Flexible sigmoidoscopy versus faecal occult blood testing for colorectal cancer screening in asymptomatic individuals.
Colorectal cancer is the third most frequent cancer in the world. As the sojourn time for this cancer is several years and a good prognosis is associated with early stage diagnosis, screening has been implemented in a number of countries. Both screening with faecal occult blood test and flexible sigmoidoscopy have been shown to reduce mortality from colorectal cancer in randomised controlled trials. The comparative effectiveness of these tests on colorectal cancer mortality has, however, never been evaluated, and controversies exist over which test to choose. To compare the effectiveness of screening for colorectal cancer with flexible sigmoidoscopy to faecal occult blood testing. We searched MEDLINE and EMBASE (November 16, 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11) and reference lists for eligible studies. Randomised controlled trials comparing screening with flexible sigmoidoscopy or faecal occult blood testing to each other or to no screening. Only studies reporting mortality from colorectal cancer were included. Faecal occult blood testing had to be repeated (annually or biennially). Data retrieval and assessment of risk of bias were performed independently by two review authors. Standard meta-analyses using a random-effects model were conducted for flexible sigmoidoscopy and faecal occult blood testing (FOBT) separately and we calculated relative risks with 95% confidence intervals (CI). We used a Bayesian approach (a contrast-based network meta-analysis method) for indirect analyses and presented the results as posterior median relative risk with 95% credibility intervals. We assessed the quality of evidence using GRADE. We identified nine studies comprising 338,467 individuals randomised to screening and 405,919 individuals to the control groups. Five studies compared flexible sigmoidoscopy to no screening and four studies compared repetitive guaiac-based FOBT (annually and biennially) to no screening. We did not consider that study risk of bias reduced our confidence in our results. We did not identify any studies comparing the two screening methods directly. When compared with no screening, colorectal cancer mortality was lower with flexible sigmoidoscopy (relative risk 0.72; 95% CI 0.65 to 0.79, high quality evidence) and FOBT (relative risk 0.86; 95% CI 0.80 to 0.92, high quality evidence). In the analyses based on indirect comparison of the two screening methods, the relative risk of dying from colorectal cancer was 0.85 (95% credibility interval 0.72 to 1.01, low quality evidence) for flexible sigmoidoscopy screening compared to FOBT. No complications occurred after the FOBT test itself, but 0.03% of participants suffered a major complication after follow-up. Among more than 60,000 flexible sigmoidoscopy screening procedures and almost 6000 work-up colonoscopies, a major complication was recorded in 0.08% of participants. Adverse event data should be interpreted with caution as the reporting of adverse effects was incomplete. There is high quality evidence that both flexible sigmoidoscopy and faecal occult blood testing reduce colorectal cancer mortality when applied as screening tools. There is low quality indirect evidence that screening with either approach reduces colorectal cancer deaths more than the other. Major complications associated with screening require validation from studies with more complete reporting of harms


Participatory research on the prevalence of Multi-Substance vaping in college students.
To assess electronic nicotine delivery system (ENDS) use and vaping behaviors and attitudes in college students. A student-faculty partnership administered a cross-sectional survey to undergraduate students (N = 339) in 2019. 49.8% of students reported using ENDS or vaping in the past 30 days. 48.9% of students who vaped reported vaping more than one substance in the past 30 days. The most commonly vaped substances were cannabis (34.9%), nicotine (26.7%), and flavor (19.2%). Reasons for initiating ENDS use were social (64.8%), for the high (40.8%), and for the flavor (32.4%). Both users and non-users believed ENDS were harmful and favored regulation. Young people who use ENDS commonly vape more than one substance; a critical finding in light of the current vaping lung injury epidemic. The importance of social reasons for initiating ENDS and broad support for regulation suggest jurisdictions consider regulation to reduce ENDS use in young adults.


Identification of Small Molecules for Prevention of Lens Epithelium-Derived Cataract Using Zebrafish.
Cataract is the leading cause of blindness worldwide. It can be treated by surgery, whereby the damaged crystalline lens is replaced by a synthetic lens. Although cataract surgery is highly effective, a relatively common complication named posterior capsular opacification (PCO) leads to secondary loss of vision. PCO is caused by abnormal proliferation and migration of residual lens epithelial cells (LECs) that were not removed during the surgery, which results in interruption to the passage of light. Despite technical improvements to the surgery, this complication has not been eradicated. Efforts are being made to identify drugs that can be applied post-surgery, to inhibit PCO development. Towards the goal of identifying such drugs, we used zebrafish embryos homozygous for a mutation in plod3 that develop a lens phenotype with characteristics of PCO. Using both biased and unbiased approaches, we identified small molecules that can block the lens phenotype of the mutants. Our findings confirm the relevance of zebrafish plod3 mutants' lens phenotype as a model for lens epithelium-derived cataract and add to our understanding of the molecular mechanisms that contribute to the development of this pathology. This understanding should help in the development of strategies for PCO prevention.


Climate change, activism, and supporting the mental health of children and young people: Perspectives from Western Australia.
The climate crisis has detrimental impacts on the mental health and wellbeing of children and young people. Psychological effects include feelings of fear, overwhelm, worry, distress, hopelessness and anger; PTSD; depression; anxiety; phobias; panic disorder; sleep disturbances; attachment disorders; learning difficulties; substance abuse; shock and trauma symptoms; adjustment problems; behavioural problems; and, suicidal thinking. First Nations' children and young people are particularly at risk due to loss of place, identity, culture, land and customs informed by kinship relationships with the Earth; while sustainable land use practices and connection to Country and community can enhance climate resilience. In Western Australia (WA), some young people engage in climate activism - including striking from school - to demand government action to address the causes of climate change, including colonisation and capitalism. Climate activism can promote resilience, particularly when children and young people can emotionally engage in the climate crisis; when mental health is systemically supported; when climate communication is transparent and comprehensive; and, when activism is informed by the knowledges and wisdoms of First Nations peoples and grounded on Country. This article is co-authored by WA young people, Aboriginal and non-Aboriginal academics, activists and practitioners engaged in youth, mental health and climate justice spaces. We argue for structural change to address the causes of the climate crisis, alongside enhanced evidence and approaches to appropriately support the mental health of children and young people. Furthermore, we support the call of Aboriginal peoples to ensure culturally appropriate, place-based responses based in caring for Country.


Fetal Brain Biometric Measurements on 3D Super-Resolution Reconstructed T2-Weighted MRI: An Intra- and Inter-observer Agreement Study.
We present the comparison of two-dimensional (2D) fetal brain biometry on magnetic resonance (MR) images using orthogonal 2D T2-weighted sequences (T2WSs) vs. one 3D super-resolution (SR) reconstructed volume and evaluation of the level of confidence and concordance between an experienced pediatric radiologist (obs1) and a junior radiologist (obs2). Twenty-five normal fetal brain MRI scans (18-34 weeks of gestation) including orthogonal 3-mm-thick T2WSs were analyzed retrospectively. One 3D SR volume was reconstructed per subject based on multiple series of T2WSs. The two observers performed 11 2D biometric measurements (specifying their level of confidence) on T2WS and SR volumes. Measurements were compared using the paired Wilcoxon rank sum test between observers for each dataset (T2WS and SR) and between T2WS and SR for each observer. Bland-Altman plots were used to assess the agreement between each pair of measurements. Measurements were made with low confidence in three subjects by obs1 and in 11 subjects by obs2 (mostly concerning the length of the corpus callosum on T2WS). Inter-rater intra-dataset comparisons showed no significant difference (p > 0.05), except for brain axial biparietal diameter (BIP) on T2WS and for brain and skull coronal BIP and coronal transverse cerebellar diameter (DTC) on SR. None of them remained significant after correction for multiple comparisons. Inter-dataset intra-rater comparisons showed statistical differences in brain axial and coronal BIP for both observers, skull coronal BIP for obs1, and axial and coronal DTC for obs2. After correction for multiple comparisons, only axial brain BIP remained significantly different, but differences were small (2.95 ± 1.73 mm). SR allows similar fetal brain biometry as compared to using the conventional T2WS while improving the level of confidence in the measurements and using a single reconstructed volume.


