Dual role of interleukin-10 in the regulation of respiratory syncitial virus (RSV)-induced lung inflammation.
RSV lower respiratory tract infections (LRTI) are among the most common diseases necessitating hospital admission in children. In addition to causing acute respiratory failure, RSV infections are associated with sequelae such as secondary bacterial infections and reactive airway disease. One characteristic host response observed in severe RSV-induced LRTI and/or subsequent development of asthma is increased expression of interleukin (IL)-10. However, contradictory results have been reported regarding whether IL-10 inhibits asthmatic responses or intensifies the disease. We aimed to reconcile these discordant observations by elucidating the role of IL-10 in regulating the host response to RSV LRTI. In this study, we used a lung-specific, inducible IL-10 over-expression (OE) transgenic mouse model to address this question. Our results showed that the presence of IL-10 at the time of RSV infection not only attenuated acute inflammatory process (i.e. 24 h post-infection), but also late inflammatory changes [characterized by T helper type 2 (Th2) cytokine and chemokine expression]. While this result appears contradictory to some clinical observations where elevated IL-10 levels are observed in asthmatic patients, we also found that delaying IL-10 OE until the late immune response to RSV infection, additive effects rather than inhibitory effects were observed. Importantly, in non-infected, IL-10 OE mice, IL-10 OE alone induced up-regulation of Th2 cytokine (IL-13 and IL-5) and Th2-related chemokine [monocyte chemoattractant protein 1 (MCP-1), chemokine (C-C motif) ligand 3 (CCL3) and regulated upon activation normal T cell expressed and secreted (RANTES)] expression. We identified a subset of CD11b(+)CD11c(+)CD49b(+)F4/80(-)Gr-1(-) myeloid cells as a prinicipal source of IL-10-induced IL-13 production. Therefore, the augmented pathological responses observed in our 'delayed' IL-10 over-expression model could be attributed to IL-10 OE alone. Taken together, our study indicated dual roles of IL-10 on RSV-induced lung inflammation which appear to depend upon the timing of when elevated IL-10 is expressed in the lung.


G9a-Mediated Regulation of OXT and AVP Expression in the Basolateral Amygdala Mediates Stress-Induced Lasting Behavioral Depression and Its Reversal by Exercise.
Chronic stress produces behavioral depression. Conversely, physical exercise is held to be beneficial in the treatment of depression. Although genomic mechanisms are likely involved in these behavioral changes, underlying mechanisms are not clearly understood. In the present study, we investigated whether stress effects and their reversal by exercise occur via genomic mechanisms in the amygdala, a core part of the limbic system important for regulating mood states. Mice treated with chronic restraint showed lasting depression-like behaviors, which were counteracted by treatment with scheduled forceful exercise. Microarray analysis identified a number of genes whose expression in the amygdala was either upregulated or downregulated after repeated stress, and these changes were reversed by exercise. Of these genes, the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) were selected as representative stress-induced and exercise-responded genes in the BLA. Stereotaxic injection of OXT or AVP receptor agonists within the BLA in normal mice produced depression-like behaviors, whereas small interfering RNA (siRNA)-mediated suppression of the OXT or AVP transcripts in the BLA was sufficient to block stress-induced depressive behaviors. Stress-induced depression-like behaviors were accompanied by a global reduction of G9a histone methyltransferase and H3K9me2 at the OXT and AVP promoters. Conversely, repeated exercise increased the levels of G9a and H3K9me2 at the OXT and AVP promoters in the BLA, which was associated with the suppression of OXT and AVP expressions. These results identify G9a-induced histone methylation at the OXT and AVP promoters in the BLA as a mechanism for mediating stress-induced lasting behavioral depression and its reversal by exercise.


Influence of periodontal ligament simulation and splints on strains developing at the cervical area of a tooth crown.
Many in vitro tooth models do not incorporate periodontal ligament (PDL) simulation. This study presents the influence of physiologically loaded occlusal splints on cervical strains in a model incorporating roots and PDL. Four sets (N = 10) of occlusal splints differing in material (hard/soft) and location (upper/lower) were prepared for first maxillary and mandibular anatomic molars. Two strain gauges were bonded to the buccal and lingual aspects of the lower molar. Teeth were embedded in acrylic resin with/without a PDL-simulating material. Force vs. strain data were acquired during loading and the maximal strains at 500 N were analyzed. When PDL was incorporated into the model without splints, buccal compressive strains were significantly decreased. Usage of a soft splint resulted in compressive strains on both tooth aspects. Usage of a hard splint on the lower tooth resulted in higher compressive strains on the lingual side compared with the buccal side, whereas usage of this splint on the upper tooth resulted in tensile strains on the lingual side. Bending towards the buccal side occurred when the splints were located on the upper tooth. Soft splints reduce buccal bending, but do not reduce cervical strains. Periodontal ligament stimulation materials should therefore be incorporated in models involving teeth.


Fast and slow intraplate ruptures during the 19 October 2020 magnitude 7.6 Shumagin earthquake.
Strong tsunami excitation from slow rupture of shallow subduction zone faults is recognized as a key concern for tsunami hazard assessment. Three months after the 22 July 2020 magnitude 7.8 thrust earthquake struck the plate boundary below the Shumagin Islands, Alaska, a magnitude 7.6 aftershock ruptured with complex intraplate faulting. Despite the smaller size and predominantly strike-slip faulting mechanism inferred from seismic waves for the aftershock, it generated much larger tsunami waves than the mainshock. Here we show through detailed analysis of seismic, geodetic, and tsunami observations of the aftershock that the event implicated unprecedented source complexity, involving weakly tsunamigenic fast rupture of two intraplate faults located below and most likely above the plate boundary, along with induced strongly tsunamigenic slow thrust slip on a third fault near the shelf break likely striking nearly perpendicular to the trench. The thrust slip took over 5 min, giving no clear expression in seismic or geodetic observations while producing the sizeable far-field tsunami.


Scientific issues related to the cytology proficiency testing regulations.
The member organizations of the Cytology Education and Technology Consortium believe there are significant flaws in current cytology proficiency testing regulations. The most immediate needed modifications include lengthening the required testing interval, utilizing stringently validated and continuously monitored slides, changing the grading scheme, and changing the focus of the test from the individual to laboratory level testing. Integration of new computer-assisted and located-guided screening technologies into the testing protocols is necessary for the testing protocol to be compliant with the law.


Spatial and temporal pattern of expression of the cellular retinoic acid-binding protein and the cellular retinol-binding protein during mouse embryogenesis.
Retinol (vitamin A) and retinoic acid are potent teratogens and also represent good candidates for normal morphogens during development. Their actions may be mediated by the cellular retinoic acid-binding protein (CRABP) and the cellular retinol-binding protein (CRBP). As a step towards understanding the possible function for CRABP and CRBP in morphogenesis, we have used in situ hybridization to analyze their expression during mouse development. Both CRABP and CRBP transcripts were detected at embryonic days 9.5-14.5. (i) In the nervous system, CRABP transcripts were found in the mantle layer of the dorsal spinal cord and hindbrain and in the marginal layer of the midbrain, whereas CRBP transcripts were found in the ependymal and mantle layer of the ventral spinal cord and of the forebrain as well as in the spinal nerves and the roof plate of the spinal cord. (ii) In the eye, CRABP is expressed in the retinal layer, and CRBP is expressed in both retinal and pigmented layers. (iii) In the craniofacial region, CRABP transcripts were found in the mesenchyme of the frontonasal mass and mandible, while CRBP transcripts were found in the mesenchyme of the nasolachrymal duct and surrounding the auditory vesicle. Two general conclusions can be made. First, all of the tissues that are known to be teratogenic targets of retinoic acid and retinol also express CRABP and CRBP transcripts. Second, the specific expression of CRABP and CRBP in numerous developing tissues indicates that these proteins may perform specific functions during morphogenesis of a broad variety of embryonic structures.


[A pharmacologic respiratory stimulant, doxapram, used in acute deterioration in patients with chronic respiratory failure].
In a controlled study with random allocation, the effect of doxapram (Dopram), a respiratory stimulant, was evaluated in 25 patients with acute on chronic respiratory failure requiring ventilator support. Eleven patients were allocated to mechanical ventilation and 14 to treatment with doxapram given as a variable rate infusion. In the doxapram group only four were transferred to mechanical ventilation after 1 1/2 to three days of treatment. In these patients, the problem giving rise to the acute exacerbation, was not under control at the time of ventilator intervention. In the remainder of the group, antibiotics, diuretics and bronchodilators had successfully treated the exacerbation. All patients were discharged alive. In the doxapram-treated group duration of hospitalization was nine days compared to 14 days (median values) in the ventilator-treated group. Only minor side-effects from doxapram were observed, and it is concluded that this respiratory stimulant can be used as a primary drug in patients with acute respiratory failure and chronic airflow limitation.


Muscarinic regulation of neonatal rat bladder spontaneous contractions.
In vitro preparations of whole urinary bladders of neonatal rats exhibit prominent myogenic spontaneous contractions, the amplitude and frequency of which can be increased by muscarinic agonists. The muscarinic receptor subtype responsible for this facilitation was examined in the present experiments. Basal spontaneous contractions in bladders from 1- to 2-wk-old Sprague-Dawley rats were not affected by M2 or M3 receptor antagonists. However, administration of 0.5 microM physostigmine, an anticholinesterase agent that increases the levels of endogenous acetylcholine, or 50-100 nM carbachol, a cholinergic agonist at low concentrations, which did not cause tonic contractions, significantly augmented the frequency and amplitude of spontaneous contractions. Blockade of M2 receptors with 0.1 microM AF-DX 116 or 1 microM methoctramine or blockade of M3 receptors with 50 nM 4-diphenylacetoxy-N-methylpiperidine methiodide or 0.1 microM 4-diphenylacetoxy-N-(2-chloroethyl)piperidine hydrochloride (4-DAMP mustard) reversed the physostigmine and carbachol responses. M2 and M3 receptor blockade did not alter the facilitation of spontaneous contractions induced by 10 nM BAY K 8644, an L-type Ca2+ channel opener, or 0.1 microM iberiotoxin, a large-conductance Ca2+-activated K+ channel blocker. NS-1619 (30 microM), a large-conductance Ca2+-activated K+ channel opener, decreased carbachol-augmented spontaneous contractions. These results suggest that spontaneous contractions in the neonatal rat bladder are enhanced by activation of M2 and M3 receptors by endogenous acetylcholine released in the presence of an anticholinesterase agent or a cholinergic receptor agonist.


