of this study was to validate the Pain Impact Questionnaire (PIQ-6) for Portuguese adults with a chronic pain condition. The Portuguese version was developed through forward-backward translations and a cognitive debriefing with chronic pain patients. A subsequent sample of patients was selected to test the validity and the obtained Portuguese measure. Patients are comprised of a sample of 104 physical therapy patients with chronic pain from four outpatient clinics. Reliability and validity were tested by administering the PIQ-6, the Medical Outcomes Study-12-Item Short Form (SF-12) questionnaire, a numerical rating pain scale, and a form to collect some of the characteristics of the patients. After obtaining the semantic and content equivalence, the Portuguese version of PIQ-6 showed good levels of reproducibility (intraclass correlation coefficient between 0.82 and 0.94) and good levels of internal consistency, with Cronbach's alpha of 0.92. The factor analysis confirmed the unidimensionality of the measure (initial eigen-value = 4.29, 71.6%). Construct validity was supported by the correlations obtained with a numerical rating pain scale (rho = 0.705), SF-12 subscales (r = -0.723 and -0.656), and the age of the patients (r = 0.274). The PIQ-6 proved to be equivalent in both cultures (American/Portuguese), and is useful, reliable, and valid for use in Portugal.


Plaque morphology correlates with cerebrovascular symptoms in patients with complex aortic arch plaque.
Studies of aortic arch plaques with transesophageal echocardiography have demonstrated that complex aortic arch plaques (CAPs) greater than or equal to 4 mm in thickness are associated with ischemic stroke. Recent studies have demonstrated that the morphological features of plaques may aid in the identification of aortic plaques that are more likely to be associated with embolic stroke. To identify aortic plaques that are more likely to be associated with embolic stroke by means of their morphological features. Transcutaneous B-mode ultrasonography was used to image aortic arch plaques in 500 consecutive patients. The criteria used to identify the morphological features of carotid artery plaques that are more likely to be associated with ischemic stroke (heterogeneous rather than homogeneous) were applied to aortic arch plaques. Statistical comparisons were made using the Fisher exact test. Ischemic symptoms (eg, stroke, transient ischemic attack, and amaurosis fugax) were present in 38% of 104 patients with CAP and in 34% of 391 patients without CAP. Nineteen (51%) of 37 patients with heterogeneous CAP were symptomatic. Twenty-one (31%) of 67 patients with homogeneous CAP were symptomatic (P = .04). Transcutaneous B-mode ultrasonography of the aortic arch can help to identify heterogeneous plaques that are more likely to be associated with ischemic stroke using morphological criteria derived from studies of carotid artery plaque.


Widespread neuronal and glial hyperphosphorylated tau deposition in ALS with cognitive impairment.
Although the biological basis of frontotemporal syndromes associated with amyotrophic lateral sclerosis (ALS) is considered to be altered metabolism of TDP-43, in ALS with cognitive impairment (ALSci) the metabolism of tau protein is also altered. This includes neuronal hyperphosphorylation (pThr(175)). Using novel polyclonal phospho-tau antibodies (pSer(208, 210), pThr(217) and pThr(175)) and antibodies directed against PHF tau (pSer(202)), TDP-43 or ubiquitin, we characterized tau deposition in ALS and ALSci. In ALS, we observed pThr(175) tau immunoreactive intraneuronal and neuritic aggregates throughout the amygdala and entorhinal cortex. In ALSci, this extended to the anterior cingulate gyrus, superior frontal cortex and substantia nigra. The pThr(217) antibody detected widespread astrocytic tau deposition, including punctuate or fibrillary aggregates, or intensely immunoreactive tufted astrocytes in the superior frontal cortex, anterior cingulate gyrus, entorhinal cortex, amygdala and basal ganglia of ALS. In ALSci, a similar but more widely distributed pThr(217) pathology was observed. There was no correlation between the extent of pathological tau deposition and TDP-43 pathology, although nuclear TDP-43 immunoreactivity was absent in neurons with tau pathology. In conclusion, ALSci is unique in possessing both tau and TDP-43 pathology. The presence of widespread astrocytic tau pathology suggests that ALSci may initially be characterized by astrocytic pathology.


Silicon-based multilayer gratings with a designable narrowband absorption in the short-wave infrared.
We demonstrate an Al/Si multilayer-grating microstructure covered on Si substrate. This microstructure presents a designable narrowband absorption in short-wave infrared (SWIR) waveband (2.0 μm-2.3 μm). We investigate its absorption mechanism by both modeling and simulations, and explain the results well with metal-insulator-metal and Fabry-Perot cavity theory. Furthermore, we present the absorption of fabricated multilayer-grating microstructure through experiment, and discuss the influence of structure's lateral angle on its absorption in detail. This work provides the possibility to design Si-based devices with designable working bands in SWIR spectrum.