IL-2 induces beta2-integrin adhesion via a wortmannin/LY294002-sensitive, rapamycin-resistant pathway. Phosphorylation of a 125-kilodalton protein correlates with induction of adhesion, but not mitogenesis.
Besides its function as a growth factor, IL-2 induces beta2-integrin-dependent, homotypic adhesion of IL-2R-positive T cells. In this study, we investigated how IL-2R are functionally and biochemically linked to the beta2-integrin adhesion pathway. After a lag period of 15 to 20 min, IL-2 induces beta2-integrin-dependent, homotypic adhesion in Ag-specific, human T cell lines. The IL-2 adhesion response is blocked by wortmannin and LY294002, inhibitors of phosphatidylinositol-3 (PI-3) kinase activity. In contrast, rapamycin strongly inhibits IL-2-induced proliferation without inhibiting IL-2-induced adhesion. Herbimycin A and genestein, inhibitors of protein tyrosine kinases, inhibit cytokine-induced adhesion and mitogenesis in parallel, whereas cytochalasin E, an inhibitor of actin polymerization, almost completely blocks the adhesion response at concentrations that have little effect on mitogenesis. IL-2R ligation rapidly (<5 min) induces tyrosine phosphorylation of several proteins, the most prominent being signal transducer and activator of transcription (Stat) proteins, the p85 subunit of the PI-3 kinase, and an as yet unidentified 125-kDa protein (p125). Wortmannin, LY294002, and cytochalasin E almost completely inhibit cytokine-induced tyrosine phosphorylation of p125, whereas tyrosine phosphorylation of PI-3 kinase, Janus kinases, Stat3, Stat5, and other proteins is unaffected. In contrast, rapamycin has little effect on IL-2-induced phosphorylation of p125. Taken together, these data suggest that 1) IL-2R ligation induces homotypic adhesion through a wortmannin/LY294002-sensitive, rapamycin-resistant pathway, 2) tyrosine kinases play a critical role in cytokine-induced adhesion, and 3) adhesion, but not mitogenesis, correlates with enhanced tyrosine phosphorylation of an as yet unidentified protein of 125 kDa.


Potassium induced dilation in bovine coronary artery involves both inward rectifier potassium channels and Na+ /K+ ATPase.
Increases in extracellular potassium (K+) concentration (up to 20 mM) cause dilation in some blood vessels. This may be particularly important in myocardial ischemia because in this condition K+ is released from ischemic cells. In this study, we investigated mechanisms of effect of increased K+ concentration on the tone of isolated bovine coronary artery. Bovine coronary arteries were isolated and mounted in organ baths for isometric tension recording. After an equilibration period, arteries were contracted with serotonin (1 microM). When serotonin contraction reached a steady-state, K+ concentration of organ baths was increased from physiological levels to 10 mM, 14 mM, 18 mM or 22 mM in four groups of the arteries. After a washout period, this procedure was repeated in presence of ouabain, a blocker of Na+ /K+ ATPase or a K+ channel blocker (tetraethylammonium, 4-aminopyridine, glibenclamide or barium). Increasing K+ concentration of the organ baths to 10 mM, 14 mM and 18 mM caused dilation in the arteries. Ouabain abolished the dilation and barium (a blocker of inward rectifier K + channels) inhibited the dilation significantly.According to our results there is K+ -induced dilation in bovine coronary artery and it involves activation of both Na+ /K+ ATPase and inward rectifier K+ channels.


4polar-STORM polarized super-resolution imaging of actin filament organization in cells.
Single-molecule localization microscopy provides insights into the nanometer-scale spatial organization of proteins in cells, however it does not provide information on their conformation and orientation, which are key functional signatures. Detecting single molecules' orientation in addition to their localization in cells is still a challenging task, in particular in dense cell samples. Here, we present a polarization-splitting scheme which combines Stochastic Optical Reconstruction Microscopy (STORM) with single molecule 2D orientation and wobbling measurements, without requiring a strong deformation of the imaged point spread function. This method called 4polar-STORM allows, thanks to a control of its detection numerical aperture, to determine both single molecules' localization and orientation in 2D and to infer their 3D orientation. 4polar-STORM is compatible with relatively high densities of diffraction-limited spots in an image, and is thus ideally placed for the investigation of dense protein assemblies in cells. We demonstrate the potential of this method in dense actin filament organizations driving cell adhesion and motility.


Kaempferol modulates TCDD- and t-BHQ-induced drug-metabolizing enzymes and luteolin enhances this effect.
The expression of drug-metabolizing enzymes is deeply involved in chemical-induced cancer progression and prevention. The aryl hydrocarbon receptor (AhR) induces phase I, and certain phase II drug-metabolizing enzymes after the binding of ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We have previously demonstrated that luteolin inhibited TCDD-induced AhR transformation, and modulated the expression of drug-metabolizing enzymes through not only the AhR, but also the nuclear factor-erythroid-2-related factor 2 (Nrf2). We have examined the effect of kaempferol on the expression of drug-metabolizing enzymes through modulation of the AhR- and Nrf2-pathways, and the effect of co-treatment with kaempferol and luteolin. Kaempferol dose-dependently inhibited not only the TCDD-induced expression of phase I and phase II drug-metabolizing enzymes, but also the tertiary butylhydroquinone (t-BHQ)-induced expression of phase II drug-metabolizing enzymes, by modulating the AhR- and Nrf2-pathways. Co-treatment with kaempferol and luteolin enhanced the inhibitory effect on the expression of drug-metabolizing enzymes, compared with either kaempferol or luteolin alone. Moreover, co-treatment with kaempferol and luteolin increased the cellular levels of kaempferol without affecting the levels of luteolin. An in vivo study was also performed and the results demonstrated that co-treatment with kaempferol and luteolin enhanced the inhibition of benzo[a]pyrene-induced drug-metabolizing enzymes compared with either kaempferol or luteolin alone, in the liver of ICR mice. These results suggest that luteolin promoted the incorporation of kaempferol into hepatocytes and enhanced the inhibitory effect of kaempferol on chemical-induced drug-metabolizing enzymes. Thus, luteolin enhances the kaempferol-inhibited expression of drug-metabolizing enzymes.


