Asthma costs and social impact.
In recent decades, both asthma prevalence and incidence have been increasing worldwide, not only due to the genetic background, but mainly because of the effect of a wide number of environmental and lifestyle risk factors. In many countries noncommunicable diseases, like asthma, are not yet considered a healthcare priority. This review will analyze and discuss disparities in asthma management in several countries and regions, such as access to healthcare human resources and medications, due to limited financial capacity to develop strategies to control and prevent this chronic disease. This review tries to explore the social and economic burden of asthma impact on society. Although asthma is generally accepted as a costly illness, the total costs to society (direct, indirect and intangible asthma costs) are difficult to estimate, mainly due to different disease definitions and characterizations but also to the use of different methodologies to assess the asthma socio-economic impact in different societies. The asthma costs are very variables from country to country, however we can estimate that a mean cost per patient per year, including all asthmatics (intermittent, mild, moderate and severe asthma) in Europe is $USD 1,900, which seems lower than USA, estimated mean $USD 3,100.


Design of ordered two-dimensional arrays mediated by noncovalent protein-protein interfaces.
We describe a general approach to designing two-dimensional (2D) protein arrays mediated by noncovalent protein-protein interfaces. Protein homo-oligomers are placed into one of the seventeen 2D layer groups, the degrees of freedom of the lattice are sampled to identify configurations with shape-complementary interacting surfaces, and the interaction energy is minimized using sequence design calculations. We used the method to design proteins that self-assemble into layer groups P 3 2 1, P 4 2(1) 2, and P 6. Projection maps of micrometer-scale arrays, assembled both in vitro and in vivo, are consistent with the design models and display the target layer group symmetry. Such programmable 2D protein lattices should enable new approaches to structure determination, sensing, and nanomaterial engineering.


Mechanisms of mindfulness: emotion regulation following a focused breathing induction.
The current study investigated whether a 15 min recorded focused breathing induction in a normal, primarily undergraduate population would decrease the intensity and negativity of emotional responses to affectively valenced picture slides and increase willingness to remain in contact with aversive picture slides. The effects of the focused breathing induction were compared with the effects of 15 min recorded inductions of unfocused attention and worrying. The focused breathing group maintained consistent, moderately positive responses to the neutral slides before and after the induction, whereas the unfocused attention and worry groups responded significantly more negatively to the neutral slides after the induction than before it. The focusing breathing group also reported lower negative affect and overall emotional volatility in response to the post-induction slides than the worry group, and greater willingness to view highly negative slides than the unfocused attention group. The lower-reported negative and overall affect in response to the final slide blocks, and greater willingness to view optional negative slides by the focused breathing group may be viewed as more adaptive responding to negative stimuli. The results are discussed as being consistent with emotional regulatory properties of mindfulness.


Right and left ventricular interaction in pulmonary hypertension: Insight from velocity vector imaging.
To evaluate whether global peak systolic strain (PSS) and peak systolic strain rate (PSSR) derived from velocity vector imaging (VVI) allow early recognition of regional and global right ventricular (RV) dysfunction and the impact of this on left ventricular (LV) function in patients with pulmonary hypertension (PHT). RV function is an important determinant of prognosis in patients with heart failure, pulmonary hypertension, heart transplant, and congenital heart diseases. However, evaluation of the right ventricle is often limited by its complex geometry and inadequate visualization of RV free wall. Furthermore, the impact of RV dysfunction on the LV function is not well elucidated. Ninety-nine participants, 35 control patients with normal RV systolic pressure (RVSP) (<30 mm Hg) and 64 patients with PHT (25 with mild-to-moderate increase in RVSP [≥36 and <60 mm Hg] and 39 with severe increase in RVSP [≥60 mm Hg]), underwent comprehensive echo-Doppler assessment and velocity vector imaging (VVI) for strain rate analysis. RV regional peak systolic and diastolic tangential velocity, strain, and strain rate were obtained from the basal, mid and apical segments of the RV free wall and interventricular septum (IVS) from apical 4-chamber view at end-expiration. Similar data were obtained from eighteen LV segments from apical 4-chamber, 2-chamber, and long-axis views. Peak systolic strain, strain rate, and tangential velocity at all segments in the RV free wall and IVS were decreased compared to controls in patients with PHT (P < 0.001). Significant correlation (r > 0.60; P < 0.001) was noted between RVSP and systolic and diastolic strain and strain rate at basal segment in IVS and global RV function. Peak early diastolic strain rate at all segments was also decreased in PHT patients compared with control patients (P < 0.01). Furthermore, RV systolic and diastolic strain and strain rate were lower in group 2 with mild-to-moderate hypertension while the conventional echo parameters were normal. Except for IVS segments, other LV segments had no statistical differences in systolic and diastolic velocity, strain, and strain rate compared to controls. However, they were lower than the published normal range. Strain and strain rate derived from VVI demonstrates early recognition of systolic and diastolic RV dysfunction in patients with PHT compared to controls. PHT is associated with global and regional RV systolic and diastolic dysfunction. Systolic and diastolic strain and strain rate from LV was lower compared to controls but were not statistically significant. This may indicate subclinical LV dysfunction in these patients, suggesting that conventional LV function parameters may not be sensitive to recognize subclinical LV dysfunction.


Influence of amide versus ester linkages on the properties of eight-armed PEG-PLA star block copolymer hydrogels.
Water-soluble eight-armed poly(ethylene glycol)-poly(l-lactide) star block copolymers linked by an amide or ester group between the PEG core and the PLA blocks (PEG-(NHCO)-(PLA)(8) and PEG-(OCO)-(PLA)(8)) were synthesized by the stannous octoate catalyzed ring-opening polymerization of l-lactide using an amine- or hydroxyl-terminated eight-armed star PEG. At concentrations above the critical gel concentration, thermosensitive hydrogels were obtained, showing a reversible single gel-to-sol transition. At similar composition PEG-(NHCO)-(PLA)(8) hydrogels were formed at significantly lower polymer concentrations and had higher storage moduli. Whereas the hydrolytic degradation/dissolution of the PEG-(OCO)-(PLA)(8) takes place by preferential hydrolysis of the ester bond between the PEG and PLA block, the PEG-(NHCO)-(PLA)(8) hydrogels degrade through hydrolysis of ester bonds in the PLA main chain. Because of their relatively good mechanical properties and slow degradation in vitro, PEG-(NHCO)-(PLA)(8) hydrogels are interesting materials for biomedical applications such as controlled drug delivery systems and matrices for tissue engineering.


On electrogenerated acid-facilitated electrografting of aryltriazenes to create well-defined aryl-tethered films.
The mechanism of electrogenerated acid-facilitated electrografting (EGAFE) of the aryltriazene, 4-(3,3-dimethyltriaz-1-enyl)benzyl-1-ferrocene carboxylate, was studied in detail using electrochemical quartz crystal microbalance (EQCM) and cyclic voltammetry. The measurements support the previously suggested mechanism that electrochemical oxidation of the EGA agent (i.e., N,N'-diphenylhydrazine) occurs on the forward oxidative sweep to generate protons, which in turn protonate the aryltriazene to form the corresponding aryldiazonium salt close to the electrode surface. On the reverse sweep, the electrochemical reduction of the aryldiazonium salt takes place, resulting in the electrografting of aryl groups. The EGAFE-generated film consists of a densely packed layer of ferrocenyl groups with nearly ideal electrochemical properties. The uncharged grafted film contains no solvent and electrolyte, but counterions and solvent can easily enter and be accommodated in the film upon charging. It is shown that all ferrocene moieties present in the multilayered film are electrochemically active, suggesting that the carbon skeleton possesses a sufficiently high flexibility to allow the occurrence of fast electron transfers between the randomly located redox stations. In comparison, EQCM measurements on aryldiazonium-grafted films reveal that they have a substantially smaller electrolyte uptake during charging and that they contain only 50% electroactive ferrocenyl groups relative to weight. Hence, half of these films consist of entrapped supporting electrolyte/solvent and/or simply electrochemically inactive material due to solvent inaccessibility.


Injury Profile of American Women's Rugby-7s.
The objective of this study is to determine incidence (injuries/1000 playing hours (ph)), severity (days of absence), and cause of match injuries in US women's Rugby-7s. We performed a prospective epidemiological study (2010-2013) of injury of 3876 under-19 to elite/national female Rugby-7s players (nonelite = 3324, elite = 552) on 323 teams (nonelite = 277, elite = 46), applying methodology and injury definitions compliant with the international consensus statement on rugby research. Injuries occurred in USA Rugby-sanctioned tournament series: USA Rugby Local Area (2010), Territorial Union (2011-2013), National and All-Star Sevens Series, and USA Sevens Invitational (2011-2012) and Collegiate Rugby Championships (2012). One hundred and twenty time-loss injuries were encountered (elite, n = 15; 13%) with an injury rate of 46.3 injuries/1000 ph. Injury rates in nonelite were 49.3/1000 ph, and in national level (elite) candidates, 32.6/1000 ph (RR = 1.5, P = 0.130). Mean days missed found elite level players at 74.9 d per injury, whereas nonelite at 41.8 d (P = 0.090). Acute injuries were significant (95%, RR = 1.9, P < 0.001), resulting in immediate removal from the pitch (56%, P < 0.001). The main mechanism of injury occurred when tackling players (73%, P < 0.001). The most common type of injury seen were ligament sprains (37%, 13.9/1000 ph), involving the lower extremity (45%, 20.5/1000 ph). The most common body parts injured were the knee and head/face (16%, 7.3/1000 ph). Time-loss injuries occurred with frequency in the US women's Rugby-7s tournaments. Overall injury rates in US women are lower than those in international elite men and women's Rugby-7s. The head and neck area in our female players was injured at greater rates (16%) than in international male Rugby-7s (5%). Injury prevention in US women's Rugby-7s must focus on injuries of the knee, head, and neck. Understanding risk factors will allow safe return-to-play decisions and formulate injury prevention protocols.


