Binding and regulatory properties of phosphofructokinase from swine kidney.
The influence of fructose 2,6-bisphosphate on the activation of purified swine kidney phosphofructokinase as a function of the concentration of fructose 6P, ATP and citrate was investigated. The purified enzyme was nearly completely inhibited in the presence of 2 mM ATP. The addition of 20 nM fructose 2,6-P2 reversed the inhibition and restored more than 80% of the activity. In the absence of fructose 2,6-P2 the reaction showed a sigmoidal dependence on fructose-6-phosphate. The addition of 10 nM fructose 2,6-bisphosphate decreased the K0.5 for fructose 6-phosphate from 3 mM to 0.4 mM in the presence of 1.5 mM ATP. These results clearly show that fructose 2,6-bisphosphate increases the affinity of the enzyme for fructose 6-phosphate and decreases the inhibitory effect of ATP. The extent of inhibition by citrate was also significantly decreased in the presence of fructose 2,6-phosphate. The influence of various effectors of phosphofructokinase on the binding of ATP and fructose 6-P to the enzyme was examined in gel filtration studies. It was found that kidney phosphofructokinase binds 5.6 moles of fructose 6-P per mole of enzyme, which corresponds to about one site per subunit of tetrameric enzyme. The KD for fructose 6-P was 13 microM and in the presence of 0.5 mM ATP it increased to 27 microM. The addition of 0.3 mM citrate also increased the KD for fructose 6-P to about 40 microM. AMP, 10 microM, decreased the KD to 5 microM and the addition of fructose 2,6-phosphate decreased the KD for fructose 6-P to 0.9 microM. The addition of these compounds did not effect the maximal amount of fructose 6-P bound to the enzyme, which indicated that the binding site for these compounds might be near, but was not identical to the fructose 6-P binding site. The enzyme bound a maximum of about 12.5 moles of ATP per mole, which corresponds to 3 moles per subunit. The KD of the site with the highest affinity for ATP was 4 microM, and it increased to 15 microM in the presence of fructose 2,6-bisphosphate. The addition of 50 microM fructose 1,6-bisphosphate increased the KD for ATP to 5.9 microM. AMP increased the KD to 5.9 microM whereas 0.3 mM citrate decreased the KD for ATP to about 2 microM.(ABSTRACT TRUNCATED AT 400 WORDS)


Anti-biofilm activity of pseudoalteromonas haloplanktis tac125 against staphylococcus epidermidis biofilm: Evidence of a signal molecule involvement?
Staphylococcus epidermidis is recognized as cause of biofilm-associated infections and interest in the development of new approaches for S. epidermidis biofilm treatment has increased. In a previous paper we reported that the supernatant of Antarctic bacterium Pseudoalteromonas haloplanktis TAC125 presents an anti-biofilm activity against S. epidermidis and preliminary physico-chemical characterization of the supernatant suggested that this activity is due to a polysaccharide. In this work we further investigated the chemical nature of the anti-biofilm P. haloplanktis TAC125 molecule. The production of the molecule was evaluated in different conditions, and reported data demonstrated that it is produced in all P. haloplanktis TAC125 biofilm growth stages, also in minimal medium and at different temperatures. By using a surface coating assay, the surfactant nature of the anti-biofilm compound was excluded. Moreover, a purification procedure was set up and the analysis of an enriched fraction demonstrated that the anti-biofilm activity is not due to a polysaccharide molecule but that it is due to small hydrophobic molecules that likely work as signal. The enriched fraction was also used to evaluate the effect on S. epidermidis biofilm formation in dynamic condition by BioFlux system.


Age-induced decreases in the messenger RNA coding for the sarcoplasmic reticulum Ca2(+)-ATPase of the rat heart.
Age-associated slowing of cardiac relaxation related to the decline in the Ca2+ pump function of cardiac sarcoplasmic reticulum (SR) has been previously described. It is unclear if the decreased Ca2+ pump function results from a lower amount of Ca2(+)-ATPase protein or a decreased pumping activity of the enzyme. To determine if these alterations could be mediated by changes in the amount of the protein itself, the level of the messenger RNA (mRNA) coding for the Ca2(+)-ATPase of the SR of Fischer rat hearts (4- and 30-month-old rats) were quantitated with a Northern blotting technique. We observed that the levels of SR Ca2(+)-ATPase mRNA were 60% lower in old rats as compared with young rats, suggesting that a quantitative reduction in the levels of the corresponding protein could occur during aging to explain the delayed diastolic relaxation documented in old animals as opposed to a change in the specific activity of this enzyme. The thyroid hormone responsiveness of SR Ca2(+)-ATPase mRNA has been previously established. We have found in this study that the thyroxine levels were consistently lower in old rats; however, this difference was relatively small (4.3 +/- 0.7 and 3.1 +/- 0.8 micrograms/dl [mean +/- SD), respectively, in young and old rats). In addition, no age-induced decrease in 3,5,3'-triiodothyronine levels was observed, suggesting that the aging process itself may be responsible for the changes in SR Ca2(+)-ATPase mRNA levels.


Pacemaker pocket infection rate and suture technique.
The incidence of cardiac implantable electronic device (CIED) infection is usually <2%. The interrupted suture technique is thought to be better than a continuous suture in order to prevent pacemaker pocket infection. The aim of this study was to determine if there was a correlation between the suture techniques and the pacemaker wound infection rate. The data of 2200 patients from the 5-year period of 2011 to 2016 were studied. There were 1096 patients in the study group and 1104 patients in the control group. Continuous sutures were used in the study group and interrupted sutures were used in the control group. Pacemaker pocket infection occurred in 33 patients (1.5%). Seventeen patients in the study group and 16 patients in the control group developed a pacemaker pocket infection. A pacemaker pocket hematoma was seen in 54 patients in the study group (4.9%) and 50 patients in the control group (4.5%). Use of the continuous or interrupted suture technique for wound closure had no significant role in the prevention of pacemaker pocket infection.


Acute exposure to silica nanoparticles enhances mortality and increases lung permeability in a mouse model of Pseudomonas aeruginosa pneumonia.
The lung epithelium constitutes the first barrier against invading pathogens and also a major surface potentially exposed to nanoparticles. In order to ensure and preserve lung epithelial barrier function, the alveolar compartment possesses local defence mechanisms that are able to control bacterial infection. For instance, alveolar macrophages are professional phagocytic cells that engulf bacteria and environmental contaminants (including nanoparticles) and secrete pro-inflammatory cytokines to effectively eliminate the invading bacteria/contaminants. The consequences of nanoparticle exposure in the context of lung infection have not been studied in detail. Previous reports have shown that sequential lung exposure to nanoparticles and bacteria may impair bacterial clearance resulting in increased lung bacterial loads, associated with a reduction in the phagocytic capacity of alveolar macrophages. Here we have studied the consequences of SiO2 nanoparticle exposure on Pseudomonas aeruginosa clearance, Pseudomonas aeruginosa-induced inflammation and lung injury in a mouse model of acute pneumonia. We observed that pre-exposure to SiO2 nanoparticles increased mice susceptibility to lethal pneumonia but did not modify lung clearance of a bioluminescent Pseudomonas aeruginosa strain. Furthermore, internalisation of SiO2 nanoparticles by primary alveolar macrophages did not reduce the capacity of the cells to clear Pseudomonas aeruginosa. In our murine model, SiO2 nanoparticle pre-exposure preferentially enhanced Pseudomonas aeruginosa-induced lung permeability (the latter assessed by the measurement of alveolar albumin and IgM concentrations) rather than contributing to Pseudomonas aeruginosa-induced lung inflammation (as measured by leukocyte recruitment and cytokine concentration in the alveolar compartment). We show that pre-exposure to SiO2 nanoparticles increases mice susceptibility to lethal pneumonia but independently of macrophage phagocytic function. The deleterious effects of SiO2 nanoparticle exposure during Pseudomonas aeruginosa-induced pneumonia are related to alterations of the alveolar-capillary barrier rather than to modulation of the inflammatory responses.


Increased TCR signal strength in DN thymocytes promotes development of gut TCRαβ(+)CD8αα(+) intraepithelial lymphocytes.
CD4(+)CD8(+) "double positive" (DP) thymocytes differentiate into diverse αβ T cell sub-types using mechanistically distinct programs. For example, conventional αβ T cells develop from DP cells after partial-agonist T cell receptor (TCR) interactions with self-peptide/MHC, whereas unconventional αβ T cells, such as TCRαβ(+)CD8αα(+) intraepithelial lymphocytes (IELs), require full-agonist TCR interactions. Despite this, DP cells appear homogeneous, and it remains unclear how distinct TCR signalling instructs distinct developmental outcomes. Moreover, whether TCR signals at earlier stages of development, for example in CD4(-)CD8(-) double negative (DN) cells, impact on later fate decisions is presently unknown. Here, we assess four strains of mice that display altered TCR signal strength in DN cells, which correlates with altered generation of unconventional TCRαβ(+)CD8αα(+) IELs. FVB/n mice (compared to C57BL/6 animals) and mice with altered preTCRα (pTα) expression, both displayed weaker TCR signalling in DN cells, an inefficient DN-to-DP transition, and reduced contribution of TCRαβ(+)CD8αα(+) IELs to gut epithelium. Conversely, TCRαβ(+)CD8αα(+) IEL development was favoured in mice with increased TCR signal strength in DN cells. Collectively, these data suggest TCR signal strength in DN cells directly impacts on subsequent DP cell differentiation, fundamentally altering the potential of thymocyte progenitors to adopt conventional versus unconventional T cell fates.


Improving the management procedures in farms infected with the Porcine Reproductive and Respiratory Syndrome virus using PDP models.
Pig meat production need to be built up in the future due to the increase of the human population worldwide. To address this challenge, there is plenty of room for improvement in terms of pig production efficiency that could be severely hampered by the presence of diseases. In this sense, Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is one of the most costly disease present in industrial pork production in Europe and North America. We have developed a model to analyze the effect of different management procedures to control this important virus in different epidemiological scenarios. Our results clearly suggest that no cross-fostering during lactation and the maintaining of litter integrity significantly decrease the number of sick and dead animals during the rearing period compared to scenarios where cross-fostering and no litter integrity are practiced. These results highlight the relevance of different management strategies to control PRRSV and quantify the effect of limiting cross-fostering and avoiding mixing animals from different litters in PRRSV positive farms to optimize animal production. Our findings will allow pig farmers to apply these management procedures to control this disease under field conditions in a very cost-effective way.