Time resolution of the plastic scintillator strips with matrix photomultiplier readout for J-PET tomograph.
Recent tests of a single module of the Jagiellonian Positron Emission Tomography system (J-PET) consisting of 30 cm long plastic scintillator strips have proven its applicability for the detection of annihilation quanta (0.511 MeV) with a coincidence resolving time (CRT) of 0.266 ns. The achieved resolution is almost by a factor of two better with respect to the current TOF-PET detectors and it can still be improved since, as it is shown in this article, the intrinsic limit of time resolution for the determination of time of the interaction of 0.511 MeV gamma quanta in plastic scintillators is much lower. As the major point of the article, a method allowing to record timestamps of several photons, at two ends of the scintillator strip, by means of matrix of silicon photomultipliers (SiPM) is introduced. As a result of simulations, conducted with the number of SiPM varying from 4 to 42, it is shown that the improvement of timing resolution saturates with the growing number of photomultipliers, and that the [Formula: see text] configuration at two ends allowing to read twenty timestamps, constitutes an optimal solution. The conducted simulations accounted for the emission time distribution, photon transport and absorption inside the scintillator, as well as quantum efficiency and transit time spread of photosensors, and were checked based on the experimental results. Application of the [Formula: see text] matrix of SiPM allows for achieving the coincidence resolving time in positron emission tomography of [Formula: see text]0.170 ns for 15 cm axial field-of-view (AFOV) and [Formula: see text]0.365 ns for 100 cm AFOV. The results open perspectives for construction of a cost-effective TOF-PET scanner with significantly better TOF resolution and larger AFOV with respect to the current TOF-PET modalities.


Exploring interaction effects in two-component gas mixtures using orthogonal signal correction of ultrasound pulses.
Within Sweden and the EU, an increased use of biogas gas and natural gas is encouraged to decrease emission of carbon dioxide. To support more effective manufacturing, distribution, and consumption of energy gases, new methods for the measurement of the calorimetric value or the gas composition are needed. This paper presents a method to extract and visualize variations in ultrasound pulse shape, caused by interaction effects between the constituents of a two-component gas mixture. The method is based on a combination of principal component analysis and orthogonal signal correction. Pulse-echo ultrasound experiments on mixtures of oxygen and ethane in the concentration range from 20% to 80% ethane show that the extracted information could be correlated with the molar fraction of ethane in the mixture.


Mesenchymal stem cells-derived exosomes ameliorate high glucose and lipopolysaccharide-induced HPMECs injury through the Nrf2/HO-1 pathway.
Mesenchymal stem cells-derived exosomes (MSC-Exo) are considered to have great potential in the treatment of human diseases. However, the role of MSC-Exo in the process of diabetes with sepsis and the underlying molecular mechanism remain unclear. Human pulmonary microvascular endothelial cells (HPMECs) were treated with high glucose (HG) and lipopolysaccharide (LPS). Cell viability, migration, angiogenesis were analyzed by cell counting kit 8 assay, transwell assay and tube formation assay. Transmembrane electrical resistance (TER) detection and FITC-dextran assay were performed to evaluate cell barrier function. The protein levels of cell permeability-related markers, ferroptosis-related markers, exosomes-related markers, Nrf2 and HO-1 were examined using western bolt (WB) analysis. Besides, the levels of inflammation factors were tested by ELISA, and the levels of ferroptosis-related indicators were examined using corresponding assay kits. Flow cytometry was employed to analyze stem cell markers. The identification of MSC-Exo was performed using transmission electron microscopy, nanoparticle tracking analysis and WB analysis. DIO staining was used to examine the uptake of MSC-Exo by HPMECs. HG treatment suppressed HPMECs viability, migration, angiogenesis and TER, while promoted permeability, inflammation and ferroptosis. LPS treatment aggravated HG-induced HPMECs dysfunction, inflammation and ferroptosis. After HPMECs were co-cultured with MSC-Exo, cell injury induced by HG + LPS could be relieved. Moreover, MSC-Exo treatment enhanced the activity of Nrf2/HO-1 pathway in HG + LPS-induced HPMECs, and Nrf2-silenced MSC-Exo could promote HG + LPS-induced HPMECs injury. MSC-Exo alleviated HG + LPS-induced HPMECs injury via activating Nrf2/HO-1 pathway, confirming that it might be used for the treatment of diabetes with sepsis.


Nutritional quality and price of food hampers distributed by a campus food bank: a Canadian experience.
Food insecurity is a mounting concern among Canadian post-secondary students. This study was conducted to evaluate the content of food hampers distributed by University of Alberta Campus Food Bank (CFB) and to assess the cost savings to students, using these hampers. Contents of hampers distributed among 1,857 students and their dependants since 2006 were evaluated against Canada's Food Guide (CFG) recommendations and Dietary Reference Intakes (DRI). Hampers were aimed at serving university students and one to five members of their households located in Edmonton, Western Canada. One thousand eight hundred fifty-seven clients in Alberta, Canada, were included in the study. Although all hampers provided adequate energy, their fat and animal protein contents were low. Compared to the CFG recommendations, the requirements of milk and alternatives and meat and alternatives were not sufficiently met for clients using > or = 3-person hampers. None of food hampers (i.e. one- to five-person hampers) met the DRI recommendations for vitamin A and zinc. Clients of CFB received Canadian dollar (CN$) 14.88 to 64.3 worth of non-perishable food items in one- to five-person hampers respectively. Hampers provided from the CFB need improvement. Nutrients missing from the food hampers could be provided from fresh fruits, vegetables, dairy, and meat products; however, these foods are more expensive than processed food items. The CFB provides a significant amount of savings to its clients even without considering the additional perishable donations that are provided to clients. Interpretation of our data required the assumption that all clients were consuming all of their hampers, which may not always be the case. Clients that do not fully consume their hampers may benefit less from the food bank.


Infrared spectroscopy of molecular submonolayers on surfaces by infrared scanning tunneling microscopy: tetramantane on Au111.
We have developed a new scanning-tunneling-microscopy-based spectroscopy technique to characterize infrared (IR) absorption of submonolayers of molecules on conducting crystals. The technique employs a scanning tunneling microscope as a precise detector to measure the expansion of a molecule-decorated crystal that is irradiated by IR light from a tunable laser source. Using this technique, we obtain the IR absorption spectra of [121]tetramantane and [123]tetramantane on Au(111). Significant differences between the IR spectra for these two isomers show the power of this new technique to differentiate chemical structures even when single-molecule-resolved scanning tunneling microscopy (STM) images look quite similar. Furthermore, the new technique was found to yield significantly better spectral resolution than STM-based inelastic electron tunneling spectroscopy, and to allow determination of optical absorption cross sections. Compared to IR spectroscopy of bulk tetramantane powders, infrared scanning tunneling microscopy (IRSTM) spectra reveal narrower and blueshifted vibrational peaks for an ordered tetramantane adlayer. Differences between bulk and surface tetramantane vibrational spectra are explained via molecule-molecule interactions.


The pentatricopeptide repeat protein PPR5 stabilizes a specific tRNA precursor in maize chloroplasts.
Genes for pentatricopeptide repeat (PPR) proteins are found in all eukaryotic genomes analyzed but are particularly abundant in land plants. The majority of analyzed PPR proteins play a role in the processing or translation of organellar RNAs. Few PPR proteins have been studied in detail, and the functional repertoire and mechanisms of action of proteins in the PPR family are poorly understood. Here we analyzed a maize ortholog of the embryo-essential Arabidopsis thaliana gene AtPPR5. A genome-wide analysis of chloroplast RNAs that coimmunoprecipitate with Zea mays PPR5 (ZmPPR5) demonstrated that ZmPPR5 is bound in vivo to the unspliced precursor of trnG-UCC. Null and hypomorphic Zmppr5 insertion mutants are embryo viable but are deficient for chloroplast ribosomes and die as seedlings. These mutants show a dramatic decrease in both spliced and unspliced trnG-UCC RNAs, while the transcription of trnG-UCC is unaffected. These results, together with biochemical data documenting the sequence-specific binding of recombinant PPR5 to the trnG-UCC group II intron, suggest that PPR5 stabilizes the trnG-UCC precursor by directly binding and protecting an endonuclease-sensitive site. These findings add to the evidence that chloroplast-localized PPR proteins that are embryo essential in Arabidopsis typically function in the biogenesis of the plastid translation machinery.