The Impact of Changes in Diagnostic Testing Practices on Estimates of COVID-19 Transmission in the United States.
Estimates of the reproductive number for novel pathogens, such as severe acute respiratory syndrome coronavirus 2, are essential for understanding the potential trajectory of epidemics and the levels of intervention that are needed to bring the epidemics under control. However, most methods for estimating the basic reproductive number (R0) and time-varying effective reproductive number (Rt) assume that the fraction of cases detected and reported is constant through time. We explored the impact of secular changes in diagnostic testing and reporting on estimates of R0 and Rt using simulated data. We then compared these patterns to data on reported cases of coronavirus disease 2019 and testing practices from different states in the United States from March 4, 2020, to August 30, 2020. We found that changes in testing practices and delays in reporting can result in biased estimates of R0 and Rt. Examination of changes in the daily numbers of tests conducted and the percentages of patients who tested positive might be helpful for identifying the potential direction of bias. Changes in diagnostic testing and reporting processes should be monitored and taken into consideration when interpreting estimates of the reproductive number of coronavirus disease.


An adaptive scheme for robot localization and mapping with dynamically configurable inter-beacon range measurements.
This work is motivated by robot-sensor network cooperation techniques where sensor nodes (beacons) are used as landmarks for range-only (RO) simultaneous localization and mapping (SLAM). This paper presents a RO-SLAM scheme that actuates over the measurement gathering process using mechanisms that dynamically modify the rate and variety of measurements that are integrated in the SLAM filter. It includes a measurement gathering module that can be configured to collect direct robot-beacon and inter-beacon measurements with different inter-beacon depth levels and at different rates. It also includes a supervision module that monitors the SLAM performance and dynamically selects the measurement gathering configuration balancing SLAM accuracy and resource consumption. The proposed scheme has been applied to an extended Kalman filter SLAM with auxiliary particle filters for beacon initialization (PF-EKF SLAM) and validated with experiments performed in the CONET Integrated Testbed. It achieved lower map and robot errors (34% and 14%, respectively) than traditional methods with a lower computational burden (16%) and similar beacon energy consumption.


Methyl-binding domain protein-based DNA isolation from human blood serum combines DNA analyses and serum-autoantibody testing.
Circulating cell free DNA in serum as well as serum-autoantibodies and the serum proteome have great potential to contribute to early cancer diagnostics via non invasive blood tests. However, most DNA preparation protocols destroy the protein fraction and therefore do not allow subsequent protein analyses. In this study a novel approach based on methyl binding domain protein (MBD) is described to overcome the technical difficulties of combining DNA and protein analysis out of one single serum sample. Serum or plasma samples from 98 control individuals and 54 breast cancer patients were evaluated upon silica membrane- or MBD affinity-based DNA isolation via qPCR targeting potential DNA methylation markers as well as by protein-microarrays for tumor-autoantibody testing. In control individuals, an average DNA level of 22.8 ± 25.7 ng/ml was detected applying the silica membrane based protocol and 8.5 ± 7.5 ng/ml using the MBD-approach, both values strongly dependent on the serum sample preparation methods used. In contrast to malignant and benign tumor serum samples, cell free DNA concentrations were significantly elevated in sera of metastasizing breast cancer patients. Technical evaluation revealed that serum upon MBD-based DNA isolation is suitable for protein-array analyses when data are consistent to untreated serum samples. MBD affinity purification allows DNA isolations under native conditions retaining the protein function, thus for example enabling combined analyses of DNA methylation and autoantigene-profiles from the same serum sample and thereby improving minimal invasive diagnostics.


Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog.
Sodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their effects by a dual action: they obstruct ion flow ("block"), and they alter the energetics of channel opening and closing ("modulation"). Ideal drugs would be modulators without blocking effect, because modulation is inherently activity-dependent, therefore selective for pathological hyperactivity. Can block and modulation be separated? It has been difficult to tell, because the effect of modulation is obscured by conformation-dependent association/dissociation of the drug. To eliminate dynamic association/dissociation, we used a photoreactive riluzole analog which could be covalently bound to the channel; and found, unexpectedly, that drug-bound channels could still conduct ions, although with modulated gating. The finding that non-blocking modulation is possible, may open a novel avenue for drug development because non-blocking modulators could be more specific in treating hyperactivity-linked diseases.


Resequencing of 243 diploid cotton accessions based on an updated A genome identifies the genetic basis of key agronomic traits.
The ancestors of Gossypium arboreum and Gossypium herbaceum provided the A subgenome for the modern cultivated allotetraploid cotton. Here, we upgraded the G. arboreum genome assembly by integrating different technologies. We resequenced 243 G. arboreum and G. herbaceum accessions to generate a map of genome variations and found that they are equally diverged from Gossypium raimondii. Independent analysis suggested that Chinese G. arboreum originated in South China and was subsequently introduced to the Yangtze and Yellow River regions. Most accessions with domestication-related traits experienced geographic isolation. Genome-wide association study (GWAS) identified 98 significant peak associations for 11 agronomically important traits in G. arboreum. A nonsynonymous substitution (cysteine-to-arginine substitution) of GaKASIII seems to confer substantial fatty acid composition (C16:0 and C16:1) changes in cotton seeds. Resistance to fusarium wilt disease is associated with activation of GaGSTF9 expression. Our work represents a major step toward understanding the evolution of the A genome of cotton.


Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome.
Wiedemann-Rautenstrauch syndrome (WRS) is a form of segmental progeria presenting neonatally, characterised by growth retardation, sparse scalp hair, generalised lipodystrophy with characteristic local fatty tissue accumulations and unusual face. We aimed to understand its molecular cause. We performed exome sequencing in two families, targeted sequencing in 10 other families and performed in silico modelling studies and transcript processing analyses to explore the structural and functional consequences of the identified variants. Biallelic POLR3A variants were identified in eight affected individuals and monoallelic variants of the same gene in four other individuals. In the latter, lack of genetic material precluded further analyses. Multiple variants were found to affect POLR3A transcript processing and were mostly located in deep intronic regions, making clinical suspicion fundamental to detection. While biallelic POLR3A variants have been previously reported in 4H syndrome and adolescent-onset progressive spastic ataxia, recurrent haplotypes specifically occurring in individuals with WRS were detected. All WRS-associated POLR3A amino acid changes were predicted to perturb substantially POLR3A structure/function. Biallelic mutations in POLR3A, which encodes for the largest subunit of the DNA-dependent RNA polymerase III, underlie WRS. No isolated functional sites in POLR3A explain the phenotype variability in POLR3A-related disorders. We suggest that specific combinations of compound heterozygous variants must be present to cause the WRS phenotype. Our findings expand the molecular mechanisms contributing to progeroid disorders.


Evidence for widespread changes in promoter methylation profile in human placenta in response to increasing gestational age and environmental/stochastic factors.
The human placenta facilitates the exchange of nutrients, gas and waste between the fetal and maternal circulations. It also protects the fetus from the maternal immune response. Due to its role at the feto-maternal interface, the placenta is subject to many environmental exposures that can potentially alter its epigenetic profile. Previous studies have reported gene expression differences in placenta over gestation, as well as inter-individual variation in expression of some genes. However, the factors contributing to this variation in gene expression remain poorly understood. In this study, we performed a genome-wide DNA methylation analysis of gene promoters in placenta tissue from three pregnancy trimesters. We identified large-scale differences in DNA methylation levels between first, second and third trimesters, with an overall progressive increase in average methylation from first to third trimester. The most differentially methylated genes included many immune regulators, reflecting the change in placental immuno-modulation as pregnancy progresses. We also detected increased inter-individual variation in the third trimester relative to first and second, supporting an accumulation of environmentally induced (or stochastic) changes in DNA methylation pattern. These highly variable genes were enriched for those involved in amino acid and other metabolic pathways, potentially reflecting the adaptation of the human placenta to different environments. The identification of cellular pathways subject to drift in response to environmental influences provide a basis for future studies examining the role of specific environmental factors on DNA methylation pattern and placenta-associated adverse pregnancy outcomes.


Molecular mechanisms of cortical differentiation.
During development, several populations of progenitor cells in the dorsal telencephalon generate a large variety of neurons which acquire distinct morphologies and physiological properties and serve distinct functions in the mammalian cortex. This paper reviews recent work that has identified (i) key molecules involved in the specification and differentiation of cortical neurons, (ii) novel genes which distinguish distinct subsets of cortical progenitors and may be involved in the diversification of cortical neurons present in different cortical layers, and (iii) mechanisms involved in the generation of different projection neuronal subtypes in the well-studied model of layer 5 of the rodent cortex.


Vitamin D status and ill health: a systematic review.
Low serum concentrations of 25-hydroxyvitamin D (25[OH]D) have been associated with many non-skeletal disorders. However, whether low 25(OH)D is the cause or result of ill health is not known. We did a systematic search of prospective and intervention studies that assessed the effect of 25(OH)D concentrations on non-skeletal health outcomes in individuals aged 18 years or older. We identified 290 prospective cohort studies (279 on disease occurrence or mortality, and 11 on cancer characteristics or survival), and 172 randomised trials of major health outcomes and of physiological parameters related to disease risk or inflammatory status. Investigators of most prospective studies reported moderate to strong inverse associations between 25(OH)D concentrations and cardiovascular diseases, serum lipid concentrations, inflammation, glucose metabolism disorders, weight gain, infectious diseases, multiple sclerosis, mood disorders, declining cognitive function, impaired physical functioning, and all-cause mortality. High 25(OH)D concentrations were not associated with a lower risk of cancer, except colorectal cancer. Results from intervention studies did not show an effect of vitamin D supplementation on disease occurrence, including colorectal cancer. In 34 intervention studies including 2805 individuals with mean 25(OH)D concentration lower than 50 nmol/L at baseline supplementation with 50 μg per day or more did not show better results. Supplementation in elderly people (mainly women) with 20 μg vitamin D per day seemed to slightly reduce all-cause mortality. The discrepancy between observational and intervention studies suggests that low 25(OH)D is a marker of ill health. Inflammatory processes involved in disease occurrence and clinical course would reduce 25(OH)D, which would explain why low vitamin D status is reported in a wide range of disorders. In elderly people, restoration of vitamin D deficits due to ageing and lifestyle changes induced by ill health could explain why low-dose supplementation leads to slight gains in survival.