Role of various nanoparticles in photodynamic therapy and detection methods of singlet oxygen.
In this review article we described the applications of various nanoparticles that can be used for photodynamic therapy (PDT), such as: plasmonic nanoparticles, quantum dots and upconversion nanoparticles. In comparison with typical organic photosensitizers such as hematoporphyrins, they exhibit higher photostability and resistance to enzymatic degradation, and hence, in some cases, they could replace organic photosensitizers in PDT therapy. It has also been found that the presence of plasmonic noble metal nanoparticles increases the efficiency of conjugated standard photosensitizers. Therefore, one can expect that, due to their very promising optical properties, plasmonic nanoparticles, plasmonic composites, and upconversion nanoconjugates will have a significant impact on the detection and treatment of cancer in the near future. Various methods of detecting the singlet oxygen produced are also reviewed.


The maximal activity of phosphate-dependent glutaminase and glutamine metabolism in late-pregnant and peak-lactating rats.
The maximal activity of phosphate-dependent glutaminase was increased in the small intestine, decreased in the liver and unchanged in the kidney of late-pregnant rats. This was accompanied by increases in the size of both the small intestine and the liver. The maximal activity of phosphate-dependent glutaminase was increased in both the small intestine and liver but unchanged in the kidney of peak-lactating rats. Enterocytes isolated from late-pregnant or peak-lactating rats exhibited an enhanced rate of utilization of glutamine and production of glutamate, alanine and ammonia. Arteriovenous-difference measurements across the gut showed an increase in the net glutamine removed from the circulation in late-pregnant and peak-lactating rats, which was accompanied by enhanced rates of release of glutamate, alanine and ammonia. Arteriovenous-difference measurements for glutamine showed that both renal uptake and skeletal-muscle release of glutamine were not markedly changed during late pregnancy or peak lactation; but pregnant rats showed a hepatic release of the amino acid. It is concluded that, during late pregnancy and peak lactation, the adaptive changes in glutamine metabolism by the small intestine, kidneys and skeletal muscle of hindlimb are similar; however, the liver appears to release glutamine during late pregnancy, but to utilize glutamine during peak lactation.


Effects of Peer Encouragement on Efficacy Perceptions and Physical Performance in Children.
Social interactions are theorized to inform relation-inferred self-efficacy (RISE), which, in turn, may influence self-efficacy and behavior. This study investigated the effects of peer encouragement on RISE, task self-efficacy, and physical performance. Children (N = 84) were assigned to dyads and randomized to provide peer encouragement to one another or not (control group). Participants completed two endurance handgrip trials, separated by a cognitively demanding task intended to induce mental fatigue and increase the salience of the peer encouragement manipulation. Participants in the experimental group exchanged words of encouragement prior to the second endurance trial, whereas those in the control group did not. The peer encouragement group reported higher RISE and showed increased performance across trials compared with controls. Providing peer encouragement prior to a challenging physical task was associated with more positive RISE perceptions and improved physical performance.


Drinks like a fish: using zebrafish to understand alcoholic liver disease.
Steatosis is the most common consequence of acute alcohol abuse, such as occurs during a drinking binge. Acute alcohol induced steatosis may predispose to more severe hepatic disease. We have developed a model of alcoholic liver disease (ALD) in zebrafish larvae to provide a system in which the genes and pathways that contribute to steatosis can be rapidly identified. Zebrafish larvae represent an attractive vertebrate model for studying acute ALD because they possess the pathways to metabolize alcohol, the liver is mature by 4 days post-fertilization (dpf), and alcohol can be simply added to their water. Exposing 4 dpf zebrafish larvae to 2% ethanol (EtOH) for 32 hours achieves ∼80 mM intracellular EtOH and upregulation of hepatic cyp2e1, sod, and bip, indicating that EtOH is metabolized and provokes oxidative stress. EtOH-treated larvae develop ALD as demonstrated by hepatomegaly and steatosis. Increased lipogenesis driven by the sterol response element binding protein (SREBP) transcription factors is essential for steatosis associated with chronic alcohol ingestion but it has not been determined if the same pathway is essential for steatosis following a drinking binge. We report that several Srebp target genes are induced in the liver of zebrafish exposed to EtOH. We used fish which harbor a mutation in the gene encoding the membrane bound transcription factor protease 1 (mbtps1; also called site-1 protease) and embryos in which the Srebp cleavage activating protein (scap) is knocked down to determine the requirement of this pathway in acute ALD. We find that both means of blocking Srebp activation prevents steatosis in response to 2% EtOH. Moreover, this is accompanied by the failure to activate several Srebp target genes in response to alcohol. We conclude that Srebps are required for steatosis in response to acute alcohol exposure. Moreover, these data highlight the utility of zebrafish as a useful new vertebrate model to study ALD.


Assessment of methods for amino acid matrix selection and their use on empirical data shows that ad hoc assumptions for choice of matrix are not justified.
In recent years, model based approaches such as maximum likelihood have become the methods of choice for constructing phylogenies. A number of authors have shown the importance of using adequate substitution models in order to produce accurate phylogenies. In the past, many empirical models of amino acid substitution have been derived using a variety of different methods and protein datasets. These matrices are normally used as surrogates, rather than deriving the maximum likelihood model from the dataset being examined. With few exceptions, selection between alternative matrices has been carried out in an ad hoc manner. We start by highlighting the potential dangers of arbitrarily choosing protein models by demonstrating an empirical example where a single alignment can produce two topologically different and strongly supported phylogenies using two different arbitrarily-chosen amino acid substitution models. We demonstrate that in simple simulations, statistical methods of model selection are indeed robust and likely to be useful for protein model selection. We have investigated patterns of amino acid substitution among homologous sequences from the three Domains of life and our results show that no single amino acid matrix is optimal for any of the datasets. Perhaps most interestingly, we demonstrate that for two large datasets derived from the proteobacteria and archaea, one of the most favored models in both datasets is a model that was originally derived from retroviral Pol proteins. This demonstrates that choosing protein models based on their source or method of construction may not be appropriate.


Fluctuating asymmetry and psychometric intelligence.
Little is known about the genetic nature of human psychometric intelligence (IQ), but it is widely assumed that IQ's heritability is at loci for intelligence per se. We present evidence consistent with a hypothesis that interindividual IQ differences are partly due to heritable vulnerabilities to environmental sources of developmental stress, an indirect genetic mechanism for the heritability of IQ. Using fluctuating asymmetry (FA) of the body (the asymmetry resulting from errors in the development of normally symmetrical bilateral traits under stressful conditions), we estimated the relative developmental instability of 112 undergraduates and administered to them Cattell's culture fair intelligence test (CFIT). A subsequent replication on 128 students was performed. In both samples, FA correlated negatively and significantly with CFIT scores. We propose two non-mutually exclusive physiological explanations for this correlation. First, external body FA may correlate negatively with the developmental integrity of the brain. Second, individual energy budget allocations and/or low metabolic efficiency in high-FA individuals may lower IQ scores. We review the data on IQ in light of our findings and conclude that improving developmental quality may increase average IQ in future generations.


A comparison of treatment approaches used after carpal tunnel release surgery.
Two treatment approaches used by two hand clinics were compared for patients who had undergone carpal tunnel release surgery. One of the clinics used an exercise program consisting of progressive resistive exercise; the other clinic used limited activity and no specific exercise program. Measurements of grip strength and active and passive wrist flexion and extension were taken 3 weeks and 6 weeks after surgery and then analyzed to determine if significant differences existed between the two treatment approaches. A significant difference was found only in active wrist extension, which increased after 3 weeks of a progressive resistive exercise program. Grip strength was also greater after 3 weeks of exercise; however, the increase was not statistically significant. The study raises a question about the efficacy of postoperative treatment for patients who have had carpal tunnel release surgery.


Results From Colombia's 2016 Report Card on Physical Activity for Children and Youth.
Physical activity (PA) is vital to the holistic development of young people. Regular participation in PA is associated with substantial benefits for health, cognitive function, and social inclusion. Recognizing the potential of PA in the context of the current peace process in Colombia, the purpose of this article is to present the methodology and results of Colombia's second Report Card on PA for children and youth. A group of experts on PA graded 14 PA indicators based on data from national surveys and policy documents. National and departmental policy indicators received a grade of B, while organized sport participation, overweight, obesity, community influence, and nongovernment initiatives indicators received a grade of C. Overall PA levels, active transportation, sedentary behaviors, and school influence received a grade of D. Active play, low physical fitness, and family influence received an Incomplete grade. PA levels are low and sedentary behaviors are high in Colombian children and youth, with notable geographic differences. A broad policy framework translated into specific actions could provide unique opportunities to bridge the gap between knowledge and practice, and contribute to social integration goals in a postconflict setting.


Prostate-specific antigen testing in Ontario: reasons for testing patients without diagnosed prostate cancer.
The use of the prostate-specific antigen (PSA) test has been increasing rapidly in Canada since its introduction in 1988. The reasons for using the PSA test in patients without known prostate cancer are unclear. This paper reports on the first study in Canada to use physician records to assess the use of PSA testing. A questionnaire was mailed to physicians attending 475 patients without diagnosed prostate cancer. The patients were randomly selected from 2 laboratory databases of PSA test records in the greater Toronto area during 1995. The physicians were asked to consult their patient records to avoid recall bias. Information obtained included physician's specialty, patient's age at time of PSA test and reason(s) for the test. There were 264 responses (56%), of which 240 (91%) were usable. Of these 240, 63% (95% confidence interval [Cl] 58%-70%) indicated that the test was conducted to screen for prostate cancer, 40% (95% Cl 34%-47%) said it was to investigate urinary symptoms, and 33% (95% Cl 27%-40%) responded that it was a follow-up to a medical procedure or drug therapy. More than one reason was permitted. Of 151 responses indicating screening as one reason for testing, 64% (95% Cl 56%-72%) stated that it was initiated by the patient, and 73% (95% Cl 65%-80%) stated that it was part of a routine examination. For 19%, both investigation of symptoms and screening asymptomatic patients were given as reasons for testing, and for another 19% both follow-up of a medical procedure and screening were given as reasons. Screening was recorded as a reason for testing far more commonly for patients seen by family physicians and general practitioners than for patients seen by urologists (67% v. 29%, p < 0.001). In contrast, the use of PSA testing to diagnose urinary symptoms was more common for patients seen by urologists than for those seen by family physicians and general practitioners (52% v. 37%, p = 0.044). No significant difference was found between physician groups in the use of PSA testing as a follow-up of a medical procedure (42% for urologists and 31% for family physicians and general practitioners). About 24% of the PSA test records were for patients younger than 50 and older than 70 years. PSA testing initiated by patients was more common in the practices of family physicians and general practitioners than in the practices of urologists (44% v. 13%, p < 0.001). Screening for prostate cancer was the most common reason for PSA testing in our study group; it occurred most commonly in the family and general practice setting and was usually initiated by the patient. Differences in reasons for testing were identified by practice specialty. Although PSA screening for prostate cancer is sometimes recommended for men between 50 and 70 years of age, it is being conducted in men outside this age group.