Synthesis of Self-Assembled Single Atomic Layer Gold Crystals-Goldene.
We report, for the first time, a technique to synthesize free-standing, one-atom thick 2D gold crystals (namely, goldene) and self-assembled 2D periodic arrays of goldene. High-resolution transmission electron microscopy (HRTEM) imaging of goldene revealed herringbone and honeycomb lattices, which are primarily gold surface features due to its reconstruction. Imaging of these surface-only features by a nonsurface characterization technique such as HRTEM is an unequivocal proof of the absence of three-dimensionality in goldene. Atomic force microscopy confirmed 1-2 Å thickness of goldene. High-resolution X-ray photoelectron spectroscopy (HR-XPS), selective area electron diffraction, and energy-dispersive X-ray spectroscopy confirmed the chemical identity of goldene. We discovered the phenomenon of electric field-induced self-assembly of goldene supracrystals with a herringbone structure and developed an electric field printing (e-print) technique for goldene arrays. Goldene showed a semiconductor response with a knee voltage of ∼3.2 V, and I/V spectroscopy revealed periodic room temperature Coulomb blockade oscillations. These observations are consistent with the theoretical calculations reported in the literature predicting enhanced Coulombic interactions between gold valence electrons and the nucleus in stable 2D gold. Goldene exhibited multiple, intense, and well-resolved optical absorption peaks and several fine bands across the UV-vis region, and we calculated its optical band gap to be 3.59 eV. Magnetic force microscopy measurements of goldene periodic arrays showed a ∼5 mV peak amplitude confirming its ferromagnetism. Optical and magnetic properties of goldene are consistent with those reported in the literature for 2D planar gold clusters with less than 12 atoms.


Life changes and myocardial infarction. How useful are life change measurements?
Although statistically significant, the relation between certain life changes and imminent myocardial infarction appears to be quantitatively weak. Of particular importance are events connected with employment. However, the summation of life changes has not proved to be of use in the prediction of imminent myocardial infarction. For patients with ischemic heart disease, variations in life change measures have proved to be of use in the prediction of changes in catecholamine output and in prognosis. When genetic factors are held constant, as in monozygotic twin pairs vulnerable to ischemic heart disease, more life changes in one partner may indicate a greater risk of unexpected sudden cardiac death in this partner than in the other twin. The self-rating of the severity of each experienced event has proved more useful than "standard weights" in the retrospective discrimination of myocardial infarction patients. Further clinical and epidemiological studies are needed in this field. For the future, the following recommendations are made: The studies should be prospective. The individual's habitual level and actual level of the change should be recorded. The severity of events should be self-rated. Risk variables, known to be of importance to the development of MI should be recorded. They are for instance smoking habits, blood pressure, serum lipids and genetic predisposition. Psychological variables should be mentioned separately in this connection.


Rate-dependent Ca2+ signalling underlying the force-frequency response in rat ventricular myocytes: a coupled electromechanical modeling study.
Rate-dependent effects on the Ca2+ sub-system in a rat ventricular myocyte are investigated. Here, we employ a deterministic mathematical model describing various Ca2+ signalling pathways under voltage clamp (VC) conditions, to better understand the important role of calmodulin (CaM) in modulating the key control variables Ca2+/calmodulin-dependent protein kinase-II (CaMKII), calcineurin (CaN), and cyclic adenosine monophosphate (cAMP) as they affect various intracellular targets. In particular, we study the frequency dependence of the peak force generated by the myofilaments, the force-frequency response (FFR). Our cell model incorporates frequency-dependent CaM-mediated spatially heterogenous interaction of CaMKII and CaN with their principal targets (dihydropyridine (DHPR) and ryanodine (RyR) receptors and the SERCA pump). It also accounts for the rate-dependent effects of phospholamban (PLB) on the SERCA pump; the rate-dependent role of cAMP in up-regulation of the L-type Ca2+ channel (ICa,L); and the enhancement in SERCA pump activity via phosphorylation of PLB. Our model reproduces positive peak FFR observed in rat ventricular myocytes during voltage-clamp studies both in the presence/absence of cAMP mediated β-adrenergic stimulation. This study provides quantitative insight into the rate-dependence of Ca2+-induced Ca2+-release (CICR) by investigating the frequency-dependence of the trigger current (ICa,L) and RyR-release. It also highlights the relative role of the sodium-calcium exchanger (NCX) and the SERCA pump at higher frequencies, as well as the rate-dependence of sarcoplasmic reticulum (SR) Ca2+ content. A rigorous Ca2+ balance imposed on our investigation of these Ca2+ signalling pathways clarifies their individual roles. Here, we present a coupled electromechanical study emphasizing the rate-dependence of isometric force developed and also investigate the temperature-dependence of FFR. Our model provides mechanistic biophysically based explanations for the rate-dependence of CICR, generating useful and testable hypotheses. Although rat ventricular myocytes exhibit a positive peak FFR in the presence/absence of beta-adrenergic stimulation, they show a characteristic increase in the positive slope in FFR due to the presence of Norepinephrine or Isoproterenol. Our study identifies cAMP-mediated stimulation, and rate-dependent CaMKII-mediated up-regulation of ICa,L as the key mechanisms underlying the aforementioned positive FFR.


Effect of inhibiting leukocyte integrin (CD18) and selectin (L-selectin) on susceptibility to infection with Pseudomonas aeruginosa.
Leukocyte (WBC) adherence to endothelial cells has been implicated in the pathogenesis of microvascular injury. The process of leukocyte adherence is mediated by both the integrin and selectin families of molecules, and their interaction with specific endothelial ligands. Antibodies directed against the leukocyte integrin CD18 and L-selectin have been developed and functionally inhibit leukocyte adherence in models of inflammatory injury. We asked the question: Does inhibition of leukocyte adherence by administration of monoclonal antibody directed against either CD18, integrins (R15.7, R7.1) or against L-selectin (DREG 200) increase susceptibility to infection? New Zealand white rabbits were shaved and injected subcutaneously on their dorsum with Pseudomonas aeruginosa (ATCC#27853) at two sites each of 10(8) and 10(7) colony forming units. Animals were monitored with daily determination of weight, temperature, WBC counts, hematocrit, and killed at 1 week for determination of abscess formation. There were four blinded experimental groups: (1) Saline (2 mL/kg); (2) DREG 200 (2 mg/kg); (3) R7.1 (2 mg/kg); or (4) R15.7 (2 mg/kg). At the 10(7) and 10(8) injection sites the R15.7 group had an increased rate and size of abscess formation compared with controls. The R7.1 group had an increased rate at the 10(8) injection site. There was no significant difference in the percentage of the abscess formation or mean area between the controls and DREG 200-treated groups. We conclude that giving antibody to CD18 increased susceptibility to infection while giving antibody to L-selectin does not.


Analyzing the impact of pulsatile flow on drug release from a single strut of a drug-eluting stent.
In this study, in-vitro experiments were performed to investigate the drug release from a single strut of a drug-eluting stent with respect to the systolic-diastolic flow and the continuous flow. Regarding, a test bench comprising a single strut and agarose gel as an arterial wall model was designed. The model chosen represents a large-scaled strut of a stent, to limit the effect of the geometrical shape of the stents on the drug release results. The comparison is carried out between two continuous flow rates and a systolic-diastolic flow pattern varying between these two flow rates, with a frequency of 70 beats per minute. The stent model is a polylactic-co-glycolic acid film (50:50) loaded with 10 % diclofenac sodium. A compartment of agarose gel (1 %) and a phosphate-buffered saline solution at 37 °C are employed to mimic the arterial wall and the blood, respectively. Our results show the importance of flow type on the drug release from the stent and distribution of drug in the hydrogel, such that the pulsatility promotes an increase in the quantity of drug absorbed into the hydrogel.


[Effects of inoculation with Rhizobium leguminosarum biovar trifolii on wheat cultivated in clover crop rotation agricultural soil in Morocco].
One hundred strains of Rhizobium leguminosarum bv. trifolii were isolated from roots of wheat cultivated in rotation with clover in two different regions of Morocco. The isolates were first screened for their effect on the growth of the cultivar Rihane of wheat cultivated in an agricultural soil under greenhouse conditions. After 5 weeks of growth, 14 strains stimulating the fresh or dry matter yield of shoots were selected and used in a second pot inoculation trial performed with two different agricultural soils. The results show that the strains behaved differently according to the soil used. In the loamy sand Rabat, strain IAT 168 behaved potentially like a plant growth promoting rhizobacteria (PGPR), as indicated by the 24% increases (P < 0.1) observed in wheat shoot dry matter and grain yields. In the silty clay Merchouch, no PGPR activity was observed, and 6 strains showed a significant deleterious effect on yields. These observations suggest that it is very important in a crop rotation system to choose a R. leguminosarum bv. trifolii strain that is effective with clover and shows PGPR activity with wheat to avoid deleterious effects on wheat yields.


Genetically Divergent Types of the Wheat Leaf Fungus Puccinia triticina in Ethiopia, a Center of Tetraploid Wheat Diversity.
Collections of Puccinia triticina, the wheat leaf rust fungus, were obtained from tetraploid and hexaploid wheat in the central highlands of Ethiopia, and a smaller number from Kenya, from 2011 to 2013, in order to determine the genetic diversity of this wheat pathogen in a center of host diversity. Single-uredinial isolates were derived and tested for virulence phenotype to 20 lines of Thatcher wheat that differ for single leaf rust resistance genes and for molecular genotypes with 10 simple sequence repeat (SSR) primers. Nine virulence phenotypes were described among the 193 isolates tested for virulence. Phenotype BBBQJ, found only in Ethiopia, was predominantly collected from tetraploid wheat. Phenotype EEEEE, also found only in Ethiopia, was exclusively collected from tetraploid wheat and was avirulent to the susceptible hexaploid wheat 'Thatcher'. Phenotypes MBDSS and MCDSS, found in both Ethiopia and Kenya, were predominantly collected from common wheat. Phenotypes CCMSS, CCPSS, and CBMSS were found in Ethiopia from common wheat at low frequency. Phenotypes TCBSS and TCBSQ were found on durum wheat and common wheat in Kenya. Four groups of distinct SSR genotypes were described among the 48 isolates genotyped. Isolates with phenotypes BBBQJ and EEEEE were in two distinct SSR groups, and isolates with phenotypes MBDSS and MCDSS were in a third group. Isolates with CCMSS, CCPSS, CBMSS, TCBSS, and TCBSQ phenotypes were in a fourth SSR genotype group. The diverse host environment of Ethiopia has selected and maintained a genetically divergent population of P. triticina.