Molecular chaperone involvement in chloroplast protein import.
Chloroplasts are organelles of endosymbiotic origin that perform essential functions in plants. They contain about 3000 different proteins, the vast majority of which are nucleus-encoded, synthesized in precursor form in the cytosol, and transported into the chloroplasts post-translationally. These preproteins are generally imported via envelope complexes termed TOC and TIC (Translocon at the Outer/Inner envelope membrane of Chloroplasts). They must navigate different cellular and organellar compartments (e.g., the cytosol, the outer and inner envelope membranes, the intermembrane space, and the stroma) before arriving at their final destination. It is generally considered that preproteins are imported in a largely unfolded state, and the whole process is energy-dependent. Several chaperones and cochaperones have been found to mediate different stages of chloroplast import, in similar fashion to chaperone involvement in mitochondrial import. Cytosolic factors such as Hsp90, Hsp70 and 14-3-3 may assist preproteins to reach the TOC complex at the chloroplast surface, preventing their aggregation or degradation. Chaperone involvement in the intermembrane space has also been proposed, but remains uncertain. Preprotein translocation is completed at the trans side of the inner membrane by ATP-driven motor complexes. A stromal Hsp100-type chaperone, Hsp93, cooperates with Tic110 and Tic40 in one such motor complex, while stromal Hsp70 is proposed to act in a second, parallel complex. Upon arrival in the stroma, chaperones (e.g., Hsp70, Cpn60, cpSRP43) also contribute to the folding, assembly or onward intraorganellar guidance of the proteins. In this review, we focus on chaperone involvement during preprotein translocation at the chloroplast envelope. This article is part of a Special Issue entitled: Protein Import and Quality Control in Mitochondria and Plastids.


Role of 14-3-3 protein and oxidative stress in diabetic cardiomyopathy.
Cardiovascular disease is a leading cause of death worldwide. Diabetes mellitus is a well-known and important risk factor for cardiovascular diseases. The occurrence of diabetic cardiomyopathy is independent of hypertension, coronary artery disease, or any other known cardiac diseases. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Diabetic cardiomyopathy is characterized by morphologic and structural changes in the myocardium and coronary vasculature mediated by the activation of various signaling pathways. Myocardial apoptosis, hypertrophy and fibrosis are the most frequently proposed mechanisms to explain cardiac changes in diabetic cardiomyopathy. Mammalian 14-3-3 proteins are dimeric phosphoserine-binding proteins that participate in signal transduction and regulate several aspects of cellular biochemistry. 14-3-3 protein regulates diabetic cardiomyopathy via multiple signaling pathways. This review focuses on emerging evidence suggesting that 14-3-3 protein plays a key role in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic cardiomyopathy.


Perceptions of the food shopping environment are associated with greater consumption of fruits and vegetables.
The present study examined whether characteristics such as quality, selection and convenience are associated with dietary intake of fruits and vegetables independent of perceived costs in an inner-city, low-income population. Secondary analysis of baseline data from a social marketing intervention designed to change household dietary practices among parents of 3- to 7-year-old children. A community sample drawn from six low-income, primarily minority neighbourhoods in Chicago, IL, USA. From the parent study, 526 respondents completed the baseline survey and were eligible for inclusion. Of this number, 495 provided complete data on sociodemographic characteristics, fruit and vegetable consumption, perceptions of the shopping environment, perceived costs of fruits and vegetables, and food shopping habits. Logistic regression analysis showed that more positive perceptions of the food shopping environment were associated with greater consumption of fruits and vegetables. There was an increase of approximately twofold in the likelihood of consuming three or more fruits and vegetables daily per level of satisfaction ascribed to the shopping environment. This association was independent of perceived cost, store type and sociodemographic characteristics. Our data show that among a generally minority and low-income population, quality, selection and convenience are important determinants of fruit and vegetable consumption. Nutrition promotion campaigns that aim to alter the built environment by increasing access to fruits and vegetables should recognize that simply increasing availability may not yield beneficial change when characteristics of the shopping context are ignored.


A lyapunov-based extension to particle swarm dynamics for continuous function optimization.
The paper proposes three alternative extensions to the classical global-best particle swarm optimization dynamics, and compares their relative performance with the standard particle swarm algorithm. The first extension, which readily follows from the well-known Lyapunov's stability theorem, provides a mathematical basis of the particle dynamics with a guaranteed convergence at an optimum. The inclusion of local and global attractors to this dynamics leads to faster convergence speed and better accuracy than the classical one. The second extension augments the velocity adaptation equation by a negative randomly weighted positional term of individual particle, while the third extension considers the negative positional term in place of the inertial term. Computer simulations further reveal that the last two extensions outperform both the classical and the first extension in terms of convergence speed and accuracy.


Azithromycin has an antiproliferative and autophagic effect on airway smooth muscle cells.
Azithromycin is used in long-term, low-dose treatment of airway diseases where airway wall remodelling is present. Since it improves total score symptom and respiratory function of such patients, we hypothesise that azithromycin's additional clinical benefits are due to an inhibition of airway smooth muscle cell (SMC) proliferation. Rabbit tracheal SMCs were treated with azithromycin (10(-5) to 10(-6) M) in the presence or absence of 10% fetal bovine serum (FBS). The proliferation was estimated using the Cell Titer 96(R) AQ(ueous) One Solution Assay (Promega, Madison, WI, USA). Cell viability was assessed with Trypan blue staining and flow cytometry after 7-aminoactinomycin D (7-AAD) staining. Induction of autophagy was studied by indirect immmunofluorescence and/or Western blotting with antibodies against human smooth muscle alpha-actin, beclin 1, light chain 3 and caspase 3. The involvement of the phosphoinositide 3-kinase pathway was investigated with the inhibitors LY294002 and wortmannin. Incubation with azithromycin for 72 h in the presence of FBS reduced SMC proliferation and viability in a dose-dependent manner. Azithromycin treatment was accompanied by the formation of cytoplasmic vacuoles, characteristic of autophagy. All these effects were reversible after azithromycin removal and prevented by the autophagy inhibitor, 3-methyladenine, or LY294002, but not by wortmannin. In conclusion, azithromycin reduces proliferation and causes autophagy of airway SMCs.


Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity.
Doxorubicin (DOX) is widely used as a first-line chemotherapeutic drug for various malignancies. However, DOX causes severe cardiotoxicity, which limits its clinical uses. Oxidative stress is one of major contributors to DOX-induced cardiotoxicity. While autophagic flux serves as an important defense mechanism against oxidative stress in cardiomyocytes, recent studies have demonstrated that DOX induces the blockage of autophagic flux, which contributes to DOX cardiotoxicity. The present study investigated whether nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD)+, prevents DOX cardiotoxicity by improving autophagic flux. We report that administration of NR elevated NAD+ levels, and reduced cardiac injury and myocardial dysfunction in DOX-injected mice. These protective effects of NR were recapitulated in cultured cardiomyocytes upon DOX treatment. Mechanistically, NR prevented the blockage of autophagic flux, accumulation of autolysosomes, and oxidative stress in DOX-treated cardiomyocytes, the effects of which were associated with restoration of lysosomal acidification. Furthermore, inhibition of lysosomal acidification or SIRT1 abrogated these protective effects of NR during DOX-induced cardiotoxicity. Collectively, our study shows that NR enhances autolysosome clearance via the NAD+/SIRT1 signaling, thereby preventing DOX-triggered cardiotoxicity.


CD161++ CD8+ T cells, including the MAIT cell subset, are specifically activated by IL-12+IL-18 in a TCR-independent manner.
CD161(++) CD8(+) T cells represent a novel subset that is dominated in adult peripheral blood by mucosal-associated invariant T (MAIT) cells, as defined by the expression of a variable-α chain 7.2 (Vα7.2)-Jα33 TCR, and IL-18Rα. Stimulation with IL-18+IL-12 is known to induce IFN-γ by both NK cells and, to a more limited extent, T cells. Here, we show the CD161(++) CD8(+) T-cell population is the primary T-cell population triggered by this mechanism. Both CD161(++) Vα7.2(+) and CD161(++) Vα7.2(-) T-cell subsets responded to IL-12+IL-18 stimulation, demonstrating this response was not restricted to the MAIT cells, but to the CD161(++) phenotype. Bacteria and TLR agonists also indirectly triggered IFN-γ expression via IL-12 and IL-18. These data show that CD161(++) T cells are the predominant T-cell population that responds directly to IL-12+IL-18 stimulation. Furthermore, our findings broaden the potential role of MAIT cells beyond bacterial responsiveness to potentially include viral infections and other inflammatory stimuli.


Activity of the elbow flexor and extensor muscles during contact placing elicited by tactile stimulation of various aspects of the forelimb in the cat.
The activity of the biceps brachii and lateral head of the triceps brachii were compared during the contact placing reactions elicited by tactile stimuli applied to the lateral, medial or dorsal aspects of the forepaw to verify the hypothesis that common movement strategy was used in all these reactions. Similar latencies and patterns of muscle activation have been found for the medial and dorsal placing while the different timing of the muscle activation was seen in lateral placing reactions. Both muscles often coactivated during lateral or dorsal and less frequently during medial placing reactions. In dorsal placing the coactivations predominated at the beginning of the reactions while in lateral placing they appeared most frequently in later phases of the reaction. The co-contraction of the elbow flexor and extensor muscles leads to locking of the elbow joint. Thus, the coactivation of these muscles in different phases of the lateral, medial and dorsal placing reactions indicates that various movement strategies have been used as the elbow flexion movement is initiated in different phases of these reactions.