Rate-dependent interface capture beyond the coffee-ring effect.
The mechanism of droplet drying is a widely concerned fundamental issue since controlling the deposition morphology of droplet has significant influence on printing, biology pattern, self-assembling and other solution-based devices fabrication. Here we reveal a striking different kinetics-controlled deposition regime beyond the ubiquitous coffee-ring effect that suspended particles tend to kinetically accumulate at the air-liquid interface and deposit uniformly. As the interface shrinkage rate exceeds the particle average diffusion rate, particles in vertical evaporation flow will be captured by the descending surface, producing surface particle jam and forming viscous quasi-solid layer, which dramatically prevents the trapped particles from being transported to drop edge and results in uniform deposition. This simple, robust drying regime will provide a versatile strategy to control the droplet deposition morphology, and a novel direction of interface assembling for fabricating superlattices and high quality photonic crystal patterns.


Reduced leukemogenicity caused by mutations in the membrane glycoprotein gene of Rauscher spleen focus-forming virus.
We isolated and characterized two spontaneous, weakly leukemogenic mutants of Rauscher spleen focus-forming virus (R-SFFV) that contain mutations in nonoverlapping regions of the membrane envelope (env) glycoprotein gene. As reported previously (M. Ruta and D. Kabat, J. Virol. 35:844-853, 1980), the replication-defective R-SFFV encodes a membrane glycoprotein with an apparent Mr of 54,000 (gp54) which is structurally and immunologically related to the membrane envelope glycoproteins of dual-tropic murine leukemia viruses. Mutant R-SFFV clones 3-25 and 4-3 encode abnormally sized gp54-related glycoproteins with apparent Mrs of 52,000 (gp52) and 45,000 (gp45), respectively. Northern and Southern blot analyses of the mutant R-SFFV nucleic acids indicated that an insertion has occurred in the 3-25 env gene and that a deletion has occurred in the 4-3 env gene. Furthermore, restriction endonuclease analyses and comparisons of the fragmentation patterns of the wild-type and mutant glycoproteins generated by partial proteolysis with Staphylococcus aureus V8 protease indicated that the mutations affect nonoverlapping domains of the envelope glycoprotein (amino-terminal fragment affected in 3-25 glycoprotein and carboxyl-terminal fragment affected in 4-3 glycoprotein). Glycosylation inhibition studies indicated that the reduced size of gp52 is caused at least partly by loss of an asparagine-linked oligosaccharide. In addition, these mutant viruses have dramatically reduced leukemogenicities compared with wild-type R-SFFV. We conclude that the gp54 structural gene is required for initiation or amplification of the splenic erythroblast hyperplasia which characterizes the preleukemic phase of Rauscher disease.


Paper-Based Magneto-Resistive Sensor: Modeling, Fabrication, Characterization, and Application.
In this work, we developed and fabricated a paper-based anisotropic magneto-resistive sensor using a sputtered permalloy (Ni 81 Fe 19 ) thin film. To interpret the characteristics of the sensor, we proposed a computational model to capture the influence of the stochastic fiber network of the paper surface and to explain the physics behind the empirically observed difference in paper-based anisotropic magneto-resistance (AMR). Using the model, we verified two main empirical observations: (1) The stochastic fiber network of the paper substrate induces a shift of 45 ∘ in the AMR response of the paper-based Ni 81 Fe 19 thin film compared to a Ni 81 Fe 19 film on a smooth surface as long as the fibrous topography has not become buried. (2) The ratio of magnitudes of AMR peaks at different anisotropy angles and the inverted AMR peak at the 90 ∘ -anisotropy angle are explained through the superposition of the responses of Ni 81 Fe 19 inheriting the fibrous topography and smoother Ni 81 Fe 19 on buried fibrous topographies. As for the sensitivity and reproducibility of the sensor signal, we obtained a maximum AMR peak of 0 . 4 % , min-max sensitivity range of [ 0 . 17 , 0 . 26 ] % , average asymmetry of peak location of 2 . 7 kA m within two consecutive magnetic loading cycles, and a deviation of 250⁻850 A m of peak location across several anisotropy angles at a base resistance of ∼100 Ω . Last, we demonstrated the usability of the sensor in two educational application examples: a textbook clicker and interactive braille flashcards.


Ultra structural evidence of axonal regeneration following intracranial transection of optic nerve.
The present work was aimed at studying the ultra structural changes of the proximal (retinal) stump of the intracranially transected optic nerve of the rat for any possible regenerative ability. Specimens were collected one (1 wpo) and four weeks(4 wpo) after the transection and the cross sections of the stumps were studied by electron microscopy by dividing them into three zones, (1) the central zone, (2) the intermediate zone, and (3) the peripheral zone. The present results showed evident morphological changes in these zones both in the 1 wpo and 4 wpo groups. The signs of degeneration were more marked in the central zone than in the peripheral zone and they were more prominent in the 1 wpo group than in the 4 wpo group. The most prominent sign of the degeneration was loss or lack of the healthy myelinated axons. The main evidence of the regenerative ability was the reappearance of the apparently healthy myelinated axonal profiles, with a parallel decrease of the non myelinated ones. This regenerative feature was more prominent peripherally and might be an indication that ischemia was the cause of optic nerve degeneration. The present work revealed a clear morphological evidence of the regenerative capability of the intracranially transected optic nerve though it is considered as a part of the CNS.


De-implementation of inappropriately tight control (of hypoglycemia) for health: protocol with an example of a research grant application.
Implementation of practice change is difficult and large scale implementation is particularly difficult. Among the challenges facing the healthcare system in general and healthcare organizations is the overuse of low value care. Improving medication safety also constitutes an attempt to reduce low value or potentially harmful care. Critical issues of overuse of low value practices and medication safety intersect in overtreatment of diabetes. Specifically, (over)intensive glycemic control increases hypoglycemia risk and morbidity without providing meaningful benefit. Our work indicates that among patients with diabetes who are at high risk for hypoglycemia, potential overtreatment is common. The Choosing Wisely Initiative to reduce low value care led by the American Board of Internal Medicine Foundation recommends not to treat most persons over 65 years of age with medications to reduce the A1c<7.5%. For most physicians this involves a change in practice. We will study the implementation of the Veterans Health Administration's Choosing Wisely Initiative (which includes hypoglycemic safety as a targeted condition) with three specific aims: (1) to assess the overall impact, both intended and unintended, of the Choosing Wisely Initiative to reduce overtreatment of diabetes in especially vulnerable populations; (2) to assess the impact of commitment to quality, teaching intensity, and safety culture on likelihood of overtreatment; and (3) to identify configurations of the implementation strategy, provider characteristics and organizational level factors that are associated with successful reduction of overtreatment rates by comparing high and low performers. Because focus on this initiative could have the unintended consequence of paying less attention to poor glycemic control (A1c>9%), we will also assess undertreatment. We will take advantage of a natural experiment and use a Type III Hybrid Design that focuses on study of implementation while at the same time observing and gathering information on clinical interventions and outcomes. This mixed methods study will use longitudinal data and qualitative methods including Qualitative Comparative Analyses. Our multi-paradigm approach to examining potential mechanisms to explain the variation in reduction of rates of overtreatment will contribute to a better understanding of implementation of national dissemination projects and multi-component interventions in complex systems.


The Impact of Human Immunodeficiency Virus Infection on Gut Microbiota α-Diversity: An Individual-level Meta-analysis.
Whether human immunodeficiency virus (HIV) infection impacts gut microbial α-diversity is controversial. We reanalyzed raw 16S ribosomal RNA (rRNA) gene sequences and metadata from published studies to examine α-diversity measures between HIV-uninfected (HIV-) and HIV-infected (HIV+) individuals. We conducted a systematic review and individual level meta-analysis by searching Embase, Medline, and Scopus for original research studies (inception to 31 December 2017). Included studies reported 16S rRNA gene sequences of fecal samples from HIV+ patients. Raw sequence reads and metadata were obtained from public databases or from study authors. Raw reads were processed through standardized pipelines with use of a high-resolution taxonomic classifier. The χ2 test, paired t tests, and generalized linear mixed models were used to relate α-diversity measures and clinical metadata. Twenty-two studies were identified with 17 datasets available for analysis, yielding 1032 samples (311 HIV-, 721 HIV+). HIV status was associated with a decrease in measures of α-diversity (P < .001). However, in stratified analysis, HIV status was associated with decreased α-diversity only in women and in men who have sex with women (MSW) but not in men who have sex with men (MSM). In analyses limited to women and MSW, controlling for HIV status, women displayed increased α-diversity compared with MSW. Our study suggests that HIV status, sexual risk category, and gender impact gut microbial community α-diversity. Future studies should consider MSM status in gut microbiome analyses.


NKp44 receptor mediates interaction of the envelope glycoproteins from the West Nile and dengue viruses with NK cells.
Dengue virus (DV) and West Nile virus (WNV) have become a global concern due to their widespread distribution and their ability to cause a variety of human diseases. Antiviral immune defenses involve NK cells. In the present study, we investigated the interaction between NK cells and these two flaviviruses. We show that the NK-activating receptor NKp44 is involved in virally mediated NK activation through direct interaction with the flavivirus envelope protein. Recombinant NKp44 directly binds to purified DV and WNV envelope proteins and specifically to domain III of WNV envelope protein; it also binds to WNV virus-like particles. These WNV-virus-like particles and WNV-domain III of WNV envelope protein directly bind NK cells expressing high levels of NKp44. Functionally, interaction of NK cells with infective and inactivated WNV results in NKp44-mediated NK degranulation. Finally, WNV infection of cells results in increased binding of rNKp44 that is specifically inhibited by anti-WNV serum. WNV-infected target cells induce IFN-gamma secretion and augmented lysis by NKp44-expressing primary NK cells that are blocked by anti-NKp44 Abs. Our findings show that triggering of NK cells by flavivirus is mediated by interaction of NKp44 with the flavivirus envelope protein.