The impact of social influence on adolescent intention to smoke: combining types and referents of influence.
Theory and research suggest that the intention to smoke is the main determinant of smoking initiation and emphasizes the role of cognitive and social factors on the prediction of the intention to smoke. However, extended models such as the I-Change and results from published studies reveal inconsistencies regarding the impact of social influence on the intention to smoke. Possible explanations for this may be the definition and measurement of the constructs that have been used. The current study was designed with two main goals: (i) to test a measurement model for social influence, combining different types of social influence (subjective norms, perceived behaviour, and direct pressure) with various referents of influence (parents, siblings, peers, and teachers); (ii) to investigate the impact of social influence on adolescent intention to smoke, controlling for smoking behaviour. LISREL was used to test these models. The sample includes 3,064 Portuguese adolescents, with a mean age of 13.5 years, at the beginning of the seventh school grade. The hypothesized measurement model of social influence was supported by results and explained 29% of the variance of the intention to smoke. A more extended model, including attitude and self-efficacy, explained 55% of the variance of the intention to smoke. Perceived behaviour of peers, parental norms, and perceived behaviour of parents were the social influence factors with impact on adolescent intention to smoke. Results suggest that different referents exert their influence through distinct types of social influence and recommend further work on the definition and measurement of social influence.


Intraspecies variation in the emergence of hyperinfectious bacterial strains in nature.
Salmonella is a principal health concern because of its endemic prevalence in food and water supplies, the rise in incidence of multi-drug resistant strains, and the emergence of new strains associated with increased disease severity. Insights into pathogen emergence have come from animal-passage studies wherein virulence is often increased during infection. However, these studies did not address the prospect that a select subset of strains undergo a pronounced increase in virulence during the infective process- a prospect that has significant implications for human and animal health. Our findings indicate that the capacity to become hypervirulent (100-fold decreased LD(50)) was much more evident in certain S. enterica strains than others. Hyperinfectious salmonellae were among the most virulent of this species; restricted to certain serotypes; and more capable of killing vaccinated animals. Such strains exhibited rapid (and rapidly reversible) switching to a less-virulent state accompanied by more competitive growth ex vivo that may contribute to maintenance in nature. The hypervirulent phenotype was associated with increased microbial pathogenicity (colonization; cytotoxin production; cytocidal activity), coupled with an altered innate immune cytokine response within infected cells (IFN-β; IL-1β; IL-6; IL-10). Gene expression analysis revealed that hyperinfectious strains display altered transcription of genes within the PhoP/PhoQ, PhoR/PhoB and ArgR regulons, conferring changes in the expression of classical virulence functions (e.g., SPI-1; SPI-2 effectors) and those involved in cellular physiology/metabolism (nutrient/acid stress). As hyperinfectious strains pose a potential risk to human and animal health, efforts toward mitigation of these potential food-borne contaminants may avert negative public health impacts and industry-associated losses.


17 beta-carboxamide steroids: highly effective inhibitors of the phytohaemagglutinin mediated blastogenesis of normal human peripheral lymphocytes.
Several novel 17 beta-carboxamide analogues of dexamethasone were synthesized. The common precursor, 9-fluoro-16 alpha-methyl-11 beta,17-dihydroxy-3-oxo-1,4-androstadiene-17 beta-carboxylic acid, did not bind to the glucocorticoid receptors of rat liver and human spleen tumours. In addition, no inhibition of the mitogen-induced blastogenesis of cultured human peripheral lymphocytes was observed. The 17 beta-carboxamide analogues, however, bound with similar affinities to the glucocorticoid receptors of both tissues. They inhibited the mitogen-induced blastogenesis of peripheral lymphocytes, showing the same potency and same order of binding affinity as the natural glucocorticoids.


[Viral infections in pediatric cancer patients].
Children with cancer or stem cell transplantation (SCT) are at considerable risk to develop life threatening viral infections. Due to both underlying disease and immunosuppressive therapy lymphocyte number and function are low and the cellular immunity against viral infections is restricted or missing. As immunosuppressive treatment regimens and mismatched or T-cell-depleted stem cell products are being used increasingly, viral infections will become an even greater problem in the future. PCR-based methods have become an indispensable tool for early recognition, preemptive therapy, and monitoring therapeutic responses by qualitative and quantitative approaches. Assays are now available that allow for parallel screening of the 16 most common viral agents. Responses to antiviral therapy are often limited in immunocompromised patients and mainly depend on the time of their initiation. Most antiviral agents have a toxicity profile that may become clinically relevant and curtail antiviral therapy. New options for treatment are therefore warranted. For the next future, these may include the transfer of specific T-cells and other immunotherapeutic approaches. This article provides the recommendations of the Infectious Diseases Working Party of the German Society for Pediatric Hematology/Oncology (GPOH) and the German Society for Pediatric Infectious Diseases (DGPI) for diagnosis and treatment of viral infections in children with cancer or post HSCT. They are based on the results of clinical trials, case series and expert opinions using the evidence criteria set forth by the Infectious Diseases Society of America (IDSA).


Pharmacist-Led Interventions for Medication Adherence in Patients with Chronic Kidney Disease: A Scoping Review.
Patients with chronic kidney disease (CKD) are routinely prescribed complex medication regimes. Medication reconciliation, medicine reviews, patient counselling and disease state and medication education are all key pharmacist-led interventions, which can improve medication adherence in patients with CKD. To characterize peer reviewed literature on the role of pharmacists in supporting medication adherence of patients with chronic kidney disease and highlight the impact they might have in the health outcomes for patients. This review was performed in accordance with the Scoping Review Framework outlined in the Joanna Briggs Institute Reviewer's Guide. Four electronic databases were searched (Medline (Ovid), Emcare, Scopus and Web of Science) for all relevant literature published up until November 2022. A total of 32 studies were reviewed against an exclusion and inclusion criteria, with findings from each study categorized into barriers, interventions, perceptions, financial implications and outcomes. Eight eligible studies were identified, where pharmacists' interventions including medication reconciliation, medicine reviews, patient counselling and disease state and medication education, were all reported to have a positive effect on medication adherence. Although pharmacy services in chronic kidney disease were acceptable to patients and pharmacists, these services were under-utilized and limited by logistical constraints, including staffing shortages and time limitations. Patient education supplemented with education tools describing disease states and medications was reported to increase patient adherence to medication regimes. Pharmacist-led interventions play an integral role in improving medication adherence in patients with chronic kidney disease, with their inclusion in renal care settings having the potential to improve outcomes for patients.


Effects of radial left ventricular dyssynchrony on cardiac performance using quantitative tissue Doppler radial strain imaging.
Our objective was to test the hypothesis that novel angle-corrected radial strain imaging can quantify left ventricular dyssynchrony associated with contractile impairment and improved with biventricular pacing. Eight open-chest dogs were studied by novel angle-corrected color-coded radial strain imaging and high-fidelity pressure-conductance catheters recording pressure-volume loops. Heart rate was controlled by right atrial pacing and all timing intervals were corrected by R-R interval (corrected interval = measured interval/(R-R interval)(1/2)). Left bundle branch block, simulated by right ventricular free wall pacing, resulted in marked radial dyssynchrony, which we defined as maximal time difference between peak segmental strain, from 39 +/- 17 to 354 +/- 49 milliseconds and stroke work decreased from 157 +/- 40 to 60 +/- 37 mJ, (P < .005 vs baseline). Depression of contractility by high-dose esmolol (end-systolic pressure-volume relationship from 5.7 +/- 2.4 to 3.6 +/- 1.0 mm Hg/mL) was associated with augmented dyssynchrony to 388 +/- 53 milliseconds (P < .05 vs baseline right ventricular pacing). Biventricular pacing improved dyssynchrony to 55 +/- 19 milliseconds and stroke work to 143 +/- 33 mJ (P < .05 vs right ventricular pacing). Changes in radial dyssynchrony correlated significantly with 6-site average regional strain (r = -0.93 +/- 0.05 individually, r = 0.80 overall) and stroke work (r = -0.88 +/- 0.12 individually, r = -0.82 overall). Angle-corrected radial strain imaging has clinical potential to quantify mechanical dyssynchrony and effects of biventricular pacing.


Mechanisms and Effect of Increased Physical Activity on General and Abdominal Obesity and Associated Metabolic Risk Factors in a Community with Very High Rates of General and Abdominal Obesity.
The growing prevalence of obesity and related type 2 diabetes is reaching epidemic proportions in the UAE. Physical inactivity is one of the possible factors linking obesity to diabetes and other related complications. However, the molecular mechanisms through which physical inactivity is contributing to increased obesity-related pathologies are not clear. to measure the effects of increased physical activity on obesity and related metabolic risk factors. We investigated the effects of physical activity on body weight, waist circumference (WC) and metabolic risk factors in 965 community free-living Emirati subjects. Physical activity, dietary intake, antioxidant enzymes and markers of oxidative damage and inflammation were measured both at baseline and follow up. A validated questionnaire was used to assess occupation and leisure-related physical activity. We compared metabolic risk factors between subjects stratified by physical activity levels. The Cox proportional hazards analysis was used to determine the independent effects of increased physical activity on presence and absence of obesity, body weight and waist circumference (WC) change at follow up. A total of 965 community free-living subjects [801 (83%) females, mean (SD) age 39 ± 12 years] were recruited and followed up with for a period of 427 ± 223 days. Using WHO cut-of-points for body mass index (BMI), 284 (30%) subjects were overweight and 584 (62%) subjects were obese, compared to 69 (8%) at normal body weight. We found men to be more physically active than women at both leisure and work times. BMI, hip circumference, total body fat, HDL and inflammatory markers (us CRP, TNF) were significantly higher in female subjects, whilst fat free-mass, WC, blood pressure and HbA1c were higher in male subjects (p < 0.05). Hypertension and diabetes were more common in male subjects compared to female subjects (p < 0.05). Increased physical activity both at baseline and follow up were associated with decreased BMI, WC and inflammatory markers, including us-CRP and TNF. Increased physical activity was associated with significant decrease in abdominal obesity in female subjects and general obesity in both male and females after adjusting for important prognostic indicators [hazard ratio (95% CI): 0.531 (0.399, 0.707); p < 0.001; 0.475 (0.341, 0.662); p < 0.001 respectively]. Our findings suggest that increased physical activity may decrease the risk of obesity and also mitigate the associated oxidative damage and inflammatory responses.