Efficacy and prognostic factors of response to carbonic anhydrase inhibitors in management of cystoid macular edema in retinitis pigmentosa.
To determine the efficacy and prognostic factors associated with carbonic anhydrase inhibitors (CAI) in the treatment of cystoid macular edema (CME) in retinitis pigmentosa (RP). This was a cohort study of 81 subjects who were assessed before and after treatment. Spectral-domain optical coherence tomography (SD-OCT) was used to quantify CME. A reduction of at least 11% in central subfield (CSF) thickness was defined as objective evidence of response. In the 125 eyes that received topical dorzolamide, 40.0% demonstrated a response to treatment with a mean reduction in OCT CSF thickness of 105 μm (95% confidence interval [CI]: 82, 128). Mean starting visual acuity (VA) increased from 6/15 to 6/12 after a median time on treatment of 3.0 months. In patients prescribed oral acetazolamide, 28.1% of eyes (41.2% of patients) showed improvement in mean OCT CSF thickness of 115 μm (95% CI: 52, 177) over a median treatment interval of 4.0 months. Visual acuity improved from 6/15 to 6/12. Eyes that responded to topical dorzolamide were more likely to have autosomal recessive than autosomal dominant RP (44.6% vs. 23.3%, P = 0.02), and a higher mean baseline OCT CSF than eyes that did not respond (P = 0.02). We report that 40.0% of eyes (53.1% of patients) showed an objective improvement in CME after treatment with topical dorzolamide and 28.1% of eyes (41.2% of patients) after treatment with oral acetazolamide. Autosomal recessive RP and greater initial central retinal thickness predicted response to treatment with topical dorzolamide.


Gel-liquid crystalline transition of some multilamellar lipid bilayers follows classical kinetics with a fractional dimensionality of approximately two.
The relaxation kinetics of the gel-liquid crystalline transition of phosphatidylcholine (DC14PC, DC16PC, and DC18PC) multilamellar vesicles have been examined using volume-perturbation calorimetry. The time-dependent temperature and pressure changes associated with a periodic volume perturbation are monitored in real time. Data collected in the time domain are transformed to the frequency domain using Fourier series representations of the perturbation and response functions. Because a very small perturbation is imposed during the experiment, linear response theory is suitable for analysis of the relaxation process. The Laplace transform of the classical Kolmogorov-Avrami relation of transition kinetics is used to describe the dynamic response in the frequency domain. For DC14PC and DC16PC, the relaxation process is better fit with an effective dimensionality of n = 2 rather than n = 1. For DC18PC, we estimate that an effective dimensionality of approximately 1.5 will best fit the data. These results indicate that the gel-liquid crystalline transition of these lipid bilayers follows the classical Kolmogorov-Avrami kinetic model with an effective dimensionality greater than 1 and the assumption of simple exponential decay (n = 1) commonly used in data analysis may not always be valid for lipid transitions. Insofar as the dimensionality of the relaxation reflects the geometry of fluctuating lipid clusters, this parameter may be useful in connecting experimental thermodynamic and kinetic results with those obtained from Monte Carlo simulations.


Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval.
Lengthening of the QT interval and torsades de pointes resulting in cardiac arrests and deaths have been noticed during treatment with cisapride, a newly developed gastrointestinal prokinetic agent. The rapid (I[Kr]) and slow (I[Ks]) components of the delayed rectifier current (I[K]) are candidate ionic currents to explain cisapride-related toxicity because of their role in repolarization of cardiac ventricular myocytes. Our objectives were to (1) characterize effects of cisapride on two major time-dependent outward potassium currents involved in the repolarization of cardiac ventricular myocytes, I(Kr) and I(Ks), and (2) determine action potential-prolonging effects of cisapride on isolated hearts. A first set of experiments was performed in isolated guinea pig ventricular myocytes with the whole-cell configuration of the patch-clamp technique. Cells were held at -40 mV while time-dependent outward currents were elicited by depolarizing pulses lasting either 250 ms (I[K250]) or 5000 ms (I[K5000]). Effects of cisapride on the I(Kr) component were assessed by measurement of time-dependent activating currents elicited by short pulses (250 ms; I[K250]) to low depolarizing potentials (-20, -10, and 0 mV). Time-dependent activating currents elicited by long pulses (5000 ms; I[K5000]) to positive potentials (>+30 mV) were recorded to assess effects of the drug on the I(Ks) component. A second set of experiments was conducted in isolated guinea pig hearts buffer-perfused in the Langendorff mode to assess effects of the drug on monophasic action potential duration measured at 90% repolarization (MAPD90). Hearts were exposed to cisapride 100 nmol/L at decremental pacing cycle lengths of 250, 225, 200, 175, and 150 ms to determine reverse frequency-dependent effects of the drug. Overall, 112 myocytes were exposed to seven concentrations of cisapride (10 nmol/L to 10 micromol/L). Cisapride inhibited I(Kr), the major time-dependent outward current elicited by short pulses (I[K250]) to low depolarizing potentials, in a concentration-dependent manner with an IC50 of 15 nmol/L (therapeutic levels, 50 to 200 nmol/L). Conversely, block of I(Ks) by the drug was less potent (estimated IC50 >10 micromol/L). In isolated hearts (n=9 experiments), cisapride 100 nmol/L increased MAPD90 by 23+/-3 (P<.05) at a basic cycle length of 250 ms but by only 7+/-1 ms (P<.05) at a basic cycle length of 150 ms. Block of I(Kr) gives an explanation to lengthening of cardiac repolarization observed in isolated guinea pig hearts. Potent block of I(Kr) is also likely to underlie prolongation of the QT interval observed in patients receiving clinically recommended doses of cisapride as well as severe cardiac toxicity (torsades de pointes) observed in patients with increased plasma concentrations of the drug.


An intronic microRNA links Rb/E2F and EGFR signaling.
The importance of microRNAs in the regulation of various aspects of biology and disease is well recognized. However, what remains largely unappreciated is that a significant number of miRNAs are embedded within and are often co-expressed with protein-coding host genes. Such a configuration raises the possibility of a functional interaction between a miRNA and the gene it resides in. This is exemplified by the Drosophila melanogaster dE2f1 gene that harbors two miRNAs, mir-11 and mir-998, within its last intron. miR-11 was demonstrated to limit the proapoptotic function of dE2F1 by repressing cell death genes that are directly regulated by dE2F1, however the biological role of miR-998 was unknown. Here we show that one of the functions of miR-998 is to suppress dE2F1-dependent cell death specifically in rbf mutants by elevating EGFR signaling. Mechanistically, miR-998 operates by repressing dCbl, a negative regulator of EGFR signaling. Significantly, dCbl is a critical target of miR-998 since dCbl phenocopies the effects of miR-998 on dE2f1-dependent apoptosis in rbf mutants. Importantly, this regulation is conserved, as the miR-998 seed family member miR-29 repressed c-Cbl, and enhanced MAPK activity and wound healing in mammalian cells. Therefore, the two intronic miRNAs embedded in the dE2f1 gene limit the apoptotic function of dE2f1, but operate in different contexts and act through distinct mechanisms. These results also illustrate that examining an intronic miRNA in the context of its host's function can be valuable in elucidating the biological function of the miRNA, and provide new information about the regulation of the host gene itself.