Evaluation of a fotonovela to increase depression knowledge and reduce stigma among Hispanic adults.
Fotonovelas-small booklets that portray a dramatic story using photographs and captions-represent a powerful health education tool for low-literacy and ethnic minority audiences. This study evaluated the effectiveness of a depression fotonovela in increasing depression knowledge, decreasing stigma, increasing self-efficacy to recognize depression, and increasing intentions to seek treatment, relative to a text pamphlet. Hispanic adults attending a community adult school (N = 157, 47.5 % female, mean age = 35.8 years, 84 % immigrants, 63 % with less than high school education) were randomly assigned to read the fotonovela or a low-literacy text pamphlet about depression. They completed surveys before reading the material, immediately after reading the material, and 1 month later. The fotonovela and text pamphlet both produced significant improvements in depression knowledge and self-efficacy to identify depression, but the fotonovela produced significantly larger reductions in antidepressant stigma and mental health care stigma. The fotonovela also was more likely to be passed on to family or friends after the study, potentially increasing its reach throughout the community. Results indicate that fotonovelas can be useful for improving health literacy among underserved populations, which could reduce health disparities.


Environmental symbiont acquisition may not be the solution to warming seas for reef-building corals.
Coral reefs worldwide are in decline. Much of the mortality can be attributed to coral bleaching (loss of the coral's intracellular photosynthetic algal symbiont) associated with global warming. How corals will respond to increasing oceanic temperatures has been an area of extensive study and debate. Recovery after a bleaching event is dependent on regaining symbionts, but the source of repopulating symbionts is poorly understood. Possibilities include recovery from the proliferation of endogenous symbionts or recovery by uptake of exogenous stress-tolerant symbionts. To test one of these possibilities, the ability of corals to acquire exogenous symbionts, bleached colonies of Porites divaricata were exposed to symbiont types not normally found within this coral and symbiont acquisition was monitored. After three weeks exposure to exogenous symbionts, these novel symbionts were detected in some of the recovering corals, providing the first experimental evidence that scleractinian corals are capable of temporarily acquiring symbionts from the water column after bleaching. However, the acquisition was transient, indicating that the new symbioses were unstable. Only those symbiont types present before bleaching were stable upon recovery, demonstrating that recovery was from the resident in situ symbiont populations. These findings suggest that some corals do not have the ability to adjust to climate warming by acquiring and maintaining exogenous, more stress-tolerant symbionts. This has serious ramifications for the success of coral reefs and surrounding ecosystems and suggests that unless actions are taken to reverse it, climate change will lead to decreases in biodiversity and a loss of coral reefs.


Presleep activities and time of sleep onset in children.
Presleep activities have been implicated in the declining sleep duration of young people. A use-of-time approach may be used to describe the presleep period. The study aims were to describe the activities undertaken 90 minutes before sleep onset and to examine the association between activities and time of sleep onset in New Zealand young people. Participants (N = 2017; 5-18 years) self-reported their time use as part of a national survey. All activities reported in the 90 minutes before sleep were extracted. The top 20 activities were grouped into 3 behavioral sets: screen sedentary time, nonscreen sedentary time, and self-care. An adjusted regression model was used to estimate presleep time spent in each behavioral set for 4 distinct categories of sleep onset (very early, early, late, or very late), and the differences between sleep onset categories were tested. In the entire sample, television watching was the most commonly reported activity, and screen sedentary time accounted for ∼30 minutes of the 90-minute presleep period. Participants with a later sleep onset had significantly greater engagement in screen time than those with an earlier sleep onset. Conversely, those with an earlier sleep onset spent significantly greater time in nonscreen sedentary activities and self-care. Screen sedentary time dominated the presleep period in this sample and was associated with a later sleep onset. The development of interventions to reduce screen-based behaviors in the presleep period may promote earlier sleep onset and ultimately improved sleep duration in young people.


Does the Addition of a "Black Bone" Sequence to a Fast Multisequence Trauma MR Protocol Allow MRI to Replace CT after Traumatic Brain Injury in Children?
Head CT is the current neuroimaging tool of choice in acute evaluation of pediatric head trauma. The potential cancer risks of CT-related ionizing radiation should limit its use in children. We evaluated the role of MR imaging, including a "black bone" sequence, compared with CT in detecting skull fractures and intracranial hemorrhages in children with acute head trauma. We performed a retrospective evaluation of 2D head CT and brain MR imaging studies including the black bone sequence of children with head trauma. Two experienced pediatric neuroradiologists in consensus created the standard of reference. Another pediatric neuroradiologist blinded to the diagnosis evaluated brain MR images and head CT images in 2 separate sessions. The presence of skull fractures and intracranial posttraumatic hemorrhages was evaluated. We calculated the sensitivity and specificity of CT and MR imaging with the black bone sequence in the diagnosis of skull fractures and intracranial hemorrhages. Twenty-eight children (24 boys; mean age, 4.89 years; range, 0-15.5 years) with head trauma were included. MR imaging with the black bone sequence revealed lower sensitivity (66.7% versus 100%) and specificity (87.5% versus 100%) in identifying skull fractures. Four of 6 incorrectly interpreted black bone MR imaging studies showed cranial sutures being misinterpreted as skull fractures and vice versa. Our preliminary results show that brain MR imaging complemented by a black bone sequence is a promising nonionizing alternative to head CT for the assessment of skull fractures in children. However, accuracy in the detection of linear fractures in young children and fractures of aerated bone remains limited.


Industry differences in psychological distress and distress-related productivity loss: A cross-sectional study of Australian workers.
This research uses Australian survey data to identify industries with high rates of psychological distress, and to estimate productivity impacts in the form of work loss and cutback days. Analyzing cross-sectional data from the 2017/2018 National Health Survey, industry prevalence of psychological distress (Kessler Screening Scale) was compared using ordered logistic regression. Productivity outcomes were distress-related work loss days and work cutback days in the previous 4 weeks. Losses were analyzed using zero-inflated negative binomial regression. The sample consisted of 9073 employed workers [4497 males (49.6%), 4576 females (50.4%)]. Compared to the reference industry, Health, the odds of very high distress for males were highest in Information media and telecommunications (OR 2.4; 95% CI 1.2-4.6) and Administrative and support services (OR 2.5; 95% CI 1.2-5.0), while for females the odds were highest in Accommodation and food services (OR 2.0; 95% CI 1.5-2.8) followed by Retail (OR 1.6; 95% CI 1.2-2.0). Very high distress was associated excess productivity losses. Industry of occupation did not impact on productivity loss over and above distress. Substantial psychological distress was reported which impacted on productivity. High-risk industries included Information media and telecommunications, Accommodation and food services, and Retail.


Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy.
Sustained hyperleptinemia of 8 ng/ml was induced for 28 days in normal Wistar rats by infusing a recombinant adenovirus containing the rat leptin cDNA (AdCMV-leptin). Hyperleptinemic rats exhibited a 30-50% reduction in food intake and gained only 22 g over the experimental period versus 115-132 g in control animals that received saline infusions or a recombinant virus containing the beta-galactosidase gene (AdCMV-beta Gal). Body fat was absent in hyperleptinemic rats, whereas control rats pair-fed to the hyperleptinemic rats retained approximately 50% body fat. Further, plasma triglycerides and insulin levels were significantly lower in hyperleptinemic versus pair-fed controls, while fatty acid and glucose levels were similar in the two groups, suggestive of enhanced insulin sensitivity in the hyperleptinemic animals. Thus, despite equivalent reductions in food intake and weight gain in hyperleptinemic and pair-fed animals, identifiable fat tissue was completely ablated only in the former group, raising the possibility of a specific lipoatrophic activity for leptin.


Viral-Induced Enhanced Disease Illness.
Understanding immune responses to viral infections is crucial to progress in the quest for effective infection prevention and control. The host immunity involves various mechanisms to combat viral infections. Under certain circumstances, a viral infection or vaccination may result in a subverted immune system, which may lead to an exacerbated illness. Clinical evidence of enhanced illness by preexisting antibodies from vaccination, infection or maternal passive immunity is available for several viruses and is presumptively proposed for other viruses. Multiple mechanisms have been proposed to explain this phenomenon. It has been confirmed that certain infection- and/or vaccine-induced immunity could exacerbate viral infectivity in Fc receptor- or complement bearing cells- mediated mechanisms. Considering that antibody dependent enhancement (ADE) is a major obstacle in vaccine development, there are continues efforts to understand the underlying mechanisms through identification of the epitopes and antibodies responsible for disease enhancement or protection. This review discusses the recent findings on virally induced ADE, and highlights the potential mechanisms leading to this condition.


Possible role of milk-derived bioactive peptides in the treatment and prevention of metabolic syndrome.
The growing prevalence of metabolic syndrome as well as its impact on public health has garnered increased attention in recent years. As a result, metabolic syndrome is now considered one of the world's leading public health problems. Bioactive peptides deriving from milk proteins may play an important role in the prevention and treatment of metabolic syndrome and its complications via several mechanisms, such as the satiety response, the regulation of insulinemia levels and blood pressure, the uptake of free radicals, and alteration of the lipid profile. These peptides can be incorporated into functional foods or administered via nutraceuticals to decrease the risk of obesity, atherogenesis, arterial hypertension, and type 2 diabetes. Recent findings have generated considerable scientific and commercial interest in milk-derived bioactive peptides, leading to numerous publications on the effectiveness of these substances. This review summarizes the current knowledge on bioactive peptides derived from milk proteins and examines the potential value of these peptides in the treatment and prevention of metabolic syndrome and its complications.