International Occupational Therapy Research Priorities.
Occupational therapy is a global profession represented by the World Federation of Occupational Therapists (WFOT). International research priorities are needed for strategic guidance on global occupational therapy practice. The objective of this study was to develop international research priorities to reflect global occupational therapy practice. A Delphi study using three rounds of electronic surveys, distributed to WFOT member organizations and WFOT accredited universities, was conducted. Data were analyzed after each round, and priorities were presented for rating and ranking in order of importance. Forty-six (53%) out of 87 WFOT member countries participated in the Delphi process. Eight research priorities were confirmed by the final electronic survey round. Differences were observed in rankings given by member organizations and university respondents. Despite attrition at Round 3, the final research priorities will help to focus research efforts in occupational therapy globally. Follow-up research is needed to determine how the research priorities are being adopted internationally.


Association between physical activity and short-term physical function changes after hip fracture: An observational study.
To investigate whether physical activity levels are predictive of short-term changes in physical function for people discharged to independent living in the community following withdrawal of rehabilitation services after hip fracture; and to describe short-term recovery in physical activity, physical function, walking confidence, health-related quality of life and walking participation. This prospective cohort study comprised 57 older adults (39 females, mean age 80.4, SD 8.4 years) living independently in the community after hip fracture. Accelerometer-based physical activity, physical function (Functional Independence Measure [FIM], de Morton Mobility Index, Frenchay Activities Index and Participation in outdoor walking), walking confidence and health-related quality of life were measured after discharge from rehabilitation services (baseline) and 12 weeks later. Multiple linear regression analyses determined the ability of physical activity (daily steps), walking self-confidence, health-related quality of life and demographic factors (age, sex and time since fracture) to predict Week 12 physical function using Week 0 physical function as a covariate. Participants at baseline averaged 4439 daily steps which did not change 12 weeks later. There were small increases in all measures of physical function and walking confidence, but not health-related quality of life. Increased walking self-confidence was associated with an increase in FIM total, FIM mobility and de Morton Index scores. Physical activity did not predict change in measures of physical function. Walking confidence of adults discharged from rehabilitation services after hip fracture had a greater association with short-term recovery of physical function than level of physical activity. Community-dwelling adults continue to make small short-term improvements in physical function and walking confidence after discharge home and withdrawal of rehabilitation services.


The real world of blood glucose point-of-care testing (POCT) system running in China teaching hospital.
The blood glucose point-of-care testing (POCT) system is important in the decision-making process involving patients suspected of having hypoglycemia. To investigate the real world of the POCT system being used in teaching hospitals in China. The survey was conducted by Hisend Research Group from May 2015 to July 2015 in four teaching hospitals in China. The survey questions were referred to the ISO 15197:2013 standard requirements for the use of the POCT system in a hospital setting. A total of 170 subjects were included from 4 hospitals, which included nursing staff, nurse unit managers, employees from the department of medical instruments, and staff members employed by the clinical laboratories in the Tianjin Metabolism Hospital, Nanjing First Hospital, First Affiliated Hospital of Dalian Medical University, and the First hospital affiliated with the Xi'an Transportation University. The average score for the four hospitals surveyed in this study was 66.6, which varied from 46.1 to 79.7. The main factors influencing the scores were the multiple choices of blood-glucose meters, and the quality control assessment. Our data indicates that the real world use of the POCT system in hospital settings in China needs more closer adherence to a quality management framework.


Visceral leishmaniasis in a Brazilian endemic area: an overview of occurrence, HIV coinfection and lethality.
The Brazilian municipality of Rondonópolis, Mato Grosso State, represents an important visceral leishmaniasis (VL) endemic area. This study described epidemiological and clinical aspects of the occurrence, VL/HIV coinfection and lethality related to VL in Rondonópolis. Data from autochthonous cases reported between 2011 and 2016 were obtained from official information systems. During this period, 81 autochthonous cases were reported, with decreasing incidence through 2016. Contrastingly, the lethality rate was 8.6% overall, but varied widely, reaching a peak (20%) in 2016. Almost 10% of patients had VL/HIVcoinfection. The occurrence of VL prevailed among men (56.8%), brown-skinned (49.4%), urban residents (92.6%), aged 0-4 years (33.3%). Housewives or retired (29.6%) were the most affected occupational groups. Lower age was the main difference among the total VL cases and those who were coinfected or died. Clinically, fever, weakness and splenomegaly were more frequent among all VL cases and VL/HIV coinfected individuals. Bacterial infections (p=0.001) and bleeding (p<0.001) were associated with death due to VL. Pentavalent antimonial and liposomal amphotericin B were the first choices for treatment among all VL cases (71.6%) and those who died (71.4%), respectively. VL/HIV patients were equally treated with both drugs. These findings may support control measures and demonstrate the need for further investigations.


Chain Mobility in Polymer Systems: On the Borderline between Solid and Melt. 2. Crystal Size Influence in Phase Transition and Sintering of Ultrahigh Molecular Weight Polyethylene via the Mobile Hexagonal Phase.
Polymorphism is a well-established phenomenon in crystalline materials and is important for pharmaceutical and polymeric materials. In our study concerning the processability of polymers, we came across an unusual observation related to polymorphism induced by pressure. The experimental observation is that polyethylene crystals transform from the stable orthorhombic crystal into a transient hexagonal phase. The occurrence of a transient hexagonal phase is shown to be dependent on the polymer crystal size; smaller crystals transform into the transient hexagonal phase at temperatures and pressures much below the thermodynamic critical point Qo, which is located at P = 3.6 kbar and T = 230 degreesC. The crystal size dependence in the phase transition was investigated by in situ X-ray studies in the unirradiated and irradiated solution-crystallized films. Since the chain mobility is rather high in the hexagonal phase, sintering has been attempted via this transient phase using ultrahigh molecular weight polyethylene (UHMW-PE) as a model system. UHMW-PE is an intractable polymer due to its high molar mass but possesses excellent abrasion resistance properties. For this reason it is used as an inlay in demanding applications such as artificial hip and knee joints. The service life of UHMW-PE in these artificial joints, however, is limited due to the poor processing characteristics notably during sintering, and often a second operation is needed to replace the UHMW-PE interface. Sintering via the transient hexagonal phase could provide a solution for this important problem which concerns an increasing number of people.


p53 Activation in Genetic Disorders: Different Routes to the Same Destination.
The tumor suppressor p53 is critical for preventing neoplastic transformation and tumor progression. Inappropriate activation of p53, however, has been observed in a number of human inherited disorders that most often affect development of the brain, craniofacial region, limb skeleton, and hematopoietic system. Genes related to these developmental disorders are essentially involved in transcriptional regulation/chromatin remodeling, rRNA metabolism, DNA damage-repair pathways, telomere maintenance, and centrosome biogenesis. Perturbation of these activities or cellular processes may result in p53 accumulation in cell cultures, animal models, and perhaps humans as well. Mouse models of several p53 activation-associated disorders essentially recapitulate human traits, and inactivation of p53 in these models can alleviate disorder-related phenotypes. In the present review, we focus on how dysfunction of the aforementioned biological processes causes developmental defects via excessive p53 activation. Notably, several disease-related genes exert a pleiotropic effect on those cellular processes, which may modulate the magnitude of p53 activation and establish or disrupt regulatory loops. Finally, we discuss potential therapeutic strategies for genetic disorders associated with p53 misactivation.


Dimethachlon Resistance in Sclerotinia sclerotiorum in China.
The dicarboximide fungicide dimethachlon has been widely used for controlling Sclerotinia sclerotiorum in China for more than a decade. To assess the current status of dimethachlon resistance in S. sclerotiorum in China, 2,424 isolates were collected from disease-infected oilseed rape and soybean plants in five provinces of China in 2011 and 2012, and dimethachlon resistance was monitored by mycelial growth inhibition method on potato dextrose agar (PDA) media. Dimethachlon at 5 μg/ml was used as a discriminatory dose to detect resistance in all isolates, and 50% effective concentration values were determined for all dimethachlon-resistant isolates and some sensitive isolates. No dimethachlon resistance was detected in isolates from Anhui province (eastern China), Gansu province (northwestern China), and Qinghai province (western China). In Hunan province (central China), 3 of 268 (1.12%) isolates collected from oilseed rape plants in 2012 were resistant to dimethachlon, and the resistance ratios for the three resistant isolates were 4.56, 32.70, and 105.53, respectively. In Heilongjiang province (northeastern China), 8 of 243 (3.29%) isolates collected from soybean plants in 2011 were resistant to dimethachlon, with resistance ratios of 5.57 to 94.80; 11 of 409 (2.69%) isolates collected in 2012 were resistant to dimethachlon, with resistance ratios of 3.21 to 9.69. Cross-resistance studies showed that there was positive cross-resistance between dimethachlon and iprodione, procymidone, and the N-phenyl carbamate fungicide diethofencarb. No cross-resistance was found between dimethachlon and carbendazim, tebuconazole, kresoxim-methyl, thiram, and boscalid. Compared with the sensitive isolates of S. sclerotiorum, the field-dimethachlon-resistant isolates were more sensitive to osmotic pressure, grew more slowly on PDA media, and were less pathogenic on leaves of oilseed rape.