Extreme masking: achieving predictable outcomes in challenging situations with lithium disilicate bonded restorations.
In contemporary dentistry, we have a vast range of materials to choose from, and metal free restorations have become the premier materials for achieving the ultimate in both esthetics and durability. Metal-free restorations are utilized with more conservative preparations to preserve the vital natural dentition, and have proven to be superior alternatives to traditional porcelain-fused-to-metal (PFM) restorations in many cases. There are always "pros and cons" when selecting materials, and to make the best choice it is essential for dental professionals to plan precisely and understand their options in any clinical situation. Selecting suitable materials and techniques involves consideration of the following factors: - Esthetic zone. - Required strength based on the patient's occlusion/dental habits. - Preparation reduction. - Position of the margin. - Type of restoration/preparation. - The treating clinician's philosophy. - Stump shade. Final shade. One of the most significant challenges in the metal-free dentistry is the reproduction of natural dentition without the influence of a "negative stump" - a very dark or metal core showing through the final restorations. There are many factors to be considered when working on such a case, and controlling the opacity of the coping and crown is the key to success. This article presents a unique "outside of the box" technique that provides consistent, predictable and durable restorations, which provide the best possible esthetic outcome.


On estimating and testing associations between random coefficients from multivariate generalized linear mixed models of longitudinal outcomes.
Different types of outcomes (e.g. binary, count, continuous) can be simultaneously modeled with multivariate generalized linear mixed models by assuming: (1) same or different link functions, (2) same or different conditional distributions, and (3) conditional independence given random subject effects. Others have used this approach for determining simple associations between subject-specific parameters (e.g. correlations between slopes). We demonstrate how more complex associations (e.g. partial regression coefficients between slopes adjusting for intercepts, time lags of maximum correlation) can be estimated. Reparameterizing the model to directly estimate coefficients allows us to compare standard errors based on the inverse of the Hessian matrix with more usual standard errors approximated by the delta method; a mathematical proof demonstrates their equivalence when the gradient vector approaches zero. Reparameterization also allows us to evaluate significance of coefficients with likelihood ratio tests and to compare this approach with more usual Wald-type t-tests and Fisher's z transformations. Simulations indicate that the delta method and inverse Hessian standard errors are nearly equivalent and consistently overestimate the true standard error. Only the likelihood ratio test based on the reparameterized model has an acceptable type I error rate and is therefore recommended for testing associations between stochastic parameters. Online supplementary materials include our medical data example, annotated code, and simulation details.


Immuno-PET and Immuno-SPECT of Rheumatoid Arthritis with Radiolabeled Anti-Fibroblast Activation Protein Antibody Correlates with Severity of Arthritis.
One of the most prominent cell populations playing a role in rheumatoid arthritis (RA) is activated fibroblast-like synoviocytes. Among many other proteins, fibroblast-like synoviocytes dominantly express fibroblast activation protein (FAP). Because of the high expression of FAP in arthritic joints, radioimmunoimaging of activated fibroblasts with anti-FAP antibodies might be an attractive noninvasive imaging tool in RA. SPECT and PET with (111)In- and (89)Zr-labeled anti-FAP antibody 28H1 was performed in mice with CIA. The radioactivity uptake in joints was quantified and correlated with arthritis score. Both (111)In-28H1 and (89)Zr-28H1 showed high uptake in inflamed joints, being 3-fold higher than that of the irrelevant isotype-matched control antibody DP47GS, clearly indicating specific accumulation of 28H1. Uptake of (111)In-28H1 ranged from 2.2 percentage injected dose per gram (%ID/g) in noninflamed joints to 32.1 %ID/g in severely inflamed joints. DP47GS accumulation ranged from 1.6 %ID/g in noninflamed tissue to 12.0 %ID/g in severely inflamed joints. Uptake of 28H1 in inflamed joints correlated with arthritis score (Spearman ρ, 0.69; P < 0.0001) and increased with severity of arthritis. SPECT/CT imaging with the anti-FAP antibody (111)In-28H1 specifically visualized arthritic joints with high resolution, and tracer accumulation correlated with the severity of the inflammation in murine experimental arthritis. Background uptake of the radiolabeled antibody was low, resulting in excellent image quality. (89)Zr-28H1 was less favorable for RA imaging because of an elevated bone uptake of (89)Zr. Future studies will focus on the potential role of 28H1 as a tool to monitor therapy response early on.


Collagen deposition during wound repair.
Collagen fiber diameters, amount of birefringent collagen (brightness) and birefringence retardation were measured in implanted collagen-based sponges containing hyaluronic acid (HA) and fibronectin (FN). In the presence of HA and FN, increased number of fibroblasts and brightness were observed 6 days after wounding. Increased brightness in the presence of HA and FN reflected increased deposition of oriented collagen fibers. From days 9 to 12, increased fiber diameters were similar in implanted collagen-based sponges with or without HA and FN. Increased birefringence retardation in sponges containing HA and FN was consistent with increased packing density of collagen fibers observed by scanning electron microscopy. Our results suggest that HA and FN are effective in promoting fibroblast movement into a collagen sponge and deposition of collagen fibers during the early phases of wound healing. Use of a collagen-based sponge containing HA and FN may enhance collagen deposition in situations where healing is compromised as in the case of dermal ulcers.


Enteropathogenicity of Aeromonas hydrophila and Plesiomonas shigelloides: prevalence among individuals with and without diarrhea in Thailand.
To evaluate the enteropathogenicity of Aeromonas hydrophila and Plesiomonas shigelloides, the rate of isolation of these organisms was compared among individuals with and without diarrhea in Thailand. In two groups of American travelers, A. hydrophila, but not P. shigelloides, was associated with episodes of travelers diarrhea more often than when individuals did not have diarrhea (P less than 0.025). Among three populations of Thais, A. hydrophila and P. shigelloides were isolated with similar frequencies from individuals with and without diarrhea. The biochemical characteristics, production of cytotoxin, and ability to distend suckling mouse intestine were similar among A. hydrophila isolates from individuals with and without diarrhea. However, cytotoxic A. hydrophila strains distended rabbit and suckling mouse intestine and produced destructive lesions in intestinal mucosa of both species of animal. P. shigelloides strains produced neither cytotoxin nor distended intestine. Oral administration of whole cultures (10(9)) of cytotoxic A. hydrophila or P. shigelloides failed to cause diarrhea in rhesus monkeys. Volunteer studies or intestinal biopsies of patients with diarrhea may be required to establish whether A. hydrophila is a gastrointestinal pathogen in humans.


Tanshinone IIA effects on ovarian cancer cell line.
To explore the potential therapeutic effect of Tanshinone IIA against ovarian cancer in vitro and elucidate the underlying molecular mechanism. The cell survival upon Tanshinone IIA treatment was determined by the clonogenic assay. Cell apoptosis was analysed by Annexin V/propidium iodide double staining. The cleaved caspase-3/poly ADP-ribose polymerase and apoptosis-related factors were quantified by Western blotting. The relative expression of microRNAs (miRs) was determined by real-time polymerase chain reaction. Tanshinone IIA treatment induced significant apoptosis in TOV-21G cells. Tanshinone suppressed survivin expression while not affected Bax, Bcl-2 and Bcl-xL. We further predicted and experimentally confirmed overexpression of miR-205 in TOV-21G, which ectopic significantly inhibited survivin and promoted cell apoptosis. miR-205-specific antagonist completely abrogated the cell suppressive effect of Tanshinone IIA. Our data suggested that Tanshinone IIA induced cell apoptosis in ovarian carcinoma TOV-21G cells via direct upregulation of miR-205. Our study highlighted the potential therapeutic application of Tanshinone IIA against ovarian malignancy.