The incidence of IgG4-positive plasma cells staining TIN in patients with biopsy-proven tubulointerstitial nephritis.
IgG4 disease is rare. However, IgG4 tubulointerstitial nephritis (TIN) is the most common renal manifestation. IgG4 disease is usually associated with elevated serum IgG4 levels and other organ involvement, low-density renal lesions on enhanced CT imaging and immune activation. The incidence of IgG4-TIN may be underestimated, as staining for IgG4 is not routine. This study sought to describe the prevalence of previously undiagnosed IgG4-TIN. Due to the complexity of the diagnosis, we only attempt to look at IgG4-positive plasma cell TIN as a potential indication for IgG4 renal disease. A retrospective review of native renal biopsies performed between 2002 and 2012 with a primary diagnosis of TIN was selected. Samples for which interstitial nephritis was secondary to a glomerular disease were excluded. The tissues were stained for IgG4 and scored by two blinded observers. Demographic and follow-up details were collected. This study was approved by the local ethics committee. 82 cases of interstitial nephritis from a total of 1238 renal biopsies (2002-2012) were available after staining for further assessment. 12 samples demonstrated staining consistent with the criteria for IgG4-positive plasma cell TIN, of which 3 had mildly positive staining, 7 moderately positive staining and 2 had markedly positive staining. There were no statistically significant differences in the baseline characteristics between the positive and negative staining groups. A number of cases of IgG4-positive plasma cell TIN were observed histologically that had been previously diagnosed as non-specific chronic TIN. IgG4-positive plasma cell TIN made up 1% of all renal biopsies performed over 10 years and 13% of all biopsies demonstrating TIN not related to glomerular disease. IgG4 staining should be considered routinely in biopsies demonstrating primary TIN.


A prospective study of reproductive factors, oral contraceptive use, and risk of colorectal cancer.
To explore the roles of reproductive factors and oral contraceptive use in the etiology of colorectal cancer, we examined incident cases of colorectal cancer (n = 501) that occurred during 1,012,280 person-years of follow-up between 1980 and 1992 in the Nurses' Health Study. The women completed mailed, self-administered questionnaires every 2 years to update information on the risk factors and major medical events. In multivariate analysis, the relative risk (RR) of colorectal cancer among women who experienced menarche at age 14 or older was 0.83 (95% confidence interval (CI) = 0.64-1.08) compared with women who had menarche at age 13; women whose menarche occurred under age 12 were at higher risk (RR = 1.22; 95% CI = 0.96-1.55, P for trend = 0.01). Compared with women whose first pregnancy was before age 24, the risk for colorectal cancer was significantly increased among women whose first pregnancy was at age 30 or older (RR = 1.57; 95% CI = 1.15-2.14; P for trend = 0.02). No important associations were seen for parity or age at menopause. Women who used oral contraceptives for 96 months or longer had a 40% lower risk of developing colorectal cancer (RR = 0.60; 95% CI = 0.40-0.89; P for trend = 0.02) compared with women who never used oral contraceptives. These prospective data suggest that a later age of menarche and use of oral contraceptives may reduce risk of colorectal cancer, whereas women with a later age at first pregnancy may have a higher risk.


Age distribution dynamics with stochastic jumps in mortality.
While deterministic age distribution models have been extensively studied and applied in various disciplines, little work has been devoted to understanding the role of stochasticity in birth and mortality terms. In this paper, we analyse a stochastic M'Kendrick-von Foerster equation in which jumps in mortality represent intense losses of population due to external events. We present explicit solutions for the probability density functions of the age distribution and the total population and for the temporal dynamics of their moments. We also derive the dynamics of the mean age of the population and its harmonic mean. The framework is then used to calculate the age distribution of salt in the soil root zone, where the accumulation of salt by atmospheric deposition is counteracted by plant uptake and by jump losses due to percolation events.


TGF-beta treatment modulates PD-L1 and CD40 expression in proximal renal tubular epithelial cells and enhances CD8 cytotoxic T-cell responses.
TGF-beta expression is increased in immune-mediated and fibrotic renal diseases and modulates the tubulointerstitial T-cell response. We examined whether TGF-beta changes the expression of PD-L1 and CD40 in the renal proximal tubular epithelial cell (TEC), and whether the activation of CD8(+) cytotoxic T cells (CTLs) is influenced by TGF-beta treatment of TECs. Murine TECs were treated with TGF-beta or IFN-gamma. The expression of PD-L1 and CD40 was examined with RT-PCR and flow cytometry. To investigate if TGF-beta treatment influenced the antigen presentation capacity of TECs, OT-1 CTLs were co-incubated with TGF-beta-treated, OVA(257-264) peptide-pulsed congeneic TECs. The cytotoxicity of OT-1 CTLs was estimated by their capacity to produce IFN-gamma and their cytolytic activity. TGF-beta treatment lead to a transition in morphology of renal TECs and downregulated the basal and the IFN-gamma-stimulated PD-L1 expression in TECs. Interestingly, TGF-beta treatment of TECs increased the constitutive and IFN-gamma-induced CD40 expression. In contrast to IFN-gamma which reduced the CTL activity, TGF-beta treatment of TECs elevated the OVA-specific CTL response. Our data show that TGF-beta changed the cellular phenotype and the expression of PD-L1 and CD40 on TECs and enhanced the activity of OVA peptide-specific CD8(+) T cells. TGF-beta may thereby play an important role in the progression of renal tubulointerstitial damage in CD8(+) T-cell-mediated renal diseases.


The secondary structure of the R region of a murine leukemia virus is important for stimulation of long terminal repeat-driven gene expression.
In addition to their role in reverse transcription, the R-region sequences of some retroviruses affect viral transcription. The first 28 nucleotides of the R region within the long terminal repeat (LTR) of the murine type C retrovirus SL3 were predicted to form a stem-loop structure. We tested whether this structure affected the transcriptional activity of the viral LTR. Mutations that altered either side of the stem and thus disrupted base pairing were generated. These decreased the level of expression of a reporter gene under the control of viral LTR sequences about 5-fold in transient expression assays and 10-fold in cells stably transformed with the LTR-reporter plasmids. We also generated a compensatory mutant in which both the ascending and descending sides of the stem were mutated such that the nucleotide sequence was different but the predicted secondary structure was maintained. Most of the activity of the wild-type SL3 element was restored in this mutant. Thus, the stem-loop structure was important for the maximum activity of the SL3 LTR. Primer extension analysis indicated that the stem-loop structure affected the levels of cytoplasmic RNA. Nuclear run-on assays indicated that deletion of the R region had a small effect on transcriptional initiation and no effect on RNA polymerase processivity. Thus, the main effect of the R-region element was on one or more steps that occurred after the template was transcribed by RNA polymerase. This finding implied that the main function of the R-region element involved RNA processing. R-region sequences of human immunodeficiency virus type 1 or mouse mammary tumor virus could not replace the SL3 element. R-region sequences from an avian reticuloendotheliosis virus partially substituted for the SL3 sequences. R-region sequences from Moloney murine leukemia virus or feline leukemia virus did function in place of the SL3 element. Thus, the R region element appears to be a general feature of the mammalian type C genus of retroviruses.


EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers.
The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18-60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.


FcγRIIIa expression on monocytes in rheumatoid arthritis: role in immune-complex stimulated TNF production and non-response to methotrexate therapy.
The expression of FcγRIIIa/CD16 may render monocytes targets for activation by IgG-containing immune complexes (IC). We investigated whether FcγRIIIa/CD16 was upregulated in rheumatoid arthritis (RA), associated with TNF production in response to IC-stimulation, and if this predicted response to methotrexate therapy. FcγRIIIa/CD16 expression on CD14(low) and CD14++ monocytes was measured by flow cytometry in healthy controls and RA patients (early and long-standing disease). Intracellular TNF-staining was carried out after in vitro LPS or heat-aggregated immunoglobulin (HAG) activation. FcγRIIIa/CD16 expression pre- and post-steroid/methotrexate treatment was examined. Increased FcγRIIIa/CD16 expression on CD14++ monocytes in long-standing RA patients compared to controls was demonstrated (p = 0.002) with intermediate levels in early-RA patients. HAG-induced TNF-production in RA patients was correlated with the percentage of CD14++ monocytes expressing FcγRIIIa/CD16 (p<0.001). The percentage of CD14++ monocytes expressing FcγRIIIa/CD16 at baseline in early DMARD-naïve RA patients was negatively correlated with DAS28-ESR improvement 14-weeks post-methotrexate therapy (p = 0.003) and was significantly increased in EULAR non-responders compared to moderate (p = 0.01) or good responders (p = 0.003). FcγRIIIa/CD16 expression was not correlated with age, presence of systemic inflammation or autoantibody titers. Increased FcγRIIIa/CD16 expression on CD14++ monocytes in RA may result in a cell that has increased responsiveness to IC-stimulation. This monocyte subset may contribute to non-response to methotrexate therapy.