Kinetics and metabolic activity of biosynthetic NPH insulin evaluated by the glucose clamp technique.
The glucose clamp technique has been used to evaluate the metabolic activity of NPH biosynthetic insulin in diabetic subjects free from anti-insulin antibodies. After overnight blood glucose normalization with a glucose-controlled insulin infusion system (Biostator), an s.c. injection of NPH insulin was given in the abdominal region. The insulin dose (0.236 +/- 0.05 U/kg body wt) was related to the usual intermediate-acting insulin requirement in the morning. Glucose was clamped at 100 mg/dl by a feedback i.v. glucose infusion. The end of the action of s.c. injected insulin considered conventionally to be the time of the spontaneous rise of blood glucose to 110 mg/dl. Free insulin levels were higher and the length of action was longer after NPH porcine than after NPH biosynthetic human insulin (BHI) (area under the free insulin curve: porcine 1423 +/- 556 mU/L/h; BHI 1045 +/- 338 mU/L/h, P less than 0.05; length of action: porcine 16.0 +/- 3.2 h; BHI 13.7 +/- 0.9 h, P less than 0.05); the glucose requirement was higher after porcine (76.8 +/- 13.5 g) than after BHI (58.5 +/- 14.6 g) without reaching statistical significance. However, the metabolic activity of the bioavailable insulin (index of plasma free insulin activity) was similar for the two insulins (porcine 381 +/- 77.4, BHI 342.8 +/- 54.2 mU/L/g of glucose/h). We conclude that a difference in pharmacokinetics exists between NPH BHI and porcine NPH insulin, which makes the latter metabolically more active. The different behavior does not seem to be related to the insulin molecule itself but could be a consequence of the unequal content of protamine in the two pharmacologic preparations.


Back to the future: brake reaction times for manual and automated vehicles.
Rear-end collisions are often quoted as being a major cause of road traffic accidents. In response to this, a great deal of ergonomics research effort has been directed towards the analysis of brake reaction times. However, the engineering solution has been to develop advanced systems for longitudinal control, which, it is argued, will mitigate the problem of rear-end collisions. So far, though, there have been few empirical studies to determine how brake reaction times will be affected by such vehicle automation. This paper presents a literature review summarizing the current state of knowledge about driver responses in non-automated vehicles. The review covers driver factors, vehicle factors and situational factors. Following the review, some empirical data are presented from a driving simulator experiment assessing brake reaction times of skilled and unskilled drivers under two different levels of automation. When compared to previous data gathered during manual driving, there seems to be a striking increase in reaction times for these automated conditions. Implications for the design and safety of automated vehicle systems are discussed.


Screening by telephone in the Alzheimer's disease anti-inflammatory prevention trial.
Compared with in-person assessment methods, telephone screening for dementia and other cognitive syndromes may improve efficiency of large population studies or prevention trials. We used data from the Alzheimer's Disease Anti-Inflammatory Prevention Trial to compare performance of a four-test Telephone Assessment Battery (TAB) that included the Telephone Interview for Cognitive Status (TICS) to that of a traditional in-person Cognitive Assessment Battery. Among 1,548 elderly participants with valid telephone and in-person screening results obtained within 90 days of each other, 225 persons were referred for a full cognitive diagnostic evaluation that was completed within six months of screening. Drawing on results from this panel of 225 individuals, we used the Capture-Recapture method to estimate population numbers of cognitively impaired participants. The latter estimates enabled us to compare the performance characteristics of the two screening batteries at specified cut-offs for detection of dementia and milder forms of impairment. Although our results provide relatively imprecise estimates of the performance characteristics of the two batteries, a comparison of their relative performance suggests that, at selected cut-off points, the TAB produces results broadly comparable to in-person screening and may be slightly more sensitive in detecting mild impairment. TAB performance characteristics also appeared slightly better than those of the TICS alone. Given its benefits in time and cost when screening for cognitive disorders, telephone screening should be considered for large samples.


Pancreas sparing resection for giant hamartoma of Brunner's glands.
Benign proliferative changes of the Brunner's glands account for about 10% of neoplasias of the duodenal bulb. The authors present a case of giant hamartoma of Brunner's glands. The patient presented clinically with vague epigastric discomfort. A pancreas-sparing duodenal resection was performed. The patient made an uneventful recovery and is well at a one year follow-up. The diagnosis was established on histopathology. Duodenal hamartomas are rare and may become very large, mandating surgical removal. A pancreas-sparing duodenal resection is one of the modalities of treating such lesions.


Polyphenol-Rich and Alcoholic Beverages and Metabolic Status in Adults Living in Sicily, Southern Italy.
Polyphenol-rich beverage consumption is not univocally accepted as a risk modulator for cardio-metabolic risk factors, despite mechanistic and epidemiological evidence suggesting otherwise. The aim of this study was to assess whether an association between polyphenol-rich beverage consumption and metabolic status could be observed in a Mediterranean cohort with relatively low intake of tea, coffee, red and white wine, beer, and fresh citrus juice. Demographic and dietary characteristics of 2044 adults living in southern Italy were analyzed. Multivariate logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) of the association between polyphenol-rich and alcoholic beverage consumption and metabolic status adjusted for potential confounding factors. Specific polyphenol-rich beverages were associated, to a various extent, with metabolic outcomes. Individuals with a higher total polyphenol-rich beverages had higher polyphenols intake and were less likely to have hypertension, type-2 diabetes, and dyslipidemia (OR = 0.57, 95% CI: 0.44-0.73; OR = 0.41, 95% CI: 0.26-0.66; and OR = 0.41, 95% CI: 0.29-0.57, respectively). However, when adjusted for potential confounding factors, only the association with hypertension remained significant (OR = 0.69, 95% CI: 0.50-0.94). Current scientific evidence suggests that such beverages may play a role on cardio-metabolic risk factors, especially when consumed within the context of a dietary pattern characterized by an intake of a plurality of them. However, these associations might be mediated by an overall healthier lifestyle.


Not your usual tRNA synthetase: hWARS serves as an enterovirus entry factor.
Enteroviruses, including subtype EV-A71, infect the brain, liver, heart, and other organs, causing a myriad of human diseases. This spectrum of disease is thought to be due, in part, to differential binding to host cells, and additional knowledge of enterovirus cell entry is essential for therapeutic development. In this issue of the JCI, Yeung et al. provide evidence of a novel EV-A71 entry factor, a host-produced tryptophan tRNA synthetase (hWARS), that facilitates entry of multiple subtypes of enteroviruses. hWARS is a cytoplasmic enzyme that is essential for translation but also upregulated and secreted during inflammatory processes. The results of this study support the notion of secreted hWARS as an unconventional virus entry factor that raises interesting questions about mechanisms by which inflammation and a tRNA synthetase facilitate viral pathogenesis.


Efficacy and tolerability of the ketogenic diet according to lipid:nonlipid ratios--comparison of 3:1 with 4:1 diet.
The ketogenic diet (KD) has been considered a highly potent antiepileptic treatment for intractable childhood epilepsy. In this study, we compared the antiepileptic efficacy and diet tolerability of two different diets with lipid:nonlipid ratios of 3:1 and 4:1. Seventy-six patients with refractory childhood epilepsy were randomly placed into two groups and were started on KD diets with nonlipid:lipid ratios of either 3:1 or 4:1. Antiepileptic efficacy and diet tolerability were evaluated 3 months after initiating the diet. Patients showing seizure-free outcome with the 4:1 diet were changed to the 3:1 diet, and those without a seizure-free outcome on the 3:1 diet were changed to the 4:1 diet, for three more months, after which time their progress was monitored. (1) Antiepileptic efficacy was higher for the 4:1 than the 3:1 diet (p < 0.05). Twenty-two (55.0%) of 40 patients on the 4:1 diet and 11 (30.5%) of 36 patients on the 3:1 diet became seizure free. Seizure reduction of over 90% was observed in 2 (5.0%) patients on the 4:1 diet, and 2 (5.6%) on the 3:1 diet. (2) Dietary tolerability was better for the 3:1 than the 4:1 diet. Gastrointestinal symptoms were observed in 5 (13.9%) patients with the 3:1 diet and 14 (35.0%) patients with the 4:1 diet (p < 0.05). (3) For seizure-free patients who started on the 4:1 diet, antiepileptic efficacy was maintained after changing to the 3:1 diet, while 10 (83.3%) of 12 patients who were not seizure free with the 3:1 diet showed increased seizure reduction after changing to the 4:1 diet. (4) Complications from the KD and laboratory data were not significantly different between the two groups. The 4:1 KD showed greater antiepileptic efficacy than the 3:1 diet with higher seizure-free outcome. In most cases, seizure free outcome was maintained even after changing the ratio to 3:1. Dietary tolerability was better in the 3:1 diet than the 4:1 with less frequent gastrointestinal symptoms.


Area-based differences in injury risks in a small Swedish municipality--Geographic and social differences.
The current study investigates the geographic and social differences in injury risks across living areas in a small semi-urban Swedish municipality. The study population consisted of all people living in the municipality during the years 1992-1996 (31,820, December 1996). Area comparisons were made based on data related to the municipality's 15 census districts and grouped according to the geographic location and three different social characteristics (proportion of unemployed, of low educated, or of people born outside Sweden). Injury data was gathered for the period 1992-1996 from two data sources: Sweden's National Hospital Discharge Register, and the local outpatient register. Three diagnosis groups were used: all injuries aggregated, traffic injuries and other unintentional injuries. Odds-ratios were calculated for males and females separately. There were no remarkable differences in injury risks between areas, whether compared on the basis of their geographic location or some of their socio-economic characteristics. These findings could be attributed to either a lack of sensitivity of the measures employed or the existence of a well-functioning safety promotion program in the municipality that impacts on injury risk distribution between areas. This, in turn, does not imply that members of underprivileged social groups are not in need of special support regardless of the area to which they belong.