Parametric study of apertured focused gaussian beams.
Using Fresnel diffraction integrals, calculations have been made of the irradiance and power distributions in the near field and in the vicinity of the focus for Gaussian beams focused through annular apertures. Universal curves have been plotted which display the calculations in terms of dimensionless parameters. For very large focal length infrared systems it has been found that the irradiance distribution is not symmetrical about the geometrical focal plane as is commonly assumed. Gaussian and sinusoidal phase aberrations in the aperture field have been included.


[The diagnostic value of serological and molecular genetic methods in detection of German measles disease].
The early diagnostic of German measles infection, especially in cases requiring differential diagnostic search, the most informative and usable in practice test-systems are needed to be applied. The sampling of patients (n = 37) included males aged from 15 to 21 year (average age - 18 years) were admitted to hospital on 1-3 day from onset of disease. The technique of polymerase chain reaction with reverse transcription was applied to detect presence of viral RNA in nasopharyngital smear. The presence of viral RNA was confirmed in 26 examined patients (70%). The serological markers of onset of disease at the moment of first examination had 24 (65%) out of 37 patients. It is demonstrated that technique of polymerase chain reaction with reverse transcription has the most diagnostic value in confirmation of diagnosis of German measles infection at the first days of disease. In the sequel, the informativeness of methods of serological diagnostic will increase because complex application of methods of IgM and polymerase chain reaction with reverse transcription are needed at different periods of disease.


Optimization of a Plaque Neutralization Test (PNT) to Identify the Exposure History of Pacific Herring to Viral Hemorrhagic Septicemia Virus (VHSV).
Methods for a plaque neutralization test (PNT) were optimized for the detection and quantification of viral hemorrhagic septicemia virus (VHSV) neutralizing activity in the plasma of Pacific Herring Clupea pallasii. The PNT was complement dependent, as neutralizing activity was attenuated by heat inactivation; further, neutralizing activity was mostly restored by the addition of exogenous complement from specific-pathogen-free Pacific Herring. Optimal methods included the overnight incubation of VHSV aliquots in serial dilutions (starting at 1:16) of whole test plasma containing endogenous complement. The resulting viral titers were then enumerated using a viral plaque assay in 96-well microplates. Serum neutralizing activity was virus-specific as plasma from viral hemorrhagic septicemia (VHS) survivors demonstrated only negligible reactivity to infectious hematopoietic necrosis virus, a closely related rhabdovirus. Among Pacific Herring that survived VHSV exposure, neutralizing activity was detected in the plasma as early as 37 d postexposure and peaked at approximately 64 d postexposure. The onset of neutralizing activity was slightly delayed in fish reared at 7.4°C relative to those in warmer temperatures (9.9°C and 13.1°C); however, neutralizing activity persisted for at least 345 d postexposure in all temperature treatments. It is anticipated that this novel ability to assess VHSV neutralizing activity in Pacific Herring will enable retrospective comparisons between prior VHS infections and year-class recruitment failures. Additionally, the optimized PNT could be employed as a forecasting tool capable of identifying the potential for future VHS epizootics in wild Pacific Herring populations. Received November 7, 2016; accepted January 14, 2017.


Treatment and control of severe infections caused by multiresistant Pseudomonas aeruginosa.
Pseudomonas aeruginosa is one of the leading causes of nosocomial infections. Severe infections, such as pneumonia or bacteraemia, are associated with high mortality rates and are often difficult to treat, as the repertoire of useful anti-pseudomonal agents is limited (some beta-lactams, fluoroquinolones and aminoglycosides, and the polymyxins as last-resort drugs); moreover, P. aeruginosa exhibits remarkable ability to acquire resistance to these agents. Acquired resistance arises by mutation or acquisition of exogenous resistance determinants and can be mediated by several mechanisms (degrading enzymes, reduced permeability, active efflux and target modification). Overall, resistance rates are on the increase, and may be different in different settings, so that surveillance of P. aeruginosa susceptibility is essential for the definition of empirical regimens. Multidrug resistance is frequent, and clinical isolates resistant to virtually all anti-pseudomonal agents are increasingly being reported. Monotherapy is usually recommended for uncomplicated urinary tract infections, while combination therapy is normally recommended for severe infections, such as bacteraemia and pneumonia, although, at least in some cases, the advantage of combination therapy remains a matter of debate. Antimicrobial use is a risk factor for P. aeruginosa resistance, especially with some agents (fluoroquinolones and carbapenems), and interventions based on antimicrobial rotation and restriction of certain agents can be useful to control the spread of resistance. Similar measures, together with the prudent use of antibiotics and compliance with infection control measures, are essential to preserve the efficacy of the currently available anti-pseudomonal agents, in view of the dearth, in the near future, of new options against multidrug-resistant P. aeruginosa strains.


Genetic analysis of atherosclerosis: a research paradigm for the common chronic diseases.
Rapid discoveries of novel and unexpected disease-associated genes for atherosclerotic coronary artery disease (CAD) are anticipated as genomic maps become more detailed and methods for mapping complex disease phenotypes become more refined. Although establishing association or linkage of a marker locus to a CAD susceptibility gene is an important first step, the long-term goal should be to define the underlying functional mutations and explore possible disease mechanisms, including the gene-environment interactions that culminate in clinically apparent disease. This review will define a contemporary research paradigm for study of the genetics of CAD and other common chronic diseases using the tools of modern molecular biology and human genetics.


The impact of guidelines on the outcomes of community-acquired and ventilator-associated pneumonia.
The correct implementation of the current guidelines for the management of community-acquired pneumonia is associated with less mortality, faster clinical stabilization, and lower costs in these patients. By contrast, implementing the current guidelines for the management of hospital-acquired pneumonia has been followed by an increase in initially adequate antibiotic treatment but has not been accompanied by a consistently improved outcome in patients.


Polycationic Silver Nanoclusters Comprising Nanoreservoirs of Ag+ Ions with High Antimicrobial and Antibiofilm Activity.
Silver-based nano-antibiotics are rapidly developing as promising alternatives to conventional antibiotics. Ideally, to remain potent against a wide range of drug-resistant and anaerobic bacteria, silver-based nano-antibiotics should easily penetrate through the bacterial cell walls and actively release silver ions. In this study, highly monodispersed, ultrasmall (<3 nm), polycationic silver nanoclusters (pAgNCs) are designed and synthesized for the elimination of a range of common Gram-negative and Gram-positive pathogens and their corresponding established and matured biofilms, including those composed of multiple species. The pAgNCs also show greatly enhanced antibacterial efficacy against anaerobic bacteria such as Fusobacterium nucleatum and Streptococcus sanguinis. These results demonstrate that the cationic nature facilitates better penetration to the bacterial cell membrane while the presence of a high percentage (>50%) of silver ions (i.e., Ag+ nanoreservoirs) on the cluster surface maintains their efficiency in both aerobic and anaerobic conditions. Significantly, the pAgNCs showed a strong capacity to significantly delay the development of bacterial resistance when compared to similar-sized negatively charged silver nanoparticles or conventional antibiotics. This study demonstrates a novel design strategy that can lay the foundation for the development of future highly potent nano-antibiotics effective against a broad spectrum of pathogens and biofilms needed in many everyday life applications and industries.


p110α Hot Spot Mutations E545K and H1047R Exert Metabolic Reprogramming Independently of p110α Kinase Activity.
The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.