Study on the mechanism causing elevation of serum CA19-9 levels in diabetic patients.
Serum CA19-9 levels are often elevated in diabetic patients. To elucidate this mechanism, we investigated the metabolism of CA19-9 in diabetic patients without obvious cancer. Study 1 included 119 patients in whom HbA1c, glycated albumin (GA) and CA19-9 were measured at the time of hospital admission. Study 2 examined 6 patients with markedly elevated CA19-9 levels (≥100 U/mL). Their half-lives for HbA1c, GA, and serum CA19-9 were calculated using the data before and after diabetes treatment. Three diabetic patients with pancreatic cancer were also examined as controls. In Study 1, serum CA19-9 (logarithmically transformed value) was significantly correlated with fasting plasma glucose (FPG), HbA1c and GA. On multivariate analysis, GA and FPG, but not HbA1c, were significant explanatory variables for serum CA19-9. In Study 2, serum CA19-9 decreased together with HbA1c and GA after diabetes treatment. The calculated half-lives for HbA1c, GA, and serum CA19-9 were 33.8 days, 16.1 days, and 10.9 days, respectively. The half-life of serum CA19-9 was longer in the study patients than that reported in patients with malignant tumors. By contrast, in the diabetic patients with pancreatic cancer serum CA19-9 showed a marginal decrease after diabetes treatment. Taken all together, prolonged half-life of serum CA19-9 may contribute to the increase in serum CA19-9 levels in diabetic patients without obvious cancer.


Effect of vitamin C supplementation on lipid profile, serum uric acid, and ascorbic acid in children on hemodialysis.
Children with end-stage renal disease (ESRD) suffer from dyslipidemia and hyperuricemia that might play a causal role in the progression of cardiovascular disease (CVD). The aim of the study is to assess the effects of Vitamin C supplementation on uric acid, ascorbic acid, and serum lipid levels among children on hemodialysis (HD). This prospective study was conducted in the pediatric nephrology unit at Menoufia University Hospital. The study included a total of 60 children with ESRD on maintenance HD therapy. They were divided into two groups: Group I (supplemented group, n = 30) received intravenous Vitamin C supplementation and Group II (control, n = 30) received placebo (intravenous saline) for three months. The results are shown as a mean ± standard deviation. Statistical evaluation was performed by SPSS software (version 11.5) using paired t-test. After supplementation with Vitamin C, the serum Vitamin C and high-density lipoprotein levels increased significantly with a significant reduction in the levels of serum uric acid, cholesterol, low-density lipoproteins, and triglyceride at the end of the study period. No significant changes were observed in the control group. Vitamin C can serve as a useful urate lowering medicine in HD patients to avoid complications of hyperuricemia. Furthermore, it had favorable effects on the lipid profile. This improvement can be considered as a preventive strategy in the progression of CVD in HD patients. Vitamin C supplementation improves ascorbic acid deficiency in these patients.


Nerve growth cone lamellipodia contain two populations of actin filaments that differ in organization and polarity.
The organization and polarity of actin filaments in neuronal growth cones was studied with negative stain and freeze-etch EM using a permeabilization protocol that caused little detectable change in morphology when cultured nerve growth cones were observed by video-enhanced differential interference contrast microscopy. The lamellipodial actin cytoskeleton was composed of two distinct subpopulations: a population of 40-100-nm-wide filament bundles radiated from the leading edge, and a second population of branching short filaments filled the volume between the dorsal and ventral membrane surfaces. Together, the two populations formed the three-dimensional structural network seen within expanding lamellipodia. Interaction of the actin filaments with the ventral membrane surface occurred along the length of the filaments via membrane associated proteins. The long bundled filament population was primarily involved in these interactions. The filament tips of either population appeared to interact with the membrane only at the leading edge; this interaction was mediated by a globular Triton-insoluble material. Actin filament polarity was determined by decoration with myosin S1 or heavy meromyosin. Previous reports have suggested that the polarity of the actin filaments in motile cells is uniform, with the barbed ends toward the leading edge. We observed that the actin filament polarity within growth cone lamellipodia is not uniform; although the predominant orientation was with the barbed end toward the leading edge (47-56%), 22-25% of the filaments had the opposite orientation with their pointed ends toward the leading edge, and 19-31% ran parallel to the leading edge. The two actin filament populations display distinct polarity profiles: the longer filaments appear to be oriented predominantly with their barbed ends toward the leading edge, whereas the short filaments appear to be randomly oriented. The different length, organization and polarity of the two filament populations suggest that they differ in stability and function. The population of bundled long filaments, which appeared to be more ventrally located and in contact with membrane proteins, may be more stable than the population of short branched filaments. The location, organization, and polarity of the long bundled filaments suggest that they may be necessary for the expansion of lamellipodia and for the production of tension mediated by receptors to substrate adhesion molecules.


Intercellular transfer of oncogenic H-Ras at the immunological synapse.
Immune cells establish dynamic adhesive cell-cell interactions at a specific contact region, termed the immunological synapse (IS). Intriguing features of the IS are the formation of regions of plasma membrane fusion and the intercellular exchange of membrane fragments between the conjugated cells. It is not known whether upon IS formation, intact intracellular proteins can transfer from target cells to lymphocytes to allow the transmission of signals across cell boundaries. Here we show by both FACS and confocal microscopy that human lymphocytes acquire from the cells they scan the inner-membrane protein H-Ras, a G-protein vital for common lymphocyte functions and a prominent participant in human cancer. The transfer was cell contact-dependent and occurred in the context of cell-conjugate formation. Moreover, the acquisition of oncogenic H-RasG12V by natural killer (NK) and T lymphocytes had important biological functions in the adopting lymphocytes: the transferred H-RasG12V induced ERK phosphorylation, increased interferon-gamma and tumor necrosis factor-alpha secretion, enhanced lymphocyte proliferation, and augmented NK-mediated target cell killing. Our findings reveal a novel mode of cell-to-cell communication-allowing lymphocytes to extend the confines of their own proteome-which may moreover play an important role in natural tumor immunity.


Behavior change due to COVID-19 among dental academics-The theory of planned behavior: Stresses, worries, training, and pandemic severity.
COVID-19 pandemic led to major life changes. We assessed the psychological impact of COVID-19 on dental academics globally and on changes in their behaviors. We invited dental academics to complete a cross-sectional, online survey from March to May 2020. The survey was based on the Theory of Planned Behavior (TPB). The survey collected data on participants' stress levels (using the Impact of Event Scale), attitude (fears, and worries because of COVID-19 extracted by Principal Component Analysis (PCA), perceived control (resulting from training on public health emergencies), norms (country-level COVID-19 fatality rate), and personal and professional backgrounds. We used multilevel regression models to assess the association between the study outcome variables (frequent handwashing and avoidance of crowded places) and explanatory variables (stress, attitude, perceived control and norms). 1862 academics from 28 countries participated in the survey (response rate = 11.3%). Of those, 53.4% were female, 32.9% were <46 years old and 9.9% had severe stress. PCA extracted three main factors: fear of infection, worries because of professional responsibilities, and worries because of restricted mobility. These factors had significant dose-dependent association with stress and were significantly associated with more frequent handwashing by dental academics (B = 0.56, 0.33, and 0.34) and avoiding crowded places (B = 0.55, 0.30, and 0.28). Low country fatality rates were significantly associated with more handwashing (B = -2.82) and avoiding crowded places (B = -6.61). Training on public health emergencies was not significantly associated with behavior change (B = -0.01 and -0.11). COVID-19 had a considerable psychological impact on dental academics. There was a direct, dose-dependent association between change in behaviors and worries but no association between these changes and training on public health emergencies. More change in behaviors was associated with lower country COVID-19 fatality rates. Fears and stresses were associated with greater adoption of preventive measures against the pandemic.


Transbronchial Lung Cryobiopsy in Diffuse Parenchymal Lung Disease: Comparison between Biopsy from 1 Segment and Biopsy from 2 Segments - Diagnostic Yield and Complications.
Transbronchial lung cryobiopsy is an innovative method of obtaining samples from the parenchyma of patients with diffuse parenchymal lung diseases. However, the technique is not yet standardized, and uncertainty exists about the optimal protocol, including the number of samples, the biopsy size, and the choice of the biopsy site. To compare the diagnostic yield and complications of cryobiopsy with different strategies adopted to sample lung tissue (number of samples, biopsy site, and sample size). We prospectively enrolled 46 patients with suspected diffuse parenchymal lung diseases for the diagnosis of which a biopsy was deemed useful. All patients underwent transbronchial lung cryobiopsy, and they were randomly assigned to group A (4 samples obtained from the same segment) or group B (2 samples obtained from one segment and 2 samples obtained from a different segment of the same lobe). Analysis of the samples was performed sequentially (from the first to the last sample), and pathologists reformulated their histopathologic diagnosis with the addition of each sample. The mean diagnostic yield of the procedure combining the 2 groups and performing only the first sampling was 69%. When a second biopsy was performed as well, the mean diagnostic yield improved, but this increase was significant only when the 2 samples were obtained from 2 different segments (96%, group B). This study suggests that the strategy of performing 2 biopsies with a cryoprobe may be associated with an increased diagnostic yield in diffuse parenchymal lung diseases if these samples are obtained from 2 different segments within the same lobe.


Spontaneous early exposure of submerged endosseous implants resulting in crestal bone loss: a clinical evaluation between stage I and stage II surgery.
Spontaneous early exposure of submerged implants during the osseointegration healing phase may be a harmful factor that results in early crestal bone loss around the implants. The objective of this study was to assess the effect of spontaneous early exposure on crestal bone loss around submerged implants, with special attention given to the relationship between the degree of exposure and the amount of peri-implant bone loss. Crestal bone level relative to the shoulder of the implant was measured at the time of placement and at the time of exposure 4 to 5 months later. During the period between stage I and stage II surgery, implant sites were observed, and each implant site in which spontaneous early exposure was detected was recorded. Perforations were classified according to the degree of implant exposure from Class 0 (no perforation) to Class IV (complete exposure). Measurements from 206 implants in 64 patients produced 85 groups valid for statistical comparison; each of these contained at least 2 lesions of different types. There was a statistically significant difference between bone loss associated with intact mucosa (Class 0) and Class I, Class II, and Class III lesions, and between Class I and II lesions. There were no significant differences between Class I and III and between Class II and III. In Class II and III lesions, there was more bone loss associated with the buccal aspect of the implants. Of the 115 perforated sites, 10 were associated with bone loss exceeding 2 mm, 2 presented 3 to 4 mm bone loss, 1 showed more than 4 mm, and 1 displayed more than 5 mm. In view of the clinical implications that spontaneous early exposure may have on the success of osseointegration, prematurely partially exposed implants should be exposed as soon as possible after the perforation is observed.