Survival and risk factors for progression after resection of the dominant tumor in multifocal, lepidic-type pulmonary adenocarcinoma.
It remains unclear whether a dominant lung adenocarcinoma that presents with multifocal ground glass opacities (GGOs) should be treated by local therapy. We sought to address survival in this setting and to identify risk factors for progression of unresected GGOs. Retrospective review of 70 patients who underwent resection of a pN0, lepidic adenocarcinoma, who harbored at least 1 additional GGO. Features associated with GGO progression were determined using logistic regression and survival was evaluated using the Kaplan-Meier method. Subjects harbored 1 to 7 GGOs beyond their dominant tumor (DT). Mean follow-up was 4.1 ± 2.8 years. At least 1 GGO progressed after DT resection in 21 patients (30%). In 11 patients (15.7%), this progression prompted resection (n = 5) or stereotactic radiotherapy (n = 6) at mean 2.8 ± 2.3 years. Several measures of the overall tumor burden were associated with GGO progression (all P values < .03) and with progression prompting intervention (all P values < .01). In logistic regression, greater DT size (odds ratio, 1.07; 95% confidence interval, 1.01-1.14) and an initial GGO > 1 cm (odds ratio, 4.98; 95% confidence interval, 1.15-21.28) were the only factors independently associated with GGO progression. Survival was not negatively influenced by GGO progression (100% with vs 80.7% without; P = .1) or by progression-prompting intervention (P = .4). At 4.1-year mean follow-up, 15.7% of patients with unresected GGOs after resection of a pN0 DT underwent subsequent intervention for a progressing GGO. Some features correlated with GGO growth, but neither growth, nor need for an intervention, negatively influenced survival. Thus, even those at highest risk for GGO progression should not be denied resection of a DT.


Assessing Soil Contamination Due to Oil and Gas Production Using Vegetation Hyperspectral Reflectance.
The remote assessment of soil contamination remains difficult in vegetated areas. Recent advances in hyperspectral spectroscopy suggest making use of plant reflectance to monitor oil and gas leakage from industrial facilities. However, knowledge about plant response to oil contamination is still limited, so only very few imaging applications are possible at this stage. We therefore conducted a greenhouse experiment on three species long-term exposed to either oil-contaminated or water-deficient soils. Reflectance measurements were regularly performed at leaf and plant scale over 61 days of exposure. Results showed an increase of reflectance in the visible (VIS), the red-edge and the short-wave infrared (SWIR) under both oil and water-deficit stress exposure. A contrasted response in the near-infrared (NIR) was also observed among species. Spectra underwent transformations to discriminate species' responses to the different treatments using linear discriminant analysis (LDA) with a stepwise procedure. Original and transformed spectra enabled to discriminate the plants' responses to the different treatments without confusion after 61 days. The discriminating wavelengths were consistent with the spectral differences observed. These results suggest differential changes in plant pigments, structure and water content as a response to various stressors, and open up promising perspectives for airborne and satellite applications.


An in vitro model to explore subchondral perfusion and intraosseous pressure.
Little is known about subchondral perfusion physiology. We developed a 3Rs (Replace, Reduce, Refine) compliant in vitro calf foot model to explore perfusion and intraosseous pressure (IOP). Calf feet were catheterised and perfused with serum. IOP was measured at three sites, the metacarpal diaphysis (MCD), metacarpal subchondral epiphysis (MCS) and proximal phalanx diaphysis (PPD) using intraosseous needles with pressure transducers and digital recorders. Fresh (< 4 h post mortem) and old feet (> 4 h post mortem) were perfused at different pressures, with and without a proximal tourniquet. There was a wide range in basal IOP with a mean IOP of 30.0 mmHg, SD 14.4, range 7.6 mmHg to 52.7 mmHg (n = 40 records) in 15 subjects. There was no significant difference between the three sites tested (p = 0.54, 0.12 and 0.051). At each individual site IOP correlated with perfusion pressure (r = 0.993). With a proximal venous tourniquet, IOP increased from 15.1 mmHg (SD 11.3 mmHg) to 44.9 mmHg (SD 24 mmHg), p < 0.0001, n = 9. Filling and emptying curves during perfusion and with using a tourniquet were similar, indicating that the model behaves in an elastic hydrodynamic manner. In fresh feet IOP peaked after about 1 min irrespective of perfusion pressure, possibly due to auto regulation. Older feet showed a continuously rising IOP and became oedematous. There was no significant difference in IOP between fresh and old feet perfused with serum at 150 cms pressure for 1 min. Though basal intraosseous pressure varies, IOP behaves predictably. IOP measurements reflect the perfusion microclimate at the individual needle tip. This 3Rs compliant model will be used for further exploration of subchondral perfusion physiology with loading.


Protective effects of mate tea (Ilex paraguariensis) on H2O2-induced DNA damage and DNA repair in mice.
Yerba mate (Ilex paraguariensis) is rich in several bioactive compounds that can act as free radical scavengers. Since oxidative DNA damage is involved in various pathological states such as cancer, the aim of this study was to evaluate the antioxidant activity of mate tea as well as the ability to influence DNA repair in male Swiss mice. Forty animals were randomly assigned to four groups. The animals received three different doses of mate tea aqueous extract, 0.5, 1.0 or 2.0 g/kg, for 60 days. After intervention, the liver, kidney and bladder cells were isolated and the DNA damage induced by H(2)O(2) was investigated by the comet assay. The DNA repair process was also investigated for its potential to protect the cells from damage by the same methodology. The data presented here show that mate tea is not genotoxic in liver, kidney and bladder cells. The regular ingestion of mate tea increased the resistance of DNA to H(2)O(2)-induced DNA strand breaks and improved the DNA repair after H(2)O(2) challenge in liver cells, irrespective of the dose ingested. These results suggest that mate tea could protect against DNA damage and enhance the DNA repair activity. Protection may be afforded by the antioxidant activity of the mate tea's bioactive compounds.


Reduced Purkinje cell number in essential tremor: a postmortem study.
Clinical and functional imaging evidence suggests that cerebellar dysfunction occurs in essential tremor (ET). In recent postmortem studies, we documented increased numbers of torpedoes (Purkinje cell axonal swellings) in ET patients without Lewy bodies. Purkinje cell loss, however, has never been rigorously assessed. To quantitatively assess the number of Purkinje cells in brains of ET patients and similarly aged controls. Postmortem cerebellar tissue was available in 14 ET cases (6 with Lewy bodies and 8 without Lewy bodies) and 11 controls. Calbindin immunohistochemistry was performed on paraffin sections of the cerebellum. Images were digitally recorded and blinded measurements of the number of Purkinje cells per millimeter of cell layer (linear density) were made. Purkinje cell linear density was inversely correlated with age (r= - 0.53, P= .006) and number of torpedoes (r= - 0.42, P= .04). Purkinje cell linear density differed by diagnosis (mean [SD], controls, 3.46 [1.27] cells/mm; ET cases with Lewy bodies, 3.33 [1.06] cells/mm; and ET cases without Lewy bodies, 2.14 [0.82] cells/mm; P= .04), with the most significant difference between ET cases without Lewy bodies and controls, where the reduction was 38.2% (P= .04). In an adjusted linear regression analysis that compared ET cases without Lewy bodies with controls, decreased linear density (outcome variable) was associated with ET (beta= .56, P= .03). We demonstrated a reduction in Purkinje cell number in the brains of patients with ET who do not have Lewy bodies. These data further support the view that the cerebellum is anatomically, as well as functionally, abnormal in these ET cases.


A multicentre retrospective analysis on growth of residual hepatocellular adenoma after resection.
Hepatocellular adenoma (HCA) is a benign liver tumour that may require resection in select cases. The aim of this study was to the assess growth of residual HCA in the remnant liver and to advise on an evidence-based management strategy. This multicentre retrospective cohort study included all patients with HCA who underwent surgery of HCA and had residual HCA in the remnant liver. Growth was defined as an increase of >20% in transverse diameter (RECIST criteria). Data on patient and HCA characteristics, diagnostic work-up, treatment and follow-up were documented and analysed. A total of 134 patients were included, one male. At diagnosis, median age was 38yrs (IQR 30.0-44.0) and median BMI was 29.9 kg/m2 (IQR 24.6-33.3). After resection, median number of residual sites of HCA was 3 (IQR 2-6). Follow-up of residual HCA showed regression in 24.6%, stable HCA in 61.9% and growth of at least one lesion in 11.2%. Three patients (2.2%) developed new HCA that were not visible on imaging prior to surgery. Four patients (3%, one male) underwent an intervention as growth was progressive. No statistically significant differences in clinical characteristics were found between patients with growing residual or new HCA versus those with stable or regressing residual HCA. In patients with multiple HCA who undergo resection, growth of residual HCA is not uncommon but interventions are rarely needed as most lesions stabilize and do not show progressive growth. Surveillance is indicated when residual HCA show growth after resection, enabling intervention in case of progressive growth.


Neurostructural correlates of strength decrease following total knee arthroplasty: A systematic review of the literature with meta-analysis.
Recent literature suggests that alterations in both neural and structural components of the neuromuscular system are major determinants of knee extensor muscle weakness after total knee arthroplasty (TKA). Therefore, the goal of this study was to investigate the maximal voluntary strength (MVS), voluntary muscle activation (VMA), and the cross-sectional area (CSA) of the muscle, up to 33 months after the TKA. We searched relevant scientific databases and literature for outcomes of interest, including quadriceps MVS, VMA, and CSA. Ten studies met the inclusion criteria and involved a total of 289 patients. The quality of the studies was evaluated by Methodological Index for Non-Randomized Studies (MINORS). Results showed that quadriceps MVS markedly declines in the early postoperative period, after which it slowly and linearly recovers over time. However, the same phenomenon was not observed for VMA and CSA, which were not significantly altered after the TKA. Furthermore, a meta-regression analysis revealed that the change in VMA accounted for 39% of the relative change in quadriceps strength (R2=0.39; p=0.015) in the early postoperative period. Patients treated with TKA had considerable weakness of the quadriceps muscle, which was detectable up to 3 months after surgery. Although the change in VMA largely explains quadriceps weakness, this change and CSA differences were not significant, suggesting that other neural correlates, such as hamstrings coactivation, might alter quadriceps muscle function. Thus, more attention should be paid to address VMA failure and coactivation of antagonist muscles. More comprehensive rehabilitation approaches may be required to target the whole neural circuit controlling the motor action.