Disparities in Health Care Utilization and Functional Limitations Among Adults With Serious Psychological Distress, 2006-2014.
This study compared health care access, utilization, and functional indicators among adults with and without serious psychological distress (SPD) in the years surrounding implementation of the Patient Protection and Affordable Care Act (ACA). Adults ages 18 to 64 from the 2006-2014 National Health Interview Survey (N=207, 853) were examined on 11 access, utilization, and functional indicators: health insurance coverage (health coverage), insufficient money for medications, delay in health care (delay in care), insufficient money for health care, visiting a doctor ten or more times in the past 12 months, change in place of health care, change in place of health care due to insurance, limitations in ability to work, limitations in activities of daily living (ADLs), insufficient money for mental health care, and having seen a mental health care provider. Multivariate models that were adjusted for health coverage and sociodemographic characteristics indicated that compared with adults without SPD, adults with SPD had greater odds of lacking money for medications (AOR=10.0) and health care (AOR=3.1), experiencing delays in care (AOR=2.7), visiting a doctor ten or more times in the past 12 months (AOR=3.2), changing usual place of health care (AOR=1.5), changing usual place of health care because of insurance (AOR=1.5), and experiencing limitations in ADLs (AOR=3.6) and ability to work (AOR=1.8). The proportions of adults with SPD who lacked health coverage and money to buy prescriptions increased during the study period. Although this trend reversed in 2014, the proportion with SPD experiencing barriers remained above 2006 levels. Health care patterns among adults with SPD require greater attention.


Performing Awake Surgeries in Times of COVID-19 - A Singapore Experience.
It has been 17 years since the severe acute respiratory syndrome outbreak and Singapore is facing yet another daunting pandemic - the novel coronavirus (COVID-19). To date, there are 57,607 cases and 27 casualties. This deadly pandemic requires significant changes especially in the field of awake surgeries for intra-axial tumors that routinely involve long clinic consults, significant interactions between patient and multiple other team members pre, intra, and postoperatively. A retrospective review of all awake cases done during the COVID-19 pandemic from February to June 2020 was done. In this article, we outline the rigorous measures adopted during the COVID-19 pandemic that has allowed us to proceed with awake surgeries and intraoperative mapping at our institution. We have divided the protocol into various phases of care of patients planned for an awake craniotomy. Preoperatively, teleconsults have been used where possible thereby limiting multiple hospital visits and interaction. Intraoperatively, safety nets have been established during asleep-awake-asleep phases of awake craniotomy for all the team members. Postoperatively, early discharge and teleconsult are being employed for rehabilitation and follow-ups. Multiple studies have shown that with intraoperative mapping, we can improve neurological outcomes. As the future of the pandemic remains unknown, the authors believe that surgical treatment should not be delayed for intracranial tumors. Awake craniotomies and intraoperative mapping can be safely carried out by adopting the described protocols with combination of multiple checkpoints and usage of telecommunication.


Efficient golden gate assembly of DNA constructs for single molecule force spectroscopy and imaging.
Single-molecule techniques such as optical tweezers and fluorescence imaging are powerful tools for probing the biophysics of DNA and DNA-protein interactions. The application of these methods requires efficient approaches for creating designed DNA structures with labels for binding to a surface or microscopic beads. In this paper, we develop a simple and fast technique for making a diverse range of such DNA constructs by combining PCR amplicons and synthetic oligonucleotides using golden gate assembly rules. We demonstrate high yield fabrication of torsionally-constrained duplex DNA up to 10 kbp in length and a variety of DNA hairpin structures. We also show how tethering to a cross-linked antibody substrate significantly enhances measurement lifetime under high force. This rapid and adaptable fabrication method streamlines the assembly of DNA constructs for single molecule biophysics.


Sex-limited mutations and the evolution of sexual dimorphism.
Although the developmental and genetic mechanisms underlying sex differences are being elucidated in great detail in a number of species, there remains a breach between proximate and evolutionary studies of sexual dimorphism. More precisely, the evolution of sex-limited gene expression at autosomal loci has not been well reasoned using either theoretical or empirical methods. Here, I show that a Mendelian genetic model including elementary details of sexual differentiation provides novel insight into the evolution of sex differences via sex limitation. This model indicates that the nature of allelic effects and the pattern of selection must be known in both sexes to predict the evolution of sex differences. That is, selection interacts with genetic variation for sexual dimorphism to produce unanticipated patterns of trait divergence or convergence between the sexes. Ultimately, this model may explain why previous models for the evolution of sexual dimorphism do not predict the erratic behavior of the sex difference during artificial selection experiments.


Comparing Primary Health-Care Service Delivery Disruptions Across Disasters.
The aim of this study was to compare primary care appointment disruptions around Hurricanes Ike (2008) and Harvey (2017) and identify patterns that indicate differing continuity of primary care or care systems across events. Primary care appointment records covering 5 wk before and after each storm were identified for Veterans Health Affairs (VA) facilities in the greater Houston and surrounding areas and a comparison group of VA facilities located elsewhere. Appointment disposition percentages were compared within and across storm events to assess care disruptions. For Hurricane Harvey, 14% of primary care appointments were completed during the week of landfall (vs 33% for Hurricane Ike and 69% in comparison clinics), and 49% were completed the following week (vs 58% for Hurricane Ike and 71% for comparison clinics). By the second week after Hurricane Ike and third week after Harvey, the scheduled appointment completion percentage returned to prestorm levels of approximately 60%. There were greater and more persistent care disruptions for Hurricane Harvey relative to Hurricane Ike. As catastrophic emergencies including major natural disasters and infectious disease pandemics become a more recognized threat to primary and preventive care delivery, health-care systems should consider implementing strategies to monitor and ensure primary care appointment continuity.


Clinical trial of jejunoileal and gastric bypass for the treatment of morbid obesity: four-year progress report.
The present status of 38 patients comprising a clinical trial of jejunoileal and gastric bypass for the treatment of morbid obesity, begun four years ago at North Carolina Memorial Hospital, is reported. Weight loss was greater in patients treated by jejunoileal bypass than those treated by gastric bypass. The poorer weight loss noted in the gastric bypass patients is associated with an excessively large proximal gastric pouch, which had characterized the 19 gastric bypass operations done prior to May 1977. The weight loss achieved with the current version of the gastric bypass, a smaller proximal gastric pouch, is comparable to that achieved with jejunoileal bypass. The objective and subjective sequelae and complications of jejunoileal bypass are more common and more serious than those of gastric bypass. Gastric bypass is the better operation for the treatment of morbid obesity.