Recapitulation of the sexual cycle of the primary fungal pathogen Cryptococcus neoformans var. gattii: implications for an outbreak on Vancouver Island, Canada.
Cryptococcus neoformans is a human fungal pathogen that exists as three distinct varieties or sibling species: the predominantly opportunistic pathogens C. neoformans var. neoformans (serotype D) and C. neoformans var. grubii (serotype A) and the primary pathogen C. neoformans var. gattii (serotypes B and C). While serotypes A and D are cosmopolitan, serotypes B and C are typically restricted to tropical regions. However, serotype B isolates of C. neoformans var. gattii have recently caused an outbreak on Vancouver Island in Canada, highlighting the threat of this fungus and its capacity to infect immunocompetent individuals. Here we report a large-scale analysis of the mating abilities of serotype B and C isolates from diverse sources and identify unusual strains that mate robustly and are suitable for further genetic analysis. Unlike most isolates, which are of both the a and alpha mating types but are predominantly sterile, the majority of the Vancouver outbreak strains are exclusively of the alpha mating type and the majority are fertile. In an effort to enhance mating of these isolates, we identified and disrupted the CRG1 gene encoding the GTPase-activating protein involved in attenuating pheromone response. crg1 mutations dramatically increased mating efficiency and enabled mating with otherwise sterile isolates. Our studies provide a genetic and molecular foundation for further studies of this primary pathogen and reveal that the Vancouver Island outbreak may be attributable to a recent recombination event.


Family members' experience of providing support for young people with traumatic physical injury during the acute hospital phase of care: A qualitative study.
The aim of this study was to explore how family members perceive and support young people with traumatic physical injury during the acute phase of hospital care. This study forms part of the qualitative explanatory follow-up phase of a mixed methods study. The paper reports on family members' experiences of providing support to young people 16-24 years admitted with major traumatic injury to an Australian Level 1 Trauma Centre. Semi-structured in-depth interviews with family members were conducted and transcribed verbatim. Data were managed using NVivo software, and thematically analysed. Family support was determined by how family members perceived the injury. Driven by a need to protect the injured young person, family members sought to control potential emotional impacts of injury, creating a buffer between the young person and other people including healthcare professionals. Family members safeguarded the psychological well-being of the young person, in an attempt to facilitate their transition back to independence. This study identifies iterative changes in family relationships and emotional and practical support provided by family members during the initial injury trajectory, extending understandings of the broader burden of injury. Key elements of family stress theory offer a useful framework for the development of anticipatory guidance for clinicians that are responsive to the emotional needs of patients and families, supporting the need for a family-centred care approach to managing major traumatic injury in young people.


Application of Behavior Change Techniques in a Personalized Nutrition Electronic Health Intervention Study: Protocol for the Web-Based Food4Me Randomized Controlled Trial.
To determine the efficacy of behavior change techniques applied in dietary and physical activity intervention studies, it is first necessary to record and describe techniques that have been used during such interventions. Published frameworks used in dietary and smoking cessation interventions undergo continuous development, and most are not adapted for Web-based delivery. The Food4Me study (N=1607) provided the opportunity to use existing frameworks to describe standardized Web-based techniques employed in a large-scale, internet-based intervention to change dietary behavior and physical activity. The aims of this study were (1) to describe techniques embedded in the Food4Me study design and explain the selection rationale and (2) to demonstrate the use of behavior change technique taxonomies, develop standard operating procedures for training, and identify strengths and limitations of the Food4Me framework that will inform its use in future studies. The 6-month randomized controlled trial took place simultaneously in seven European countries, with participants receiving one of four levels of personalized advice (generalized, intake-based, intake+phenotype-based, and intake+phenotype+gene-based). A three-phase approach was taken: (1) existing taxonomies were reviewed and techniques were identified a priori for possible inclusion in the Food4Me study, (2) a standard operating procedure was developed to maintain consistency in the use of methods and techniques across research centers, and (3) the Food4Me behavior change technique framework was reviewed and updated post intervention. An analysis of excluded techniques was also conducted. Of 46 techniques identified a priori as being applicable to Food4Me, 17 were embedded in the intervention design; 11 were from a dietary taxonomy, and 6 from a smoking cessation taxonomy. In addition, the four-category smoking cessation framework structure was adopted for clarity of communication. Smoking cessation texts were adapted for dietary use where necessary. A posteriori, a further 9 techniques were included. Examination of excluded items highlighted the distinction between techniques considered appropriate for face-to-face versus internet-based delivery. The use of existing taxonomies facilitated the description and standardization of techniques used in Food4Me. We recommend that for complex studies of this nature, technique analysis should be conducted a priori to develop standardized procedures and training and reviewed a posteriori to audit the techniques actually adopted. The present framework description makes a valuable contribution to future systematic reviews and meta-analyses that explore technique efficacy and underlying psychological constructs. This was a novel application of the behavior change taxonomies and was the first internet-based personalized nutrition intervention to use such a framework remotely. ClinicalTrials.gov NCT01530139; https://clinicaltrials.gov/ct2/show/NCT01530139 (Archived by WebCite at http://www.webcitation.org/6y8XYUft1).


The alphavbeta5 integrin of hematopoietic and nonhematopoietic cells is a transduction receptor of RGD-4C fiber-modified adenoviruses.
Epithelial and endothelial cells expressing the primary Coxsackie virus B adenovirus (Ad) receptor (CAR) and integrin coreceptors are natural targets of human Ad infections. The fiber knob of species A, C, D, E and F Ad serotypes binds CAR by mimicking the CAR-homodimer interface, and the penton base containing arginine-glycine-aspartate (RGD) motifs binds with low affinity to alphav integrins inducing cell activation. Here, we generated seven different genetically modified Ad vectors with RGD sequences inserted into the HI loop of fiber knob. All mutants bound and infected CAR and alphav integrin-positive epithelial cells with equal efficiencies. However, the Ads containing two additional cysteines, both N and C terminals of the RGD sequence (RGD-4C), were uniquely capable of transducing CAR-less hematopoietic and nonhematopoietic human tumor cell lines and primary melanoma cells. Both binding and transduction of RGD-4C Ad were blocked by soluble RGD peptides. Flow cytometry of cell surface integrins and virus binding to CAR-less cells in the presence of function-blocking anti-integrin antibodies indicated that the alphavbeta5 integrin, but not alphavbeta3, alphaIIbbeta3 or beta1,alpha5 or alpha6-containing integrins served as a functional transduction receptor of the RGD-4C Ads. However, in cells with low levels of alphavbeta5 integrin, the function-blocking anti-alphavbeta5 antibodies were not effective, unlike soluble RGD peptides. Collectively, our data demonstrate that the alphavbeta5 integrin is a functional transduction receptor of RGD-4C Ads in the absence of CAR, and that additional RGD receptors are targets of these viruses. The RGD-4C vectors further extend the tropism of Ads towards potential human therapies.


Evaluating excited state atomic polarizabilities of chromophores.
Ground and excited state dipoles and polarizabilities of the chromophores N-methyl-6-oxyquinolinium betaine (MQ) and coumarin 153 (C153) in solution have been evaluated using time-dependent density functional theory (TD-DFT). A method for determining the atomic polarizabilities has been developed; the molecular dipole has been decomposed into atomic charge transfer and polarizability terms, and variation in the presence of an electric field has been used to evaluate atomic polarizabilities. On excitation, MQ undergoes very site-specific changes in polarizability while C153 shows significantly less variation. We also conclude that MQ cannot be adequately described by standard atomic polarizabilities based on atomic number and hybridization state. Changes in the molecular polarizability of MQ (on excitation) are not representative of the local site-specific changes in atomic polarizability, thus the overall molecular polarizability ratio does not provide a good approximation for local atom-specific polarizability changes on excitation. Accurate excited state force fields are needed for computer simulation of solvation dynamics. The chromophores considered in this study are often used as molecular probes. The methods and data reported here can be used for the construction of polarizable ground and excited state force fields. Atomic and molecular polarizabilities (ground and excited states) have been evaluated over a range of functionals and basis sets. Different mechanisms for including solvation effects have been examined; using a polarizable continuum model, explicit solvation and via sampling of clusters extracted from a MD simulation. A range of different solvents have also been considered.


Risk factors for early mortality after valve surgery in Europe in the 1990s: lessons from the EuroSCORE pilot program.
The characteristics of valve surgery are evolving. The study aim was to explore its demographics and risk factors in Europe in the 1990s, using the EuroSCORE database. For the EuroSCORE program, information on 98 variables regarding risk factors, procedures and outcome were collected for 5,672 patients undergoing valve surgery under cardiopulmonary bypass in 128 European centers. Bivariate (i.e. Mann-Whitney test or chi-square when appropriate), then logistic regression analyses were carried out to identify risk factors for early mortality. The predictive value of EuroSCORE was analyzed using the Hosmer-Lemershow test and by computing the area under the receiver operating characteristic (ROC) curve. Aortic valve stenosis was the most common diagnosis (47.6%), whilst mitral valve surgery accounted for 42% of procedures. Coronary surgery was performed concomitantly in 21% of cases. Hospital mortality was 6.1%. Predictive factors for early mortality were: age (p = 0.0001), preoperative serum creatinine >200 micromol/l (p = 0.014), previous heart surgery (p = 0.0001), poor left ventricular function (p = 0.008), chronic congestive heart failure (p = 0.0001), pulmonary hypertension (p = 0.0001), active acute endocarditis (p = 0.0001), emergency procedure (p = 0.05), critical preoperative status (p = 0.0001), tricuspid surgery (p = 0.015), aortic and mitral surgery (p = 0.002), combined thoracic surgery (p = 0.0001), and combined coronary surgery (p = 0.0001). The predictive value of EuroSCORE for mortality was good (area under the ROC curve = 0.75). The 'valve' subset of the EuroSCORE database provides an instant picture of European valve surgery in the 1990s that can be used either for individual assessment, or for country- or institution-based epidemiological studies of risk factors and practices.


Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors.
Sphingosine 1-phosphate (S1P) is stored in and released from platelets in response to cell activation. However, recent studies show that it is also released from a number of cell types, where it can function as a paracrine/autocrine signal to regulate cell proliferation, differentiation, survival, and motility. This review discusses the role of S1P in cellular regulation, both at the molecular level and in terms of health and disease. The main biochemical routes for S1P synthesis (sphingosine kinase) and degradation (S1P lyase and S1P phosphatase) are described. The major focus is on the ability of S1P to bind to a novel family of G-protein-coupled receptors (endothelial differentiation gene [EDG]-1, -3, -5, -6, and -8) to elicit signal transduction (via G(q)-, G(i)-, G(12)-, G(13)-, and Rho-dependent routes). Effector pathways regulated by S1P are divergent, such as extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, phospholipases C and D, adenylyl cyclase, and focal adhesion kinase, and occur in multiple cell types, such as immune cells, neurones, smooth muscle, etc. This provides a molecular basis for the ability of S1P to act as a pleiotropic bioactive lipid with an important role in cellular regulation. We also give an account of the expanding role for S1P in health and disease; in particular, with regard to its role in atherosclerosis, angiogenesis, cancer, and inflammation. Finally, we describe future directions for S1P research and novel approaches whereby S1P signalling can be manipulated for therapeutic intervention in disease.


The immunosuppressive activity of L-leucyl-L-leucine methyl ester: selective ablation of cytotoxic lymphocytes and monocytes.
L-Leucyl-L-leucine methyl ester (Leu-Leu-OMe), a dipeptide condensation product of L-leucine methyl ester generated by human monocytes (M phi) or polymorphonuclear leukocytes, eliminates all natural killer cell (NK) function from mixed lymphocyte populations. In the present studies, the specificity of the action of Leu-Leu-OMe was examined. It was found that a variety of tissue culture cells and tumor lines of nonlymphoid origin were completely resistant to any demonstrable Leu-Leu-OMe-mediated toxicity. Furthermore, the erythroleukemia line K562, the T cell line Molt-4, the B cell lines HS-Sultan and Daudi, and EBV-transformed B cell lines were unaffected by concentrations of this compound that completely eliminated NK cells. Similarly, the vast majority of OKT4+ lymphocytes manifested no significant toxicity after Leu-Leu-OMe exposure. Furthermore, they retained the capacity to proliferate normally in response to allogeneic cells as well as the ability to provide help for the generation of immunoglobulin-secreting cells (ISC). However, Leu-Leu-OMe caused partial depletion of OKT8+ cells from mixed populations of lymphocytes. After such exposure, the remaining OKT8+ cells were still capable of proliferating in mixed lymphocyte cultures, but the suppressive effect of these cells on ISC generation was abolished. Furthermore, both precursors and activated effectors of cytotoxic T lymphocyte (CTL) and activated NK-like activity generated in mixed lymphocyte cultures were eliminated by exposure to low concentrations of Leu-Leu-OMe. Indeed, both OKT4+ and OKT8+ CTL were eliminated by Leu-Leu-OMe. In addition, both peripheral blood M phi and U937 cells, a human cell line with many M phi-like characteristics, were sensitive to Leu-Leu-OMe-mediated toxicity, although only at two- to fivefold higher concentrations than those completely eliminating NK cells. These findings indicate that Leu-Leu-OMe has selective toxicity for NK cells, CTL, and M phi without adverse effects on a variety of other lymphoid or nonlymphoid cell types.


The impact of chronic carbohydrate manipulation on mucosal immunity in elite endurance athletes.
Carbohydrate (CHO) availability could alter mucosal immune responses to exercise. This study compared the effect of three dietary approaches to CHO availability on resting and post-exercise s-IgA levels. Elite race walkers (n = 26) adhered to a high CHO diet (HCHO), periodised CHO availability (PCHO) or a low CHO/high fat diet (LCHF) for 3 weeks while completing an intensified training program. HCHO and PCHO groups consumed 8.0-8.5 g.kg-1 CHO daily, with timing of ingestion manipulated to alter CHO availability around key training sessions. The LCHF diet comprised 80% fat and restricted CHO to < 50 g.day-1. A race walk test protocol (19 km females, 25 km males) was completed at baseline, after adaptation, and following CHO restoration. On each occasion, saliva samples were obtained pre- and post-exercise to quantify s-IgA levels. Resting s-IgA secretion rate substantially increased ~ two-fold post-intervention in all groups (HCHO: 2.2 ± 2.2, PCHO: 2.8 ± 3.2, LCHF: 1.6 ± 1.6; fold-change± 95% confidence limits), however, no substantial differences between dietary treatments were evident. Post-exercise, substantial 20-130% increases in s-IgA concentration and 43-64% reductions in flow rate occurred in all dietary treatments, with trivial differences evident between groups. It appears that high volume training overrides any effect of manipulating CHO availability on mucosal immunity in elite athletes.


Epidemiology and genetics of rheumatoid arthritis.
The prevalence of rheumatoid arthritis (RA) is relatively constant in many populations, at 0.5-1.0%. However, a high prevalence of RA has been reported in the Pima Indians (5.3%) and in the Chippewa Indians (6.8%). In contrast, low occurrences have been reported in populations from China and Japan. These data support a genetic role in disease risk. Studies have so far shown that the familial recurrence risk in RA is small compared with other autoimmune diseases. The main genetic risk factor of RA is the HLA DRB1 alleles, and this has consistently been shown in many populations throughout the world. The strongest susceptibility factor so far has been the HLA DRB1*0404 allele. Tumour necrosis factor alleles have also been linked with RA. However, it is estimated that these genes can explain only 50% of the genetic effect. A number of other non-MHC genes have thus been investigated and linked with RA (e.g. corticotrophin releasing hormone, oestrogen synthase, IFN-gamma and other cytokines). Environmental factors have also been studied in relation to RA. Female sex hormones may play a protective role in RA; for example, the use of the oral contraceptive pill and pregnancy are both associated with a decreased risk. However, the postpartum period has been highlighted as a risk period for the development of RA. Furthermore, breastfeeding after a first pregnancy poses the greatest risk. Exposure to infection may act as a trigger for RA, and a number of agents have been implicated (e.g. Epstein-Barr virus, parvovirus and some bacteria such as Proteus and Mycoplasma). However, the epidemiological data so far are inconclusive. There has recently been renewed interest in the link between cigarette smoking and RA, and the data presented so far are consistent with and suggestive of an increased risk.


The neurological emergency room and prehospital stroke alert: the whole is greater than the sum of its parts.
Emergency medical services (EMS) prenotification to hospitals regarding the arrival of patients who have had a stroke is recommended to facilitate the workup once the patient arrives. Most hospitals have the patient enter the emergency department (ED) before obtaining a head computed tomography (CT) scan. At Capital Health, prehospital stroke-alert patients are delivered directly to CT and met by a neurological emergency team. The goal of bypassing the ED is to reduce the time to treatment. To evaluate (1) door-to-CT and door-to-needle time in patients with an acute stroke who arrive as prehospital stroke alerts and (2) the accuracy of EMS assessment. A prospective database of all prehospital stroke alert patients was kept and data retrospectively reviewed for patients who were seen between July 2012 and July 2013. Between July 2012 and July 2013, 141 prehospital stroke alerts were called to our emergency department, and the patients were stable enough to bypass the ED and go directly to CT. EMS assessment of stroke was accurate 66% of the time, and the diagnosis was neurological 89% of the time. The average time between patient arrival and acquisition of CT imaging was 11.8 minutes. Twenty-six of the 141 patients (18%) received intravenous tissue plasminogen activator. The median time from arrival to intravenous tissue plasminogen activator bolus was 44 minutes. Trained EMS responders are able to correctly identify patients who are experiencing neurological/neurosurgical emergencies and deliver patients to our comprehensive stroke center in a timely fashion after prenotification. The prehospital stroke alert protocol bypasses the ED, allowing the patient to be met in CT by the neurological ED team, which has proven to decrease door-to-CT and door-to-needle times from our historical means. ASLS, Advanced Stroke Life SupportDTN, door-to-needleED, emergency departmentEMS, emergency medical servicesEMT, emergency medical technicianIV, intravenousMEND, Miami Emergency Neurological DeficitPHSA, prehospital stroke alerttPA, tissue plasminogen activator.


Validation of the Modified Raymond-Roy classification for intracranial aneurysms treated with coil embolization.
The Raymond-Roy Occlusion Classification (RROC) qualitatively assesses intracranial aneurysm occlusion following endovascular coil embolization. The Modified Raymond-Roy Classification (MRRC) was developed as a refinement of this classification scheme, and dichotomizes RROC III occlusions into IIIa (opacification within the interstices of the coil mass) and IIIb (opacification between the coil mass and aneurysm wall) closures. To demonstrate in an external cohort the predictive accuracy of the MRRC, the records of 326 patients with 345 intracranial aneurysms treated with endovascular coil embolization from January 2007 to December 2013 were retrospectively analyzed. Within this cohort, 84 (24.3%) and 83 aneurysms (24.1%) had MRRC IIIa and IIIb closures, respectively, during initial coil embolization. Progression to complete occlusion was more likely with IIIa than IIIb closures (53.6% vs 19.2%, p≤0.01), while recanalization was more likely with IIIb than IIIa closures (65.1% vs 27.4%, p<0.01). Kaplan-Meier estimates demonstrated a significant difference in the test of equality for progression to complete occlusion (p=0.02) and recurrence (p<0.01) between class IIIa and IIIb distributions. For the entire cohort, male gender (p<0.01), ruptured aneurysm (p=0.04), intraluminal thrombus (p<0.01), and MRRC IIIb closure (p<0.01) were identified as predictors of recanalization. For aneurysms with an initial RROC III occlusion, MRRC IIIa closure was found to be an independent predictor of progression to complete occlusion (p=0.02). This study confirms that the MRRC enhances the predictive accuracy of the RROC.