Phytophthora have distinct endogenous small RNA populations that include short interfering and microRNAs.
In eukaryotes, RNA silencing pathways utilize 20-30-nucleotide small RNAs to regulate gene expression, specify and maintain chromatin structure, and repress viruses and mobile genetic elements. RNA silencing was likely present in the common ancestor of modern eukaryotes, but most research has focused on plant and animal RNA silencing systems. Phytophthora species belong to a phylogenetically distinct group of economically important plant pathogens that cause billions of dollars in yield losses annually as well as ecologically devastating outbreaks. We analyzed the small RNA-generating components of the genomes of P. infestans, P. sojae and P. ramorum using bioinformatics, genetic, phylogenetic and high-throughput sequencing-based methods. Each species produces two distinct populations of small RNAs that are predominantly 21- or 25-nucleotides long. The 25-nucleotide small RNAs were primarily derived from loci encoding transposable elements and we propose that these small RNAs define a pathway of short-interfering RNAs that silence repetitive genetic elements. The 21-nucleotide small RNAs were primarily derived from inverted repeats, including a novel microRNA family that is conserved among the three species, and several gene families, including Crinkler effectors and type III fibronectins. The Phytophthora microRNA is predicted to target a family of amino acid/auxin permeases, and we propose that 21-nucleotide small RNAs function at the post-transcriptional level. The functional significance of microRNA-guided regulation of amino acid/auxin permeases and the association of 21-nucleotide small RNAs with Crinkler effectors remains unclear, but this work provides a framework for testing the role of small RNAs in Phytophthora biology and pathogenesis in future work.


Relationship between posture and occlusion: a clinical and experimental investigation.
Recently many postural diseases have been classified among occlusal-functional alterations, mostly on a clinical basis. However some anatomic and physiologic aspects are still unknown. The purpose of this study was to review the literature and to support the correlations by means of a balance platform on a group of 50 patients (30 males and 20 females, mean age 25.8 years) belonging to every Angle classification of malocclusion. The subjects were asked to stand on the balance platform and perform five different tests. The results showed that subjects with a Class II malocclusion exhibit an anteriorly displaced posture, whereas subjects with a Class III malocclusion exhibit a posteriorly displaced posture.


Synthesis, Cytotoxicity and Antioxidant Activity of New Analogs of RC-121 Synthetic Derivatives of Somatostatin.
Based on the structure of RC-121 (D-Phe-c (Cys-Tyr-D-Trp-Lys-Val-Cys)-Thr-NH2, - synthetic derivatives of somatostatin), some analogs were synthesized and tested for in vitro cytotoxic and antioxidant activity. The new analogs were modifyed at position 5 with Dap (diaminopropanoic acid), Dab (diaminobutanoic acid) and Orn and at position 6 with the unnatural amino acids Tle (t-leucine). The in vitro cytotoxic effects of the substances were investigated against a panel of human tumor cell lines HT-29 (Human Colorectal Cancer Cell Line), MDA-MB-23 (Human Breast Cancer Cell Line), Hep G-2 (Human Hepatocellular Carcinoma Cell Line) and HeLa (cervical cancer cell line). The antioxidant capacities were tested by ORAC (Oxygen Radical Antioxidant Capacity) and HORAC (Hydroxyl Radical Averting Capacity) methods. All substances expressed significantly higher antioxidant capacity by comparison with galic acid and Trolox. All substances showed considerable antioxidant capacity as well. Compound 2T (D-Phe-c(Cys-Tyr-DTrp- Dap-Tle-Cys)-Thr-NH2)had the highest antioxidant effect. The compound 4T (D-Phe-c(Cys-Tyr-D-Trp- Orn-Tle-Cys)-Thr-NH2) displayed antiproliferative effect on HeLa cells with IC50 30 µM. The peptide analog 3T (D-Phe-c(Cys-Tyr-D-Trp-Lys-Tle-Cys)-Thr-NH2) exerted the most pronounced inhibition on the cell vitality up to 53%, 56% and 65% resp. against MDA-MB-23, Hep G-2, HeLa in the higher tested concentration. The somatostatin analogs showed moderate influence on the vitality of different tumor cells and could be used in changing their pathology.


Clouded leopard phylogeny revisited: support for species recognition and population division between Borneo and Sumatra.
The clouded leopard (Neofelis nebulosa) is one of the least known cat species and depletion of their forested habitats puts it under heavy pressure. Recently reclassification of Bornean clouded leopards (N. nebulosa diardi) to species level (N.diardi) was suggested based on molecular and morphological evidence. Since the genetic results were based solely on three Bornean samples we re-evaluated this partition using additional samples of Bornean clouded leopards (N = 7) and we were also able to include specimens from Sumatra (N = 3), which were lacking in previous analysis. We found strong support for the distinction between N. nebulosa and N. diardi based on three fragments of mtDNA (900 bp) and 18 microsatellites. Forty-one fixed mitochondrial nucleotide differences and non-overlapping allele sizes in 8 of 18 microsatellite loci distinguished N. nebulosa and N. diardi. This is equivalent to the genetic divergence among recognized species in the genus Panthera. Sumatran clouded leopards clustered with specimens from Borneo, suggesting that Sumatran individuals also belong to N. diardi. Additionally, a significant population subdivision was apparent among N. diardi from Sumatra and Borneo based on mtDNA and microsatellite data. Referring to their origin on two Sunda Islands we propose to give N. diardi the common name "Sundaland clouded leopard". The reduced gene flow between Borneo and Sumatra might suggest the recognition of two subspecies of N. diardi. Based on this reclassification of clouded leopards not only species, but also the populations on Borneo and Sumatra should be managed separately and a higher priority should be placed to protect the different populations from extinction.


The impact of day care on socially disadvantaged families: an example of the use of process evaluation within a randomized controlled trial.
This paper describes a process evaluation that was conducted alongside a randomized controlled trial of out-of-home pre-school day care. The evaluation aimed to: (1) describe the intervention; (2) document the day care received by participating families; (3) describe the social context of the trial; and (4) provide data to assist in the interpretation of trial outcomes. The setting for the trial was an out-of-home day care Centre in Hackney, East London. Process data were collected through the use of questionnaires, interviews, and researcher field-notes. Data from questionnaires were collected from 120 mothers and included data on 143 children. Interviews were undertaken with 21 participating mothers. Staff also completed questionnaires and the Head of the Centre was interviewed. The quality of care provided was assessed using the Early Childhood Environment Rating Scale. Process data collected during the trial suggest that the day care provided was education-led, flexible in catering to families' needs, and was of a very high quality. The social context of the trial resulted in financial pressures, which may well have influenced the intervention provided. Data collected through in-depth interviews suggested that it may be the flexibility of day care that is particularly important in allowing women to return to paid employment, but that the loss of benefits when starting work may have meant no increase in household income. The paper illustrates the value of conducting a process evaluation alongside a randomized trial, particularly where complex interventions are involved. In this case, where the intervention was not provided by the research team, the evaluation allowed an insight into the content of a multifaceted intervention, which is useful in interpreting the trial's results, and in explaining the possible effects of the social context on the intervention.


Using DRS during breast conserving surgery: identifying robust optical parameters and influence of inter-patient variation.
Successful breast conserving surgery consists of complete removal of the tumor while sparing healthy surrounding tissue. Despite currently available imaging and margin assessment tools, recognizing tumor tissue at a resection margin during surgery is challenging. Diffuse reflectance spectroscopy (DRS), which uses light for tissue characterization, can potentially guide surgeons to prevent tumor positive margins. However, inter-patient variation and changes in tissue physiology occurring during the resection might hamper this light-based technology. Here we investigate how inter-patient variation and tissue status (in vivo vs ex vivo) affect the performance of the DRS optical parameters. In vivo and ex vivo measurements of 45 breast cancer patients were obtained and quantified with an analytical model to acquire the optical parameters. The optical parameter representing the ratio between fat and water provided the best discrimination between normal and tumor tissue, with an area under the receiver operating characteristic curve of 0.94. There was no substantial influence of other patient factors such as menopausal status on optical measurements. Contrary to expectations, normalization of the optical parameters did not improve the discriminative power. Furthermore, measurements taken in vivo were not significantly different from the measurements taken ex vivo. These findings indicate that DRS is a robust technology for the detection of tumor tissue during breast conserving surgery.


A role for tissue transglutaminase in hepatic injury and fibrogenesis, and its regulation by NF-kappaB.
This study was undertaken to delineate a possible role for tissue transglutaminase (tTG), an enzyme that catalyzes protein cross-linking, in hepatic fibrogenesis. Rats were treated with CCl4 solution and then killed at different stages of liver injury and fibrogenesis. Liver tTG mRNA levels were markedly increased as early as 6 h after the first injection, peaked at 4 days and 1 wk, and remained increased for 8 wk. The enzymatic activity of tTG was increased in livers of rats treated with CCl4, in a fashion that paralleled the Northern blot results. Cell isolation experiments indicated that all hepatic cell types synthesize tTG mRNA. Increased binding to the nuclear factor-kappaB (NF-kappaB) motif of the tTG promoter was found in the nuclear extracts prepared from CCl4-treated samples. These data demonstrate an increase in tTG gene expression during hepatic injury and fibrosis, suggesting a possible role for this enzyme in stabilizing the fibrotic bands during hepatic fibrogenesis. Moreover, increased NF-kappaB binding to the tTG promoter may represent one of the mechanisms by which cell injury induces tTG transcription and thus potentiates the process of fibrogenesis.