Using morphs of familiar objects to examine how shape discriminability influences view sensitivity.
We investigated how the difficulty of detecting a shape change influenced the achievement of object constancy across depth rotations for object identification and categorization tasks. In three sequential matching experiments, people saw pictures of morphs between two everyday, nameable objects (e.g., bath-sink morphs, along a continuum between "bath" and "sink" end-point shapes). In each experiment, both view changes and shape changes influenced performance. Furthermore, the deleterious effects of view changes were strongest when shape discrimination was hardest. In our earlier research, using morphs of novel objects, we found a similar interaction between view sensitivity and shape sensitivity (Lawson, 2004b; Lawson & Bülthoff, 2006; Lawson, Bülthoff, & Dumbell, 2003). The present results extend these findings to familiar-object morphs. They suggest that recognition remains view-sensitive at the basic level of identification for everyday, nameable objects, and that the difficulty of shape discrimination plays a critical role in determining the degree of this view sensitivity.


Retinoic acid induced mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase-dependent MAP kinase activation needed to elicit HL-60 cell differentiation and growth arrest.
Retinoic acid (RA) activated the extracellular signal-regulated kinase (ERK) 2 mitogen-activated protein kinase (MAPK) of HL-60 human myeloblastic leukemia cells before causing myeloid differentiation and cell cycle arrest associated with hypophosphorylation of the retinoblastoma (RB) tumor suppressor protein. ERK2 activation by mitogen-activated protein/ERK kinase (MEK) was necessary for RA-induced differentiation in studies using PD98059 to block MEK phosphorylation. G0 growth arrest and RB tumor suppressor protein hypophosphorylation (which is typically associated with induced differentiation and G0 arrest), two putatively RB-regulated processes, also depended on ERK2 activation by MEK. Activation of ERK2 by RA occurred within hours and persisted until the onset of RB hypophosphorylation, differentiation, and arrest. ERK2 activation was probably needed early, because delaying the addition of PD98059 relative to that of RA restored most of the RA-induced cellular response. In contrast to RA (which activates RA receptors (RARs) and retinoid X receptors in HL-60 cells with its metabolite retinoids), a retinoid that selectively binds RAR-gamma, which is not expressed in HL-60 cells, was relatively ineffective in causing ERK2 activation. This is consistent with the need for a nuclear retinoid receptor function in RA-induced ERK2 activation. RA reduced the amount of unphosphorylated RAR-alpha, whose activation is necessary for RA-induced differentiation and arrest. This shifted the ratio of phosphorylated:unphosphorylated RAR-alpha to predominantly the phosphorylated form. Unlike other steroid thyroid hormone receptors susceptible to phosphorylation and activation by MAPKs, RAR-alpha was not phosphorylated by the activated ERK2 MAPK. The results thus show that RA augments MEK-dependent ERK2 activation that is needed for subsequent RB hypophosphorylation, cell differentiation, and G0 arrest. The process seems to be nuclear receptor dependent and an early seminal component of RA signaling causing differentiation and growth arrest.


Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation.
Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot-Marie-Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson's and Alzheimer's disease patients, implicating addressable mitochondrial dysdynamism in these illnesses.


Pathogenesis of HIV in the central nervous system.
HIV can infect the brain and impair central nervous system (CNS) function. Combination antiretroviral therapy (cART) has not eradicated CNS complications. HIV-associated neurocognitive disorders (HAND) remain common despite cART, although attenuated in severity. This may result from a combination of factors including inadequate treatment of HIV reservoirs such as circulating monocytes and glia, decreased effectiveness of cART in CNS, concurrent illnesses, stimulant use, and factors associated with prescribed drugs, including antiretrovirals. This review highlights recent investigations of HIV-related CNS injury with emphasis on cART-era neuropathological mechanisms in the context of both US and international settings.


A Three-Locus, PCR-based Method for Forensic Identification of Plant Material.
Plant residue is currently an underutilized resource in forensic investigations despite the fact that many crime scenes, as well as suspects and victims, harbor plant-derived residue that could be recovered and analyzed. Notwithstanding the considerable skill of forensic botanists, current methods of species determination could benefit from tools for DNA-based species identification. However, DNA barcoding in plants has been hampered by sequence complications in the plant genome. Following a database search for usable barcodes, broad-spectrum primers were designed and utilized to amplify and sequence the rbcL, trnL-F, and rrn18 genetic loci from a variety of household plants. Once obtained, these DNA sequences were used to design species-targeted primers that could successfully discriminate the source of plant residue from among the 21 species tested.


Enantioselective Catalysis with Pyrrolidinyl Gold(I) Complexes: DFT and NEST Analysis of the Chiral Binding Pocket.
A new generation of chiral gold(I) catalysts based on variations of complexes with JohnPhos-type ligands with a remote C2-symmetric 2,5-diarylpyrrolidine have been synthesized with different substitutions at the top and bottom aryl rings: from replacing the phosphine by a N-heterocyclic carbene (NHC) to increasing the steric hindrance with bis- or tris-biphenylphosphine scaffolds, or by directly attaching the C2-chiral pyrrolidine in the ortho-position of the dialkylphenyl phosphine. The new chiral gold(I) catalysts have been tested in the intramolecular [4+2] cycloaddition of arylalkynes with alkenes and in the atroposelective synthesis of 2-arylindoles. Interestingly, simpler catalysts with the C2-chiral pyrrolidine in the ortho-position of the dialkylphenyl phosphine led to the formation of opposite enantiomers. The chiral binding pockets of the new catalysts have been analyzed by DFT calculations. As revealed by non-covalent interaction plots, attractive non-covalent interactions between substrates and catalysts direct specific enantioselective folding. Furthermore, we have introduced the open-source tool NEST, specifically designed to account for steric effects in cylindrical-shaped complexes, which allows predicting experimental enantioselectivities in our systems.


Density Dependence Influences the Efficacy of Wastewater Remediation by Lemna minor.
As part of a circular economy (CE) approach to food production systems, Lemnaceae, i.e., duckweed species, can be used to remediate wastewater due to rapid nutrient assimilation and tolerance of non-optimal growing conditions. Further, given rapid growth rates and high protein content, duckweed species are a valuable biomass. An important consideration for duckweed-mediated remediation is the density at which the plants grow on the surface of the wastewater, i.e., how much of the surface of the medium they cover. Higher duckweed density is known to have a negative effect on duckweed growth, which has implications for the development of duckweed-based remediation systems. In the present study, the effects of density (10-80% plant surface coverage) on Lemna minor growth, chlorophyll fluorescence and nutrient remediation of synthetic dairy processing wastewater were assessed in stationary (100 mL) and re-circulating non-axenic (11.7 L) remediation systems. Overall, L. minor growth, and TN and TP removal rates decreased as density increased. However, in the stationary system, absolute TN and TP removal were greater at higher densities (50-80% coverage). The exact cause of density related growth reduction in duckweed is unclear, especially at densities well below 100% surface coverage. A further experiment comparing duckweed grown at 'low' and 'high' density conditions with the same biomass and media volume conditions, showed that photosynthetic yield, Y(II), is reduced at high density despite the same nutrient availability at both densities, and arguably similar shading. The results demonstrate a negative effect of high density on duckweed growth and nutrient uptake, and point towards signals from neighbouring duckweed colonies as the possible cause.


Different dose regimes and administration methods of tranexamic acid in cardiac surgery: a meta-analysis of randomized trials.
The efficacy of tranexamic acid (TXA) to reduce perioperative blood loss and allogeneic blood transfusion in cardiac surgeries has been proved in previous studies, but its adverse effects especially seizure has always been a problem of concern. This meta-analysis aims to provide information on the optimal dosage and delivery method which is effective with the least adverse outcomes. We searched Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE for all relevant articles published before 2018/12/31. Inclusion criteria were adult patients undergoing elective heart surgeries, and only randomized control trials comparing TXA with placebo were considered. Two authors independently assessed trial quality and extracted relevant data. We included 49 studies with 10,591 patients into analysis. TXA significantly reduced transfusion rate (RR 0.71, 95% CI 0.65 to 0.78, P<0.00001). The overall transfusion rate was 35%(1573/4477) for patients using TXA and 49%(2190/4408) for patients in the control group. Peri-operative blood loss (MD - 246.98 ml, 95% CI - 287.89 to - 206.06 ml, P<0.00001) and re-operation rate (RR 0.62, 95% CI 0.49 to 0.79, P<0.0001) were also reduced significantly. TXA usage did not increase risk of mortality, myocardial infarction, stroke, pulmonary embolism and renal dysfunction, but was associated with a significantly increase in seizure attack (RR 3.21, 95% CI 1.04 to 9.90, P = 0.04).The overall rate of seizure attack was 0.62%(21/3378) for patients using TXA and 0.15%(5/3406) for patients in the control group. In subgroup analysis, TXA was effective for both on-pump and off-pump surgeries. Topical application didn't reduce the need for transfusion requirement, while intravenous delivery no matter as bolus injection alone or bolus plus continuous infusion were effective. Intravenous high-dose TXA didn't further decrease transfusion rate compared with low-dose regimen, and increased the risk of seizure by 4.83 times. No patients in the low-dose group had seizure attack. TXA was effective in reducing transfusion requirement in all kinds of cardiac surgeries. Low-dose intravenous infusion was the most preferable delivery method which was as effective as high-dose regimen in reducing transfusion rate without increasing the risk of seizure.


The lcrE gene is part of an operon in the lcr region of Yersinia enterocolitica O:3.
The low-calcium response (lcr) region of the virulence plasmid of Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica has been associated with calcium-dependent growth of bacteria. Mutations in the previously identified lcrE locus within the lcr region lack the repressor control of production of the lcr specific proteins, Yersinia outer membrane proteins (Yops) and V and W antigens. We sequenced a 3.3-kilobase-pair BamHI-ClaI fragment of the lcrE locus of pYVO3, the virulence plasmid of Y. enterocolitica O:3. The sequence of lcrE locus revealed six tightly packed open reading frames (ORFs), one of which was identified as the structural gene, lcrE, of the 32.9-kilodalton outer membrane protein LcrE (formerly known as Yop4b or YopN). Detection of large (greater than 2.3-kilobase-pair) transcripts strongly supports the conclusion that the lcrE gene and ORF1 to -5 function as an operon. Transcription of the lcrE-containing operon and the adjacent lcrB locus was found to be divergent, and the corresponding transcripts overlapped about 1,200 nucleotides. This extremely long overlap of the 5' ends of the transcripts produced from face-to-face promoters is a new finding; the longest overlap thus far found has been a few hundred nucleotides. Temperature was found to play the major role in regulation of transcription of the lcrE-containing operon of pYVO3, whereas Ca2+ concentration seemed to affect it only moderately.


Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease.
The genetic risk architecture of Alzheimer disease (AD) is complex with single pathogenic mutations leading to early-onset AD, while both rare and common genetic susceptibility variants contribute to the more widespread late-onset AD (LOAD); we sought to discover novel genes contributing to LOAD risk. Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOAD. Variants of interest were then evaluated in a large cohort of LOAD cases and aged controls. We detected a single rare, nonsynonymous variant shared in all 11 LOAD individuals, a missense change in the tetratricopeptide repeat domain 3 (TTC3) gene. The missense variant, rs377155188 (p.S1038C), is predicted to be damaging. Affecteds-only multipoint linkage analysis demonstrated that this region of TTC3 has a LOD score of 2.66 in this family. The TTC3 p.S1038C substitution may represent a segregating, rare LOAD risk variant. Previous studies have shown that TTC3 expression is consistently reduced in LOAD patients and negatively correlated with AD neuropathology and that TTC3 is a regulator of Akt signaling, a key pathway disrupted in LOAD. This study demonstrates how utilizing whole-exome sequencing in a large, multigenerational family with a high incidence of LOAD could reveal a novel candidate gene.


The Pain Anxiety Symptom Scale: Initial Development and Evaluation of 4 and 8 Item Short Forms.
Elevated levels of anxiety in relation to chronic pain have been consistently associated with greater distress and disability. Thus, accurate measurement of pain-related anxiety is an important requirement in modern pain services. The Pain Anxiety Symptom Scale (PASS) was introduced over 30 years ago, with a shortened 20-item version introduced 10 years later. Both versions of the PASS were derived using Principal Components Analysis, an established method of measure development with roots in classical test theory. Item Response Theory (IRT) is a complementary approach to measure development that can reduce the number of items needed and maximize item utility with minimal loss of statistical and clinical information. The present study used IRT to shorten the 20-item PASS (PASS-20) in a large sample of people with chronic pain (N = 2,669). Two shortened versions were evaluated, 1 composed of the single best-performing item from each of its 4 subscales (PASS-4) and the other with the 2 best-performing items from each subscale (PASS-8). Several supplementary analyses were performed, including comparative item convergence evaluations based on sample characteristics (ie, female or male sex; clinical or online sample), factor invariance testing, and criterion validity evaluation of the 4, 8, and 20-item versions of the PASS in hierarchical regression models predicting pain-related distress and interference. Overall, both shortened PASS versions performed adequately across these supplemental tests, although the PASS-4 had more consistent item convergence between samples, stronger evidence for factor invariance, and accounted for 83% of the variance accounted for by the PASS-20% and 92% of the variance accounted for by the PASS-8 in criterion variables. Consequently, the PASS-4 is recommended for use in situations where a briefer evaluation of pain-related anxiety is appropriate. PERSPECTIVE: The Pain Anxiety Symptom Scale (PASS) is an established measure of pain-related fear. This study derived 4 and 8-item versions of the PASS using IRT. Both versions showed strong psychometric properties, stability of factor structure, and relation to important aspects of pain-related functioning.


[Analysis of 39 cases of maternal deaths caused by incorrect use of oxytocin].
Thirty-nine cases of maternal deaths directly caused by incorrect use of oxytocin in Fujian Province from 1986 to 1992 were analysed. The results showed that 90.00% of these deaths occurred in the rural and mountainous areas. The main reason was the ignorance of the birth attendents on the pros and cons of oxytocin administration and therefore the incorrect use. The causes of maternal deaths were ranged in the following order: uterine rupture, soft tissue injury of the birth canal and amniotic fluid embolism. All were emergent deaths with 79.49% dying in intrapartum period or within four hours after delivery and 28.20% at patients' home or on their way to hospital.


Scorpionfish BPI is highly active against multiple drug-resistant Pseudomonas aeruginosa isolates from people with cystic fibrosis.
Chronic pulmonary infection is a hallmark of cystic fibrosis (CF) and requires continuous antibiotic treatment. In this context, Pseudomonas aeruginosa (Pa) is of special concern since colonizing strains frequently acquire multiple drug resistance (MDR). Bactericidal/permeability-increasing protein (BPI) is a neutrophil-derived, endogenous protein with high bactericidal potency against Gram-negative bacteria. However, a significant range of people with CF (PwCF) produce anti-neutrophil cytoplasmic antibodies against BPI (BPI-ANCA), thereby neutralizing its bactericidal function. In accordance with literature, we describe that 51.0% of a total of 39 PwCF expressed BPI-ANCA. Importantly, an orthologous protein to human BPI (huBPI) derived from the scorpionfish Sebastes schlegelii (scoBPI) completely escaped recognition by these autoantibodies. Moreover, scoBPI exhibited high anti-inflammatory potency towards Pa LPS and was bactericidal against MDR Pa derived from PwCF at nanomolar concentrations. In conclusion, our results highlight the potential of highly active orthologous proteins of huBPI in treatment of MDR Pa infections, especially in the presence of BPI-ANCA.


Tuberculosis in Texas: trends and issues in surveillance.
This study examined, risk factors and trends related to tuberculosis (TB) in Texas from 1987 through 1993. We found a significantly greater incidence of TB among racial/ethnic minorities than among whites. Country of origin, group risk, individual risk, and occupational risk were investigated also. The percentage of affected persons born in either Mexico or Vietnam increased throughout the time of the study. The state-level percentage trends of the individual risk group (alcohol and/or drug abuse) mirrored those of the national level. The most striking observation, however, proved to be the poor quality of data. Drastic yearly differences existed in completion of the "country of origin" field. The fields for "individual risk," "group risk," and "occupational risk" showed completion rates of less than 50%; completeness continued to be a problem in 1997. The poor quality of data diminishes the validity of conclusions about trends in TB in Texas. Recommendations for improving the quality of data are noted.


Phytoplasma infection in tomato is associated with re-organization of plasma membrane, ER stacks, and actin filaments in sieve elements.
Phytoplasmas, biotrophic wall-less prokaryotes, only reside in sieve elements of their host plants. The essentials of the intimate interaction between phytoplasmas and their hosts are poorly understood, which calls for research on potential ultrastructural modifications. We investigated modifications of the sieve-element ultrastructure induced in tomato plants by 'Candidatus Phytoplasma solani,' the pathogen associated with the stolbur disease. Phytoplasma infection induces a drastic re-organization of sieve-element substructures including changes in plasma membrane surface and distortion of the sieve-element reticulum. Observations of healthy and stolbur-diseased plants provided evidence for the emergence of structural links between sieve-element plasma membrane and phytoplasmas. One-sided actin aggregates on the phytoplasma surface also inferred a connection between phytoplasma and sieve-element cytoskeleton. Actin filaments displaced from the sieve-element mictoplasm to the surface of the phytoplasmas in infected sieve elements. Western blot analysis revealed a decrease of actin and an increase of ER-resident chaperone luminal binding protein (BiP) in midribs of phytoplasma-infected plants. Collectively, the studies provided novel insights into ultrastructural responses of host sieve elements to phloem-restricted prokaryotes.


Analysis of membrane-enriched and high molecular weight proteins in Leishmania infantum promastigotes and axenic amastigotes.
Membrane and high molecular weight (HMW) proteins tend to be underrepresented in proteome analyses. Here, we optimized a protocol designed for the extraction and purification of membranes from the protozoan parasite Leishmania using a combination of serial centrifugation and free-flow zone electrophoresis (ZE-FFE). We also enriched for Leishmania HMW proteins from total extracts using the Gelfree 8100 fractionation system. This allowed the study of expression of both membrane-enriched and HMW proteins in Leishmania infantum promastigotes and amastigotes. We identified 194 proteins with at least one transmembrane domain (TMD) and 171 HMW proteins (≥100 kDa) in the invertebrate promastigote stage and 66 proteins with at least one TMD and 154 HMW proteins in the mammalian amastigote stage. Several of the proteins identified in one of the stages are part of pathways consistent with the known biology of the parasite, with many proteins involved in lipid synthesis, numerous dynein heavy chains, and some surface antigen proteins 2 detected in the promastigote stage. Notably, some proteins involved in transport and proteolysis were detected either in promastigote or amastigote. The present study is using improved proteomic methods for studying membrane-enriched and HMW proteins helping to achieve a better understanding of the parasite life cycle.


Free Transplantation of a Tissue Engineered Bone Graft into an Irradiated, Critical-Size Femoral Defect in Rats.
Healing of large bone defects remains a challenge in reconstructive surgery, especially with impaired healing potential due to severe trauma, infection or irradiation. In vivo studies are often performed in healthy animals, which might not accurately reflect the situation in clinical cases. In the present study, we successfully combined a critical-sized femoral defect model with an ionizing radiation protocol in rats. To support bone healing, tissue-engineered constructs were transferred into the defect after ectopic preossification and prevascularization. The combination of SiHA, MSCs and BMP-2 resulted in the significant ectopic formation of bone tissue, which can easily be transferred by means of our custom-made titanium chamber. Implanted osteogenic MSCs survived in vivo for a total of 18 weeks. The use of SiHA alone did not lead to bone formation after ectopic implantation. Analysis of gene expression showed early osteoblast differentiation and a hypoxic and inflammatory environment in implanted constructs. Irradiation led to impaired bone healing, decreased vascularization and lower short-term survival of implanted cells. We conclude that our model is highly valuable for the investigation of bone healing and tissue engineering in pre-damaged tissue and that healing of bone defects can be substantially supported by combining SiHA, MSCs and BMP-2.


JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.
JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.