Does Medical Risk Perception and Risk Taking Change with Age?
Across adulthood, people face increasingly more risky medical problems and decisions. However, little is known about changes in medical risk taking across adulthood. Therefore, the current cross-sectional study investigated age-related differences in medical risk taking with N = 317 adults aged 20-77 years using newly developed scenarios to assess medical risk taking, and additional measures designed to evaluate risk-taking behavior in the medical domain. Greater expected benefits on the Domain-Specific Risk-Taking Scale-Medical (DOSPERT-M) predicted more active risk taking, whereas higher perceived risk predicted less active risk taking. Next, we examined differences in active and passive risk taking, where passive risk taking refers to risk taking that is associated with inaction. Age was associated with less passive risk taking, but not with active risk taking, risk perception, or expected benefits on the DOSPERT-M. Participants were overall more likely to opt for taking medical action than not, even more so for a scenario about a vaccine for a deadly flu than for a scenario about a chemotherapy treatment for cancer. Overall, participants were more likely to accept medication (vaccine or chemotherapy) for their child than for themselves. Increasing age was associated with a lower likelihood of accepting the treatment or vaccine for oneself. Taken together, our study provides important insights about changes in medical risk taking across adulthood when people face an increasing number of complex and risky medical decisions.


Understanding and Promoting Effective Engagement With Digital Behavior Change Interventions.
This paper is one in a series developed through a process of expert consensus to provide an overview of questions of current importance in research into engagement with digital behavior change interventions, identifying guidance based on research to date and priority topics for future research. The first part of this paper critically reflects on current approaches to conceptualizing and measuring engagement. Next, issues relevant to promoting effective engagement are discussed, including how best to tailor to individual needs and combine digital and human support. A key conclusion with regard to conceptualizing engagement is that it is important to understand the relationship between engagement with the digital intervention and the desired behavior change. This paper argues that it may be more valuable to establish and promote "effective engagement," rather than simply more engagement, with "effective engagement" defined empirically as sufficient engagement with the intervention to achieve intended outcomes. Appraisal of the value and limitations of methods of assessing different aspects of engagement highlights the need to identify valid and efficient combinations of measures to develop and test multidimensional models of engagement. The final section of the paper reflects on how interventions can be designed to fit the user and their specific needs and context. Despite many unresolved questions posed by novel and rapidly changing technologies, there is widespread consensus that successful intervention design demands a user-centered and iterative approach to development, using mixed methods and in-depth qualitative research to progressively refine the intervention to meet user requirements.


Aerosol pentamidine prophylaxis following Pneumocystis carinii pneumonia in AIDS patients: results of a blinded dose-comparison study using an ultrasonic nebulizer.
To compare the efficacy and safety of three different doses of prophylactic aerosol pentamidine in patients with one prior episode of Pneumocystis carinii pneumonia (PCP) and the acquired immunodeficiency syndrome. The design of the study was a double-blind, randomized, dose-comparison clinical trial conducted at 13 medical centers within the United States. In stage I of the trial, patients were randomized to receive either 5 mg, 60 mg, or 120 mg of aerosol pentamidine delivered biweekly with the Fisoneb (Fisons, Inc., Rochester, New York) ultrasonic nebulizer. After 24 weeks of therapy, patients entered stage II of the trial, where the 5-mg group was re-randomized to either the 60-mg or 120-mg group. One hundred seventy-five patients entered stage I of the trial and received prophylaxis for a mean of 123.6 days. Seven assigned to the 5-mg biweekly dosing schedule had a confirmed recurrence of PCP, compared with none in the 60-mg group (p = 0.007) and three in the 120-mg group (p = 0.304). During stage II of the trial, eight patients in the 60-mg group and one additional patient in the 120-mg group had recurrent PCP. After 52 weeks of observation, the likelihood of being PCP-free was 88.0% in the 60-mg group and 93% in the 120-mg group (p = 0.712). Minor adverse events related to aerosol pentamidine administration included cough, taste perversion, chest pain, bronchospasm, and dyspnea. These side effects were more common in the 60-mg and 120-mg treatment groups and resulted in withdrawal from the study by one patient. Serious events were more common after 24 weeks of therapy and included asymptomatic hypoglycemia (five), pancreatitis (two), pneumothorax (one), and extrapulmonary pneumocystosis (one). These results demonstrate that biweekly administration of 60 mg or 120 mg of aerosol pentamidine significantly decreases PCP recurrence when compared with a 5-mg regimen or findings in historic controls and is generally well tolerated. There is no significant difference in effect or safety between these two dosing regimens in patients followed for at least 52 weeks of therapy.


Early specialization in surgical training: an old concept whose time has come?
The complexity of surgical science and surgical patient care is increasing at an accelerating pace. As a consequence, many areas of surgical practice once within the scope of general surgery have evolved into distinct specialties with unique advanced training requirements. Given this evolution in surgical specialization, many have considered that our current model of surgical training--a 5-year residency in general surgery, followed by any of a wide variety of fellowships to acquire refined, advanced training--is due for major restructuring. The current debate focuses on the benefits and potential disadvantages of earlier differentiation of surgeons into specialty training pathways. The structure of surgical training, including the definition of core surgical training and the optimal structure to introduce advanced specialty training tracks, is the central issue in this debate. This article reviews the question and current deliberations of the stakeholders in graduate surgical education and training.


Protective Effect of Bendavia (SS-31) Against Oxygen/Glucose-Deprivation Stress-Induced Mitochondrial Damage in Human Brain Microvascular Endothelial Cells.
Mitochondria play a key role in cell survival by perfoming functions such as adenosine tri-phosphate (ATP) synthesis, regulation of apoptotic cell death, calcium storage. Hypoxic conditions induce mitochondrial dysfunction, which leads to endothelial injury in cerebral ischemia. Functional disorders include the following: collapse of mitochondrial membrane potential, reduction of ATP synthesis, and generation of reactive oxygen species (ROS). Bendavia, a novel tetra-peptide, has been reported to restrict the uncoupling of the mitochondrial membrane chain, protect the synthesis of ATP, and inhibit ROS generation. In the present study, we investigated whether bendavia protects mitochondria under hypoxic and starved conditions by using human brain microvascular endothelial cells (HBMVECs). After pre-treatment with bendavia, we exposed HBMVECs to oxygen glucose deprivation (OGD) for 6 h. We then assessed cell viability, the level of caspase-3/7 activity, ROS generation, mitochondrial membrane potential, ATP contents, and the number of mitochondria. Bendavia recovered cell viability and reduced the caspase-3/7 activity induced by OGDinduced damage. Bendavia also recovered mitochondrial functions. These results suggest that bendavia protects mitochondrial function against OGD-induced injury and inhibits apoptosis in HBMVECs. Consequently, our findings indicate that bendavia might become the new therapeutic drug of choice to target mitochondria in case of cerebral ischemia.


A GICA-TVGL framework to study sex differences in resting state fMRI dynamic connectivity.
Functional magnetic resonance imaging (fMRI) has been implemented widely to study brain connectivity. In particular, time-varying connectivity analysis has emerged as an important measure to uncover essential knowledge within the network. On the other hand, independent component analysis (ICA) has served as a powerful tool to preprocess fMRI data before performing network analysis. Together, they may lead to novel findings. We propose a new framework (GICA-TVGL) that combines group ICA (GICA) with time-varying graphical LASSO (TVGL) to improve the power of analyzing functional connectivity (FNC) changes, which is then applied for neuro-developmental study. To investigate the performance of our proposed approach, we apply it to capture dynamic FNC using both the Philadelphia Neurodevelopmental Cohort (PNC) and the Pediatric Imaging, Neurocognition, and Genetics (PING) datasets. Our results indicate that females and males in young adult group possess substantial difference related to visual network. In addition, some other consistent conclusions have been reached by using these two datasets. Furthermore, the GICA-TVGL model indicated that females had a higher probability to stay in a stable state. Males had a higher tendency to remain in a globally disconnected mode. The performance of sliding window approach is largely affected by the window size selection. In addition, it also assumes temporal locality hypothesis. Our proposed framework provides a feasible method to investigate brain dynamics and has the potential to become a widely used tool in neuroimaging studies.


Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase.
A thermostable DNA polymerase was used in an in vitro DNA amplification procedure, the polymerase chain reaction. The enzyme, isolated from Thermus aquaticus, greatly simplifies the procedure and, by enabling the amplification reaction to be performed at higher temperatures, significantly improves the specificity, yield, sensitivity, and length of products that can be amplified. Single-copy genomic sequences were amplified by a factor of more than 10 million with very high specificity, and DNA segments up to 2000 base pairs were readily amplified. In addition, the method was used to amplify and detect a target DNA molecule present only once in a sample of 10(5) cells.


Quantitative assessment of soil parameter (KD and TC) estimation using DGT measurements and the 2D DIFS model.
Diffusive gradients in thin films (DGT) is a dynamic, in situ measuring technique that can be used to supply diverse information on concentrations and behaviour of solutes. When deployed in soils and sediments, quantitative interpretation of DGT measurements requires the use of a numerical model. An improved version of the DGT induced fluxes in soils and sediments model (DIFS), working in two dimensions (2D DIFS), was used to investigate the accuracy with which DGT measurements can be used to estimate the distribution coefficient for labile metal (KD) and the response time of the soil to depletion (TC). The 2D DIFS model was used to obtain values of KD and TC for Cd, Zn and Ni in three different soils, which were compared to values determined previously using 1D DIFS for these cases. While the 1D model was shown to provide reasonable estimates of KD, the 2D model refined the estimates of the kinetic parameters. Desorption rate constants were shown to be similar for all three metals and lower than previously thought. Calculation of an error function as KD and TC are systematically varied showed the spread of KD and TC values that fit the experimental data equally well. These automatically generated error maps reflected the quality of the data and provided an appraisal of the accuracy of parameter estimation. They showed that in some cases parameter accuracy could be improved by fitting the model to a sub-set of data.


Unsafe caregiving practices experienced by 3-year-old children born prematurely.
Unsafe caregiving practices were studied in relation to risk factors for unintentional injuries as reported in the literature. A total of 54 premature children at 3 years of age and their mothers were observed twice in their homes for 2-hour periods, and the HOME Inventory was scored at one of the visits. Field notes from these visits were analyzed for unsafe practices, including hazards in the environment and inadequate parental supervision. Unsafe practices occurred for approximately 30% of the children studied. T-tests indicated that children with no unsafe practices had higher HOME scores than children with unsafe practices. In addition, lower HOME scores and later birth order were correlated with a greater number of unsafe practices. Maternal age and education, family size, child birthweight, and maternal perception of child vulnerability were not related to the presence of unsafe caregiving practices. The findings also suggest that the HOME Inventory may have promise as a useful tool in screening for unsafe caregiving of preschool children.