Ankle-Brachial Index and Energy Production in People Without Peripheral Artery Disease: The BLSA.
Background Lower ankle-brachial index (ABI) values within the 0.90 to 1.40 range are associated with poorer mitochondrial oxidative capacity of thigh muscles in cross-sectional analyses. Whether ABI decline is associated with greater declines in thigh muscle oxidative capacity with aging is unknown. Method and Results We analyzed data from 228 participants (100 men) of the BLSA (Baltimore Longitudinal Study of Aging), aged 39 to 97 years, with an ABI between 0.9 and 1.40 at baseline and at follow-up (mean follow-up period of 2.8 years). We examined mitochondrial oxidative capacity of the left thigh muscle, by measuring the postexercise phosphocreatine recovery rate constant (kPCr) from phosphorus-31 magnetic resonance spectroscopy. Greater kPCr indicated higher mitochondrial oxidative capacity. Although kPCr was available on the left leg only, ABI was measured in both legs. Longitudinal rates of change (Change) of left and right ABI and kPCr of the left thigh muscle were estimated using linear mixed effects models, and their association was analyzed by standardized multiple linear regressions. In multivariate analysis including sex, age, baseline kPCr, both left and right baseline ABI, and ABI change in both legs, (kPCr)Change was directly associated with ipsilateral (left) (ABI)Change (standardized [STD]-β=0.14; P=0.0168) but not with contralateral (right) (ABI)Change (P=0.22). Adjusting for traditional cardiovascular risk factors, this association remained significant (STD-β=0.18; P=0.0051). (kPCr)Change was steeper in White race participants (STD-β=0.16; P=0.0122) and body mass index (STD-β=0.13; P=0.0479). There was no significant association with current smoking status (P=0.63), fasting glucose (P=0.28), heart rate (P=0.67), mean blood pressure (P=0.78), and low-density lipoprotein (P=0.75), high-density lipoprotein (P=0.82), or triglycerides (P=0.15). Conclusions In people without peripheral arterial disease, greater decline in ABI over time, but not baseline ABI, was associated with faster decline in thigh mitochondrial oxidative capacity in the ipsilateral leg. Further studies are needed to examine whether early interventions that improve lower extremity muscle perfusion can improve and prevent the decline of muscle energetics.


The potential role of CAMSAP1L1 in symptomatic epilepsy.
In a recent genome-wide association study (GWAS) of symptomatic epilepsy in the Chinese population, the most significant single nucleotide polymorphism (SNP) allele was rs2292096 [G] (P=1.0×10(-8), odds ratio [OR]=0.63), in the CAMSAP1L1 gene (also known as CAMSAP2). Here, we report that rs2292096 genotypes tended to associate with expression of CAMSAP1L1 RNA in the temporal lobe (p=0.054) and hippocampus (p=0.20) of epilepsy surgery patients, with expression tending to increase with the G allele. CAMSAP1L1 and β-tubulin double immunofluorescence exhibited partial overlap. CAMSAP1L1 siRNA transfection of human SH-SY5Y neuroblastoma cells treated with or without retinoic acid reduced the CAMSAP1L1 protein level nearly 60% and stimulated neurite outgrowth, as measured by total length, number of processes and number of branches. Therefore, the rs2292096 G allele of CAMSAP1L1, which was associated with reduced risk of symptomatic epilepsy, tended to associate with increased expression of CAMSAP1L1, which represses neurite outgrowth. Greater neurite growth in response to brain insults might increase formation of ectopic neural circuits and thus the risk of epileptogenesis.


Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles.
Long-acting parenteral (LAP) antiretroviral drugs have generated considerable interest for treatment and prevention of HIV-1 infection. One new LAP is cabotegravir (CAB), a highly potent integrase inhibitor, with a half-life of up to 54 days, allowing for every other month parenteral administrations. Despite this excellent profile, high volume dosing, injection site reactions and low body fluid drug concentrations affect broad use for virus infected and susceptible people. To improve the drug delivery profile, we created a myristoylated CAB prodrug (MCAB). MCAB formed crystals that were formulated into nanoparticles (NMCAB) of stable size and shape facilitating avid monocyte-macrophage entry, retention and reticuloendothelial system depot formulation. Drug release kinetics paralleled sustained protection against HIV-1 challenge. After a single 45 mg/kg intramuscular injection to BALB/cJ mice, the NMCAB pharmacokinetic profiles was 4-times greater than that recorded for CAB LAP. These observations paralleled replicate measurements in rhesus macaques. The results coupled with improved viral restriction in human adult lymphocyte reconstituted NOD/SCID/IL2Rγc-/- mice led us to conclude that NMCAB can improve biodistribution and viral clearance profiles upon current CAB LAP formulations.