Change in cognitive function in older persons from a community population: relation to age and Alzheimer disease.
To examine change in cognitive function in older persons sampled from a community population, and its relation to age and Alzheimer disease. Prospective cohort study with an average of 3.5 years of follow-up. East Boston, Mass--a geographically defined, urban, working-class community. A stratified, random sample of persons 65 years and older underwent uniform, structured clinical evaluation for Alzheimer disease. The 388 persons (89.2% of those eligible) who completed at least 1 annual follow-up evaluation were studied: 97 had Alzheimer disease at baseline; 95 developed Alzheimer disease during the study; and 196 were unaffected. Eight cognitive performance tests were administered, then converted to population-weighted z scores and averaged to create a composite summary measure of cognitive function. Initial level of and change in this score were the outcome measures. In the population as a whole, many persons experienced a decline in cognitive performance, and age was related to both initial level and rate of decline. Analyses were conducted in 3 subgroups: persons with Alzheimer disease at baseline, those who developed Alzheimer disease during the study, and those who remained unaffected. In both Alzheimer disease subgroups, substantial cognitive decline was observed, but neither initial level nor rate of decline was related to age. In unaffected persons, little cognitive decline was evident, and there was a small, inverse association of age with initial level of cognitive function. In a general population sample, there was little evidence of cognitive decline during a 3.5-year period among persons who remained free of Alzheimer disease.


Thirty-nine-month xylitol chewing-gum programme in initially 8-year-old school children: a feasibility study focusing on mutans streptococci and lactobacilli.
To investigate the use of xylitol-containing chewing-gums in public elementary schools as a means to affect the growth of salivary and plaque mutans streptococci and salivary lactobacilli. Over a period of 24 months, 750 8- to 9-year-old children chewed xylitol (X group; n = 255) or xylitol-sorbitol (XS group; n = 264) gum on school days (454 days over 2 years), or chewed no gum at all (C group; n = 231). Consumption of xylitol in the X and the XS groups was 6.6 and 5.4g per day, respectively. Use of gum took place at school in four daily episodes of which three were supervised by teachers. Following the 24-month chewing-gum period, the subjects were re-examined after 15 months (total follow-up period: 39 months) at which time an extraneous comparison group (ExC; n = 117) was also examined. The numbers of subjects examined after 39 months were: X, 239; XS, 248; C3 217. Salivary and plaque levels of mutans streptococci and the salivary levels of aerobically cultured aciduric bacteria (mostly representing lactobacilli) were determined using the Orion Diagnostica Dentocult SM and LB test kits, respectively. There were statistically significant differences after 24 and 39 months between the two xylitol chewing-gum groups and the C group with regard to salivary and plaque mutans streptococci and salivary lactobacilli: the use of xylitol-containing chewing-gums significantly reduced these bacterial scores. The reductions were statistically more significant in the X group than in the XS group. The bacterial scores of groups C and ExC were similar. Long-term use of xylitol-containing chewing-gum can reduce the growth of mutans streptococci in saliva and dental plaque, and lactobacilli-type bacteria in saliva, even if xylitol is used only on school days. The results also suggest that xylitol gum use can have a long-term, delayed growth-retarding effect on these micro-organisms, since reduced bacterial growth was still observed 15 months following the termination of xylitol use. The results indicate a close biochemical relationship between xylitol and mutans streptococci, and suggest that a similar relationship may exist regarding aerobically cultured aciduric bacteria present in saliva.


Five-year update on the mouse model of orthotopic lung transplantation: Scientific uses, tricks of the trade, and tips for success.
It has been 5 years since our team reported the first successful model of orthotopic single lung transplantation in the mouse. There has been great demand for this technique due to the obvious experimental advantages the mouse offers over other large and small animal models of lung transplantation. These include the availability of mouse-specific reagents as well as knockout and transgenic technology. Our laboratory has utilized this mouse model to study both immunological and non-immunological mechanisms of lung transplant physiology while others have focused on models of chronic rejection. It is surprising that despite our initial publication in 2007 only few other laboratories have published data using this model. This is likely due to the technical complexity of the surgical technique and perioperative complications, which can limit recipient survival. As two of the authors (XL and WL) have a combined experience of over 2500 left and right single lung transplants, this review will summarize their experience and delineate tips and tricks necessary for successful transplantation. We will also describe technical advances made since the original description of the model.


Retardation of atherosclerosis by overexpression of catalase or both Cu/Zn-superoxide dismutase and catalase in mice lacking apolipoprotein E.
Oxidative stress has been suggested to potentiate atherogenesis. However, studies that have investigated the effect of antioxidants on atherosclerosis showed inconsistent results, ie, atherosclerosis was either retarded or not changed by dietary antioxidants. This report directly examined the effect of overexpressing Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and/or catalase on atherosclerosis and lipid peroxidation in mice lacking apolipoprotein E (ApoE-/-). Based on lipid staining of the en face of the aorta tree and the serial sections of the proximal aorta, ApoE-/- mice overexpressing catalase or both Cu/Zn-SOD and catalase had smaller and relatively early stages of atherosclerotic lesions (eg, foam cells and free lipids) when compared with ApoE-/- mice, who developed more advanced lesions (eg, fibrous caps and acellular areas). In addition, the retarded development of atherosclerosis was correlated with a reduced F2-isoprostanes in the plasma and aortas in ApoE-/- mice overexpressing catalase or both Cu/Zn-SOD and catalase. In contrast, the levels of F2-isoprostanes and atherosclerosis in the ApoE-/- mice overexpressing Cu/Zn-SOD alone were comparable to ApoE-/- control mice. These observations implied that endogenously produced hydrogen peroxide, but not superoxide anions, contributed to the formation of oxidized lipids and the development of atherosclerosis in ApoE-/- mice.


Does age impact the obese asthma phenotype? Longitudinal asthma control, airway function, and airflow perception among mild persistent asthmatics.
The relationship between obesity and asthma remains inadequately defined. Studies about how obesity affects asthma control and lung function show conflicting results. Additional focus on the effect of age as a modifier may make clearer the interaction between obesity and asthma phenotype. We sought to use a diverse and well-phenotyped cohort of asthmatic patients to determine how age impacts the relationship between obesity and spirometry, peak flow variability, airflow perception, and asthma control. The characteristics of 490 patients with mild persistent asthma taken from 2,794 study visits from a prospective trial studying strategies of step-down therapy were included in this post hoc analysis. A longitudinal mixed-effect model was used to determine if age affects the relationship between obesity and asthma characteristics, including spirometry, asthma control, airway pH, and perception of airflow changes. The effect of obesity on asthma outcomes changes with age and gender. Obese 6- to 11-year-old children had the largest reduction in lung function but reported relatively fewer asthma symptoms than did similar nonobese asthmatics. Obese 12- to 17-year-olds showed a trend toward greater airflow obstruction and asthma symptoms compared with nonobese asthmatics. Adults in general displayed few obesity-related alterations in asthma phenotype. Female gender among 12- to 17- and 18- to 44-year-olds was associated with greater obesity-related asthma impairment. Age is a significant effect modifier on the relationship between obesity and asthma phenotype. With increasing age, the influence of obesity on the asthma phenotype is generally reduced. The asthma phenotype may be most impacted by obesity among children and women. ClinicalTrials.gov; No.: NCT00156819; URL: www.clinicaltrials.gov.


Case fatality of myocardial infarction among shift workers.
Shift work has been associated with an excess risk of cardiovascular disease (CVD) and more specifically myocardial infarction (MI). The majority of the studies that found a positive association between shift work and CVD have been based on incidence data. The results from studies on cardiovascular-related mortality among shift workers have shown little or no elevated mortality associated with shift work. None of the previous studies have analysed short-term mortality (case fatality) after MI. Therefore, we investigated whether shift work is associated with increased case fatality after MI compared with day workers. Data on incident cases with first MI were obtained from case-control study conducted in two geographical sites in Sweden (Stockholm Heart Epidemiology Program and Västernorrland Heart Epidemiology Program), including 1,542 cases (1,147 men and 395 women) of MI with complete working time information and 65 years or younger. Case fatality was defined as death within 28 days of onset of MI. Risk estimates were calculated using logistic regression. The crude odds ratios for case fatality among male shift workers were 1.63 [95 % confidence interval (CI) 1.12, 2.38] and 0.56 (95 % CI 0.26, 1.18) for female shift workers compared with day workers. Adjustments for established cardiovascular risk factors such as diabetes type II and socio-economic status did not alter the results. Shift work was associated with increased risk of case fatality among male shift workers after the first MI.


A method for the asymmetric hydrosilylation of N-aryl imines.
[reaction: see text] The asymmetric reduction of N-aryl imines to yield chiral amines with enantiomeric excesses above 90% was achieved. Ethylenebis(eta5-tetrahydroindenyl)titanium difluoride ((EBTHI)TiF2, 1) was employed as the precatalyst with polymethylhydrosiloxane (PMHS) as the stoichiometric reducing agent. A variety of N-aryl imines derived from nonaromatic ketones were reduced with high ee.


Approach to chronic wound infections.
Infection is the likeliest single cause of delayed healing in healing of chronic open wounds by secondary intention. If neglected it can progress from contamination to colonization and local infection through to systemic infection, sepsis and multiple organ dysfunction syndrome, and it can be life-threatening. Infection in chronic wounds is not as easy to define as in acute wounds, and is complicated by the presence of biofilms. There is, as yet, no diagnostic for biofilm presence, but it contributes to excessive inflammation - through excessive and prolonged stimulation of nitric oxide, inflammatory cytokines and free radicals - and activation of immune complexes and complement, leading to a delay in healing. Control of biofilm is a key part of chronic wound management. Maintenance debridement and use of topical antimicrobials (antiseptics) are more effective than antibiotics, which should be reserved for treating spreading local and systemic infection. The continuing rise of antimicrobial resistance to antibiotics should lead us to reserve their use for these indications, as no new effective antibiotics are in the research pipeline. Antiseptics are effective through many mechanisms of action, unlike antibiotics, which makes the development of resistance to them unlikely. There is little evidence to support the theoretical risk that antiseptics select resistant pathogens. However, the use of antiseptic dressings for preventing and managing biofilm and infection progression needs further research involving well-designed, randomized controlled trials.