Pediatric calfactant in acute respiratory distress syndrome trial.
Our previous studies in children with acute lung injury/acute respiratory distress syndrome demonstrated improved outcomes with exogenous surfactant (calfactant) administration. Sample sizes in those studies were small, however, and the subject populations heterogeneous, thus making recommendations tenuous. To investigate the efficacy of surfactant administration in a larger, more homogenous population of children with lung injury/acute respiratory distress syndrome due to direct lung injury. Masked, randomized, placebo-controlled trial in 24 children's hospitals in six different countries. Children 37 weeks postconception to 18 years old with lung injury/acute respiratory distress syndrome due to direct lung injury were randomized to receive up to three doses of 30 mg/cm height of surfactant (calfactant) versus placebo (air) within 48 hours of intubation and initiation of mechanical ventilation. The primary outcome was mortality at 90 days. Ventilator-free days, changes in oxygenation, and adverse events were also assessed. The study was stopped at the sponsor's request after the second interim analysis for presumed futility. A total of 110 subjects were enrolled, with consent withdrawn from one whose data are unavailable. There were no significant differences between groups except in hospital-free days (10.4 ± 7.8 placebo vs 6.4 ± 7.8 surfactant; p = 0.01). Overall 90-day mortality was 11% (seven surfactant, five placebo). No immediate improvement in oxygenation was associated with surfactant administration. Surfactant did not improve outcomes relative to placebo in this trial of children with direct lung injury/acute respiratory distress syndrome. Differences in concentration of the surfactant, failure to recruit the lung during surfactant administration, or using two rather than four position changes during administration are possible explanations for the difference from previous studies. Exogenous surfactant cannot be recommended at this time for children with direct lung injury/acute respiratory distress syndrome.


Disconjugate adaptation to long-standing, large-amplitude, spectacle-corrected anisometropia.
A 12-yr-old anisometropic patient had worn corrective eyeglasses (right eye, -0.50 +1.50 x 125; LE, -9.75 +2.50 x 60) for 7 yr, and then changed to contact lenses. Eye movements were recorded before and after the change to contact lenses using binocular search coils. In habitual spectacle viewing, the patient showed disconjugate adaptation. During monocular viewing, for example, ocular alignment changed by as much as 4 degrees during a 20 degrees saccade. Also, during monocular viewing, with either eye, placing the spectacle lens in front of the eye caused an increase in the disconjugate adaptive response compared with viewing without lenses. This finding emphasizes the context specificity of adaptive responses. After switching to contact lenses, the patient still wore his spectacles for 20-40 min each day. Although there was little residual disconjugate adaptation for vertical saccades, he showed considerable adaptation for horizontal saccades, especially for gaze changes that required divergence. The persistence of a partial state of disconjugate adaptation allowed the patient to use immediate, disparity-induced, horizontal vergence to aid ocular alignment in either the contact-lens-viewing or the spectacle-viewing condition. A more complete reversion to conjugacy occurred after nine days of exclusive use of his contact lenses. Then, in a short-term experiment, two minutes of binocular viewing through the eyeglasses induced a considerable reversion toward the previous state of disconjugate adaptation (up to 1.25 degrees of vergence change during monocular viewing). Finally, the waveform of the adapted (to spectacles) intrasaccadic vergence change with monocular viewing was similar to the waveform of the unadapted intrasaccadic vergence change during binocular refixations between targets that required a combined saccade and vergence. This finding suggests a common mechanism for adaptation to spectacle-corrected anisometropia and for normal binocular vergence-saccade interactions.


A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal.
High-fat, high-carbohydrate (HFHC) meals are known to induce oxidative and inflammatory stress, an increase in plasma endotoxin concentrations, and an increase in the expression of suppressor of cytokine signaling-3 (SOCS-3). The intake of a nutritional supplement containing resveratrol and muscadine grape polyphenols reduces HFHC meal-induced oxidative and inflammatory stress and stimulates the activity of the antioxidant transcription factor, NF-E2-related factor-2 (Nrf-2), and its downstream targets. Ten normal, healthy subjects were given a 930-kcal HFHC meal either with placebo or with the supplement. Indices of oxidative stress, inflammation, Nrf-2 binding activity, the concentrations of endotoxin (lipopolysaccharide) and lipoprotein binding protein (LBP), and the expression of toll-like receptor 4 (TLR-4), CD14, IL-1β, TNFα, SOCS-3, Keap-1, NAD(P)H:quinone oxidoreductase-1 (NQO-1), and GST-P1 were measured. The intake of the supplement suppressed the meal-induced elevations of plasma endotoxin and LBP concentrations, the expression of p47(phox), TLR-4, CD14, SOCS-3, IL-1β, and Keap-1, while enhancing Nrf-2 binding activity and the expression of NQO-1 and GST-P1 genes. A supplement containing resveratrol and muscadine polyphenols suppresses the increase in oxidative stress, lipopolysaccharide and LBP concentrations, and expression of TLR-4, CD14, IL-1β and SOCS-3 in mononuclear cells after an HFHC meal. It also stimulates specific Nrf-2 activity and induces the expression of the related antioxidant genes, NQO-1 and GST-P1. These results demonstrate the acute antioxidant and antiinflammatory effects of resveratrol and polyphenolic compounds in humans in the postprandial state.


A phase I study of abacavir (1592U89) alone and in combination with other antiretroviral agents in infants and children with human immunodeficiency virus infection. AIDS Clinical Trials Group 330 Team.
To evaluate the pharmacokinetic features, safety, and tolerance of abacavir, given alone and in combination with other nucleoside antiretroviral agents, in symptomatic human immunodeficiency virus (HIV)-infected children. HIV-infected children discontinued prior antiretroviral therapy and were given abacavir orally, 4 mg/kg every 12 hours for 6 weeks, followed by 8 mg/kg every 12 hours for 6 weeks (n = 39); or 8 mg/kg every 12 hours for 12 weeks (n = 8). Children then were randomized to receive a second nucleoside antiretroviral agent (zidovudine, stavudine, didanosine, or lamivudine), plus abacavir. Pharmacokinetics, safety, tolerance, CD4(+) lymphocyte counts, and plasma HIV RNA concentrations were evaluated. At a dose of 8 mg/kg every 12 hours, area under the plasma concentration-versus-time curves and plasma half-life values were comparable with those reported for adults receiving abacavir at a dose of 300 mg twice daily. One case each of hypersensitivity reaction and peripheral neuropathy occurred during abacavir monotherapy. Three children experienced neutropenia while receiving abacavir in combination with another antiretroviral agent. Mean CD4(+) lymphocyte count and plasma HIV RNA concentration did not change when prior antiretroviral therapy was changed to abacavir monotherapy. Abacavir therapy is associated with good short-term tolerance and safety in HIV-infected children. Phase III studies are in progress to assess the antiviral activity of abacavir in children and adults.


Long-Term Ultra-High Hydrostatic Pressurized Brown Rice Intake Prevents Bone Mineral Density Decline in Elderly Japanese Individuals.
Bone embrittlement with aging, namely osteoporosis, is characterized by low bone mass and deterioration of bone tissue, and can lead to increased risk of fracture. The development of functional foods that can prevent geriatric diseases is in progress. Our focus was on brown rice because of its properties. An interventional study using of ultra-high hydrostatic pressurized brown rice (UHHPBR) for human has not yet been conducted. In this study, we investigated whether long-term dietary intake of UHHPBR prevents aging-related decline of bone mineral density in elderly Japanese individuals. Elderly participants (n=40; mean 73.1 y) in Iinan-cho, Shimane, Japan, were randomly divided into two groups. The UHHPBR-intake group (n=20) consumed 100 g of UHHPBR and 100 g of white rice (WR) per day for 12 mo, while the WR-intake group (n=20) consumed 200 g of WR per day. Pre- and 12-mo post-intervention, bone mineral density was evaluated by quantitative ultrasound. After 12 mo of intervention, the UHHPBR group's bone mineral density was significantly higher than the WR group's bone mineral density. Moreover, chronic intake of UHHPBR had no adverse side effects on participants. Long-term oral UHHPBR intake may have beneficial effects on bone mineral density decline and may attenuate osteoporosis in the elderly.


Mechanisms of genetic resistance to Friend virus leukemia in mice. IV. Identification of a gene (Fv-3) regulating immunosuppression in vitro, and its distinction from Fv-2 and genes regulating marrow allograft reactivity.
Friend leukemia viru (FV) suppresses the proliferative response of normal lymphocytes to mitogens. The in vitro suppressive effect of FV on lymphocyte mitogenesis is mediated by T-suppressor cells and is under host genetic control. Lymphocytes from strains of mice of the C57BL background (e.g., C57BL/6) are resistant while cells from other strains (e.g., 129 and DBA/2) are susceptible. Genetic analyses utilizing resistant and susceptible parental strains, their F1, intercross and backcross progeny indicated that susceptibility to in vitro suppression is regulated by a single autosomal gene, dominant for susceptibility to suppression. This gene, which is not linked to the H-2 complex, segregated independently of the Fv-2 gene which controls resistance to spleen focus formation in vivo. The gene is also unlinked to the Ir-like genes which regulate the ability of H-2d mice to reject H-2b bone marrow grafts. The gene is therefore designated as Fv-3. Fv-3 may mediate its effect by regulating the numbers and/or functions of T-suppressor cells.


Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2.
The COVID-19 pandemic brought attention to studies about viral infections and their impact on the cell machinery. SARS-CoV-2, for example, invades the host cells by ACE2 interaction and possibly hijacks the mitochondria. To better understand the disease and to propose novel treatments, crucial aspects of SARS-CoV-2 enrolment with host mitochondria must be studied. The replicative process of the virus leads to consequences in mitochondrial function, and cell metabolism. The hijacking of mitochondria, on the other hand, can drive the extrusion of mitochondrial DNA (mtDNA) to the cytosol. Extracellular mtDNA evoke robust proinflammatory responses once detected, that may act in different pathways, eliciting important immune responses. However, few receptors are validated and are able to detect and respond to mtDNA. In this review, we propose that the mtDNA and its detection might be important in the immune process generated by SARS-CoV-2 and that this mechanism might be important in the lung pathogenesis seen in clinical symptoms. Therefore, investigating the mtDNA receptors and their signaling pathways might provide important clues for therapeutic interventions.