The development of self skills in an authentic learning environment: A qualitative study.
The contemporary healthcare environment is an authentic, demanding, challenging and ever-changing environment that requires learners to possess good self skills when they need to engage in meaningful, critical discourse in order to solve authentic problems. However, nurse educators assume that learners already have well-developed self skills at the commencement of their nursing training and as a result do not explicitly teach and develop such skills in the learners. The objectives of this research were to explore and describe nurse educators' views on how learners' self skills can be developed within an authentic learning (AL) environment, and to formulate recommendations based on the findings. A qualitative and contextual research design was used to seek rich, in-depth data from 20 nurse educators who were purposively sampled. Semi-structured individual interviews were conducted, and the data were analysed using Miles, Huberman and Saldaña method. The three themes that emerged were that nurse educators should (1) ensure an AL environment that promotes self skills, (2) engage learners in activities that will consciously evoke authentic self and (3) evaluate the developed self skills and metacognition. By developing good self skills, learners should be able to deliver quality patient care, find solutions to complex problems and handle cognitive complexity and authentic conditions whilst creating their own identity.


Influence of donor-to-acceptor ratio on excited-state electron transfer within covalently tethered CdSe/CdTe quantum dot colloidal heterostructures.
Carbodiimide-mediated coupling chemistry was used to synthesize heterostructures of CdSe and CdTe quantum dots (QDs) with varying ratios of electron-donating CdTe QDs and electron-accepting CdSe QDs. Heterostructures were assembled via the formation of amide bonds between the terminal functional groups of CdTe-adsorbed 4-aminothiophenol (4-ATP) ligands and CdSe-adsorbed N-hydroxysuccinimide (NHS) ligands. The number of charge acceptors on the surfaces of QDs can greatly influence the rate constant of excited-state charge transfer with QDs capable of accommodating far more acceptors than molecular chromophores. We report here on excited-state electron transfer within heterostructure-forming mixtures of 4-ATP-capped CdTe and NHS-capped CdSe QDs with varying molar ratios of CdTe to CdSe. Photophysical properties and charge transfer were characterized using UV-vis absorption, steady-state emission, and time-resolved emission spectroscopy. As the relative concentration of electron-accepting CdSe QDs within mixtures of 4-ATP-capped CdTe and NHS-capped CdSe QDs increased, the rate and efficiency of electron transfer increased by 100-fold and 7.4-fold, respectively, as evidenced by dynamic quenching of band-edge emission from CdTe QDs. In contrast, for non-interacting mixtures of thiophenol capped CdTe QDs and NHS-capped CdSe QDs, which served as control samples, photophysical properties of the constituent QDs were unperturbed and excited-state charge transfer between the QDs was negligible. Our results reveal that carbodiimide-mediated coupling chemistry can be used to control the relative number of donor and acceptor QDs within heterostructures, which, in turn, enables fine-tuning of charge-transfer dynamics and yields. These amide-bridged dual-QD heterostructures are, thus, intriguing for light harvesting, charge transfer, and photocatalysis.


Cutaneous leishmaniasis among Syrian refugees in Jordan.
Old World cutaneous leishmaniasis (CL) is one of the most prevalent vector-borne diseases within the World Health Organization's Eastern Mediterranean Region. The conflict in the Syrian Arab Republic generated large population movements and raised concerns about spreading of CL to countries where Syrians have relocated, including Jordan. A review of electronic and paper-based registries of CL cases in Jordan was conducted to assess burden of disease and associated socio-demographic factors. Increasing numbers of CL cases have been reported in Jordan between 2010 and 2016 (from 140 to 281), paralleled by significant increases in incidence rate (from 2.09 per 100 000 person-years, 95% CI (1.77-2.47), to 2.87 per 100 000 person-year, 95% CI (2.55-3.22), p = 0.002) and in the proportion of cases who are Syrian (from 8.6%-55.2%, p < 0.001). Syrian refugees have higher odds of presenting with leishmaniasis than Jordanian nationals (adjusted OR 7.1, 95% CI (6.3-8.0), p = 0.000). Presence of large numbers of Syrian refugees within Jordan has so far not contributed to increased risk of developing CL for Jordanians, however surveillance, diagnosis and case management for CL should be reinforced to meet the increased burden. Electronic surveillance can help identify priority populations and areas for interventions.