Interpretable many-class decoding for MEG.
Multivariate pattern analysis (MVPA) of Magnetoencephalography (MEG) and Electroencephalography (EEG) data is a valuable tool for understanding how the brain represents and discriminates between different stimuli. Identifying the spatial and temporal signatures of stimuli is typically a crucial output of these analyses. Such analyses are mainly performed using linear, pairwise, sliding window decoding models. These allow for relative ease of interpretation, e.g. by estimating a time-course of decoding accuracy, but have limited decoding performance. On the other hand, full epoch multiclass decoding models, commonly used for brain-computer interface (BCI) applications, can provide better decoding performance. However interpretation methods for such models have been designed with a low number of classes in mind. In this paper, we propose an approach that combines a multiclass, full epoch decoding model with supervised dimensionality reduction, while still being able to reveal the contributions of spatiotemporal and spectral features using permutation feature importance. Crucially, we introduce a way of doing supervised dimensionality reduction of input features within a neural network optimised for the classification task, improving performance substantially. We demonstrate the approach on 3 different many-class task-MEG datasets using image presentations. Our results demonstrate that this approach consistently achieves higher accuracy than the peak accuracy of a sliding window decoder while estimating the relevant spatiotemporal features in the MEG signal.


Impact of Patient Portal Use on Duplicate Laboratory Tests in Diabetes Management.
Background: Patients seek care across multiple health care settings. One coordination issue is the unnecessary duplication of laboratory across different health care settings. This analysis examined the association between patient portal use and duplication of laboratory testing among Veterans who are dual users of Veterans Affairs (VA) and non-VA providers. Materials and Methods: A national sample of Veterans who were newly authenticated users of the portal during fiscal year (FY) 2013 who used Blue Button at least once were compared with a random sample of Veterans who were not registered to use the portal. From these two groups, Veterans who were also Medicare-eligible users in FY2014 were identified. Duplicate testing was defined as receipt of more than five HbA1c (hemoglobin A1c) in 1 year. Results: Use of the Blue Button decreased the odds of duplicate HbA1c testing in VA and Medicare-covered facilities across three comparisons: (1) overall between users and nonusers: portal users were less likely to have duplicate testing; (2) pre-post comparison: there was a trend toward lower duplicate testing in both groups across time; and (3) pre-post comparisons accounting for use of the portal: the trend toward lower duplicate testing was greater in Blue Button users. Conclusion: Duplicate HbA1c testing was significantly lower in dual users of VA and Medicare services who used the Blue Button feature of their VA patient portal. Non-VA providers encounter barriers to access of complete information about Veterans who also use VA health care. Provider endorsement of consumer-mediated health information exchange could help further this model of sharing information.


The Role of the Equine Herpesvirus Type 1 (EHV-1) US3-Encoded Protein Kinase in Actin Reorganization and Nuclear Egress.
The serine-threonine protein kinase encoded by US3 gene (pUS3) of alphaherpesviruses was shown to modulate actin reorganization, cell-to-cell spread, and virus egress in a number of virus species. However, the role of the US3 orthologues of equine herpesvirus type 1 and 4 (EHV-1 and EHV-4) has not yet been studied. Here, we show that US3 is not essential for virus replication in vitro. However, growth rates and plaque diameters of a US3-deleted EHV-1 and a mutant in which the catalytic active site was destroyed were significantly reduced when compared with parental and revertant viruses or a virus in which EHV-1 US3 was replaced with the corresponding EHV-4 gene. The reduced plaque sizes were consistent with accumulation of primarily enveloped virions in the perinuclear space of the US3-negative EHV-1, a phenotype that was also rescued by the EHV-4 orthologue. Furthermore, actin stress fiber disassembly was significantly more pronounced in cells infected with parental EHV-1, revertant, or the recombinant EHV-1 expressing EHV-4 US3. Finally, we observed that deletion of US3 in EHV-1 did not affect the expression of adhesion molecules on the surface of infected cells.


Patterns in hydraulic architecture from roots to branches in six tropical tree species from cacao agroforestry and their relation to wood density and stem growth.
For decades it has been assumed that the largest vessels are generally found in roots and that vessel size and corresponding sapwood area-specific hydraulic conductivity are acropetally decreasing toward the distal twigs. However, recent studies from the perhumid tropics revealed a hump-shaped vessel size distribution. Worldwide tropical perhumid forests are extensively replaced by agroforestry systems often using introduced species of various biogeographical and climatic origins. Nonetheless, it is unknown so far what kind of hydraulic architectural patterns are developed in those agroforestry tree species and which impact this exerts regarding important tree functional traits, such as stem growth, hydraulic efficiency and wood density (WD). We investigated wood anatomical and hydraulic properties of the root, stem and branch wood in Theobroma cacao and five common shade tree species in agroforestry systems on Sulawesi (Indonesia); three of these were strictly perhumid tree species, and the other three tree species are tolerating seasonal drought. The overall goal of our study was to relate these properties to stem growth and other tree functional traits such as foliar nitrogen content and sapwood to leaf area ratio. Our results confirmed a hump-shaped vessel size distribution in nearly all species. Drought-adapted species showed divergent patterns of hydraulic conductivity, vessel density, and relative vessel lumen area between root, stem and branch wood compared to wet forest species. Confirming findings from natural old-growth forests in the same region, WD showed no relationship to specific conductivity. Overall, aboveground growth performance was better predicted by specific hydraulic conductivity than by foliar traits and WD. Our study results suggest that future research on conceptual trade-offs of tree hydraulic architecture should consider biogeographical patterns underlining the importance of anatomical adaptation mechanisms to environment.


Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma.
Vorinostat is a histone deacetylase inhibitor that induces differentiation, growth arrest, and/or apoptosis of malignant cells both in vitro and in vivo and has shown clinical responses in approximately 30% of patients with advanced mycosis fungoides and Sézary syndrome cutaneous T-cell lymphoma (CTCL). The purpose of this study was to identify biomarkers predictive of vorinostat response in CTCL using preclinical model systems and to assess these biomarkers in clinical samples. The signal transducer and activator of transcription (STAT) signaling pathway was evaluated. The data indicate that persistent activation of STAT1, STAT3, and STAT5 correlate with resistance to vorinostat in lymphoma cell lines. Simultaneous treatment with a pan-Janus-activated kinase inhibitor resulted in synergistic antiproliferative effect and down-regulation of the expression of several antiapoptotic genes. Immunohistochemical analysis of STAT1 and phosphorylated tyrosine STAT3 (pSTAT3) in skin biopsies obtained from CTCL patients enrolled in the vorinostat phase IIb trial showed that nuclear accumulation of STAT1 and high levels of nuclear pSTAT3 in malignant T cells correlate with a lack of clinical response. These results suggest that deregulation of STAT activity plays a role in vorinostat resistance in CTCL, and strategies that block this pathway may improve vorinostat response. Furthermore, these findings may be of prognostic value in predicting the response of CTCL patients to vorinostat.


A structural, functional and molecular analysis of plastids of the holoparasites Cuscuta reflexa and Cuscuta europaea.
In the plastids of Cuscuta reflexa the number of thylakoids is strongly reduced compared with true chloroplasts and no typical grana are visible. The plastids of Cuscuta europaea lack thylakoids and the stroma is filled with either starch grains or lipid droplets. In Cuscuta reflexa both chlorophylls are present in low concentrations, while in C. europaea chlorophylls are totally absent. Light slightly stimulates the incorporation of (14)CO2 in C. reflexa. This is in accordance with a low activity of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) which was measured in extracts of this parasite. No stimulation of (14)CO2 incorporation by light was observed in C. europaea. Instead, a relatively strong incorporation was measured in darkness. Malate and aspartate were the main products of this incorporation. In agreement with these results, no Rubisco activity was detected in C. europaea but there was a moderate activity of phosphoenolpyruvate-carboxylase. The presence of the genes for both subunits of Rubisco (rbcL, rbcS) and of the gene which codes for the 32-kDa protein of photosystem II (psbA) was established for C. europaea by hybridization experiments. In both species only very small amounts of transcripts of these genes were detected.


Increased stathmin1 expression in the dentate gyrus of mice causes abnormal axonal arborizations.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in multiple brain functions. To clarify the cause of abnormal behavior in PACAP deficient-mice, we attempted the identification of genes whose expression was altered in the dentate gyrus of PACAP-deficient mice using the differential display method. Expression of stathmin1 was up-regulated in the dentate gyrus at both the mRNA and protein levels. PACAP stimulation inhibited stathmin1 expression in PC12 cells, while increased stathmin1expression in neurons of the subgranular zone and in primary cultured hippocampal neurons induced abnormal arborization of axons. We also investigated the pathways involved in PACAP deficiency. Ascl1 binds to E10 box of the stathmin1 promoter and increases stathmin1 expression. Inhibitory bHLH proteins (Hes1 and Id3) were rapidly up-regulated by PACAP stimulation, and Hes1 could suppress Ascl1 expression and Id3 could inhibit Ascl1 signaling. We also detected an increase of stathmin1 expression in the brains of schizophrenic patients. These results suggest that up-regulation of stathmin1 in the dentate gyrus, secondary to PACAP deficiency, may create abnormal neuronal circuits that cause abnormal behavior.


[Studies of effects of aluminum oxide nanoparticles after intragastric administration].
Growing Wistar rats received intragastrically nanoparticles (NPs) of aluminum oxide (Al2O3) daily during 28 days at doses of 1 or 100 mg per kg body mass. There were studied body mass of animals, relative mass of internals, rate of protein macromolecules absorption in the gut, oxidative damage of DNA, pool of tissue thiols, activity of hepatic enzymes of xenobiotic detoxication system, biochemical and hematological blood indices, stability of lysosome membranes, condition of antioxidant defense system, apoptosis of hepatocytes. Conducted experiments didn't reveal any marked toxic action of Al2O3 NPs on rats after 28 days of administration both in high and low dose. Among effects probably related to NPs influence on animals there were lowering of relative liver and lung masses, decrease of hepatic thiol pool, activity of CYP1A1 isoform in liver and glutathione reductase in erythrocytes, increase of diene conjugates of fatty acids in blood plasma. Said shifts were small in magnitude, didn't come out of margins of physiological norm and didn't show any distinct relation to NPs dose. However considering great importance of this nanomaterial as probable environmental contaminant the studies of it's toxicity must be continued in conditions of low doses (less than 1 mg per kg body mass) for long period of time.