An unusual pigmented tonsil neoplasm presenting to Head & Neck Clinic: a case report and literature review of primary tonsillar malignant mucosal melanoma.
Primary mucosal melanoma of the tonsil is rare, with 27 reported cases. Careful diagnosis is necessary, as the tonsil is more often a site of metastatic melanoma from a cutaneous primary tumour. In this report, we present a case of primary right tonsillar mucosal melanoma with widespread metastasis in a 31-year-old man who presented with a 3-month history of enlarging neck lumps. On examination, he had cervical lymphadenopathy and a pigmented, vascular lesion of his right tonsil, which was diagnosed as melanoma following investigation. He had widespread metastases upon presentation, and is currently undergoing palliative immunotherapy. Owing to the aggressive behaviour, late presentations and lack of effective treatment to cure mucosal melanomas, they have a poor prognosis. Treatment involves wide local excision in local disease, and immunotherapy as the first-line for metastatic disease.


Translational alterations in maize leaves responding to pathogen infection, paraquat treatment, or heat shock : polysome dissociation and accumulation of a 57 kilodalton protein.
Translational alterations occur in maize (Zea mays L.) leaves stressed by pathogen infection or herbicide paraquat treatment. These translational changes include: (a) dissociation of large polysomes to small polysomes, monosomes, and subunits; (b) a decreased rate of total protein synthesis; and (c) a reduced synthesis of several proteins by polysomes in vitro. The polysome dissociation was neither due to an extraction artifact nor to degradation of RNA by RNase. The protein patterns of polysomes isolated from leaves inoculated with Bipolaris maydis at 6 to 48 hours showed an increase in the intensity of a 57 kilodalton protein. When inoculated with less virulent pathogens, such as B. zeicola, Exserohilum turcicum, or Colletotrichum graminicola, the protein was accumulated in polysomes of leaves at 24 to 48 hours after inoculation. The 57 kilodalton protein was also accumulated in polysomes of maize leaves responding to heat shock or herbicide paraquat treatments. The purified 57 kilodalton protein reassociated with polysomes isolated from healthy leaves and inhibited polysomal translation in vitro. Since the 57 kilodalton protein is rapidly accumulated in maize polysomes in response to various biological and environmental stresses and may affect protein synthesis, it may be involved in translational regulation of maize leaves during stress response.


Autophagy and plant innate immunity: Defense through degradation.
Autophagy is a process of bulk degradation and nutrient sequestration that occurs in all eukaryotes. In plants, autophagy is activated during development, environmental stress, starvation, and senescence. Recent evidence suggests that autophagy is also necessary for the proper regulation of hypersensitive response programmed cell death (HR-PCD) during the plant innate immune response. We review autophagy in plants with emphasis on the role of autophagy during innate immunity. We hypothesize a role for autophagy in the degradation of pro-death signals during HR-PCD, with specific focus on reactive oxygen species and their sources. We propose that the plant chloroplasts are an important source of pro-death signals during HR-PCD, and that the chloroplast itself may be targeted for autophagosomal degradation by a process called chlorophagy.


Cloning, expression, and characterization of bacterial L-arabinose 1-dehydrogenase involved in an alternative pathway of L-arabinose metabolism.
Azospirillum brasiliense converts L-arabinose to alpha-ketoglutarate via five hypothetical enzymatic steps. We purified and characterized L-arabinose 1-dehydrogenase (EC 188.8.131.52), catalyzing the conversion of L-arabinose to L-arabino-gamma-lactone as an enzyme responsible for the first step of this alternative pathway of L-arabinose metabolism. The purified enzyme preferred NADP+ to NAD+ as a coenzyme. Kinetic analysis revealed that the enzyme had high catalytic efficiency for both L-arabinose and D-galactose. The gene encoding L-arabinose 1-dehydrogenase was cloned using a partial peptide sequence of the purified enzyme and was overexpressed in Escherichia coli as a fully active enzyme. The enzyme consists of 308 amino acids and has a calculated molecular mass of 33,663.92 Da. The deduced amino acid sequence had some similarity to glucose-fructose oxidoreductase, D-xylose 1-dehydrogenase, and D-galactose 1-dehydrogenase. Site-directed mutagenesis revealed that the enzyme possesses unique catalytic amino acid residues. Northern blot analysis showed that this gene was induced by L-arabinose but not by D-galactose. Furthermore, a disruptant of the L-arabinose 1-dehydrogenase gene did not grow on L-arabinose but grew on D-galactose at the same growth rate as the wild-type strain. There was a partial gene for L-arabinose transport in the flanking region of the L-arabinose 1-dehydrogenase gene. These results indicated that the enzyme is involved in the metabolism of L-arabinose but not D-galactose. This is the first identification of a gene involved in an alternative pathway of L-arabinose metabolism in bacterium.