Parkinson's disease mortality and pesticide exposure in California 1984-1994.
In the last two decades reports from different countries emerged associating pesticide and herbicide use with Parkinson's disease (PD). California growers use approximately 250 million pounds of pesticides annually, about a quarter of all pesticides used in the US. We employed a proportional odds mortality design to compare all cases of PD recorded as underlying (1984-1994) or associated causes (1984-1993) of death occurring in California with all deaths from ischaemic heart disease (ICD-9 410-414) during the same period. Based on pesticide use report data we classified California counties into several pesticide use categories. Agricultural census data allowed us to create measures of percentage of land per county treated with pesticides. Employing logistic regression models we estimated the effect of pesticide use controlling for age, gender, race, birthplace, year of deaths, and education. Mortality from PD as the underlying cause of death was higher in agricultural pesticide-use counties than in non-use counties. A dose response was observed for insecticide use per county land treated when using 1982 agricultural census data, but not for amounts of restricted pesticides used or length of residency in a country prior to death. Our data show an increased PD mortality in California counties using agricultural pesticides. Unless all of our measures of county pesticide use are surrogates for other risk factors more prevalent in pesticide use counties, it seems important to target this prevalent exposure in rural California in future studies that use improved case finding mechanisms and collect pesticide exposure data for individuals.


Characterization of a Bacillus thuringiensis strain collection isolated from diverse Costa Rican natural ecosystems.
Costa Rican natural ecosystems are among the most diverse in the world. For this reason, we isolated strains of the entomopathogenic bacteria Bacillus thuringiensis (Bt) to determine their diversity, distribution and abundance. A total of 146 Bt strains were obtained from environmental samples collected from diverse natural ecosystems and life zones of Costa Rica. We recovered Bt strains from 71%, 63%, 61% and 54% of soil samples, fresh leaves, other substrates and leaf litter respectively. Bt was isolated in 65% of the samples collected in the humid tropical forest in national parks (Braulio Carrillo, Gandoca Manzanillo, Sierpe, Hitoy Cerere, and Cahuita), and in 59% of the samples collected in the dry tropical forest (Parque Nacional Marino las Baulas, Palo Verde and Santa Rosa). In the very humid tropical forest (Tortuguero) Bt was isolated in 75% of the samples and in the very humid tropical forest transition perhumid (Carara) it was found in 69% of the samples. The strains exhibit a diverse number, size and morphology of parasporal inclusion bodies: irregular (47%), oval (20%), bipyramidal (3%), bipyramidal and cubic (1%), bipyramidal, oval and irregular (5%) and bipyramidal, oval and cubic crystals (2%). Strains isolated from Braulio Carrillo, Tortuguero and Cahuita, presented predominantly irregular crystals. On the other hand, more than 60% of the isolates from Térraba-Sierpe and Hitoy-Cerere had medium oval crystals. Strains from Gandoca-Manzanillo, Palo Verde and Carara presented mainly combinations of oval and irregular crystals. Nevertheless, the greatest diversity in crystal morphology was observed in those from Santa Rosa, Llanos del Rio Medio Queso and Parque Marino las Baulas. Protein analyses of the crystal-spore preparations showed delta-endotoxin with diverse electrophoretic patterns, with molecular weights in the range of 20 to 160 kDa. Fifty six percent of the strains amplified with the cry2 primer, 54% with vip3, 20% with cry1, 9% with cry3-cry7 and 8% with cry8. The cry11 and cyt genes were found in 8% and 7% of the strains, respectively. When analyzed with specific primers for the cryl subfamily, 13 different genetic profiles were obtained. In addition, twenty-four strains did not amplify with any of the primers used, suggesting they contain novel cry genes. The diversity of Bt genes found in this collection indicates it could have great potential for the control of different species of insect pests. The toxicological characterization of the strains by bioassays against important insect pests will provide useful information about their potential use for the formulation of biological insecticides and their respective cry and vip genes for the transformation of crops to confer resistance to insects.


The DeMarco factor: interview with a health policy advocate.
An interview with Vincent DeMarco, President of the Maryland Citizen's Health Initiative, reviews the history and strategies used to win victories for public health on gun policy and tobacco taxes and to seek passage of higher alcohol taxes in the state of Maryland. DeMarco emphasizes the need to build broad coalitions, to engage policy makers at election time and not just or primarily during legislative sessions, and to take advantage of the power of the news media as a microphone for reaching millions of possible supporters. The interview concludes with recommendations for public health training and practitioners in order to become successful policy advocates in a rapidly changing media and political landscape.


Spatial performance correlates with in vitro potentiation in young and aged Fischer 344 rats.
Young adult (2-4 months old) and aged (24-26 months old) Fischer 344 (F344) rats were trained for spatial behavior (locating a hidden escape platform) in a circular water maze. The aged rats showed deficits in both the acquisition and retention of the learned response. Following the behavioral training, hippocampal slices from the rats were prepared. Potentiation of CA1 extracellular, somatic field potentials was studied in vitro following either a short stimulus train (4 pulses) or a longer train (50 pulses). Slices from the aged rats showed less short-term potentiation (124.8 +/- 4.9% baseline, mean +/- S.E.M.) at 1 min following the short train in comparison to slices from the young rats (151.8 +/- 7.5%, P less than 0.05). However, following the longer train, no differences were found between the groups in the degree of either short-term (measured at 1 min after stimulation) or long-term potentiation (measured at 60 min). The amount of potentiation seen at various time points after either train correlated with the behavioral measure of retention. These results indicate that F344 rats exhibit age-related behavioral deficits, and age-related synaptic potentiation deficits in response to short stimulation trains. The correlation between the degree of potentiation (both short-term and long-term) and retention of a behavioral task adds strength to the hypothesis that potentiation mechanisms may underlie memory processes.


Optical-Thermally Excited Graphene Resonant Mass Detection: A Molecular Dynamics Analysis.
In consideration of the presented optical-thermally excited resonant mass detection scheme, molecular dynamics calculations are performed to investigate the thermal actuation and resonant mass sensing mechanism. The simulation results indicate that an extremely high temperature exists in a 6% central area of the graphene sheet exposed to the exciting laser. Therefore, constraining the laser driving power and enlarging the laser spot radius are essential to weaken the overheating in the middle of the graphene sheet, thus avoiding being burned through. Moreover, molecular dynamics calculations demonstrate a mass sensitivity of 214 kHz/zg for the graphene resonator with a pre-stress of 1 GPa. However, the adsorbed mass would degrade the resonant quality factor from 236 to 193. In comparison, the sensitivity and quality factor could rise by 1.3 and 4 times, respectively, for the graphene sheet with a pre-stress of 5 GPa, thus revealing the availability of enlarging pre-stress for better mass sensing performance.


Engineering α-amylase levels in wheat grain suggests a highly sophisticated level of carbohydrate regulation during development.
Wheat starch degradation requires the synergistic action of different amylolytic enzymes. Our spatio-temporal study of wheat α-amylases throughout grain development shows that AMY3 is the most abundant isoform compared with the other known α-amylases. Endosperm-specific over-expression of AMY3 resulted in an increase of total α-amylase activity in harvested grains. Unexpectedly, increased activity did not have a significant impact on starch content or composition but led to an increase of soluble carbohydrate (mainly sucrose) in dry grain. In AMY3 overexpression lines (A3OE), germination was slightly delayed and triacylglycerol (TAG) content was increased in the endosperm of mature grain. Despite increased AMY3 transcript and protein content throughout grain development, alterations of α-amylase activity and starch granule degradation were not detected until grain maturation, suggesting a post-translational inhibition of α-amylase activity in the endosperm during the starch filling period. These findings show unexpected effects of a high level of α-amylase on grain development and composition, notably in carbon partitioning and TAG accumulation, and suggest the presence of a hitherto unknown regulatory pathway during grain filling.


An aromatase polymorphism (g.132810C>T) predicts risk of bisphosphonate-related osteonecrosis of the jaw.
Bisphosphonate (BP)-related osteonecrosis of the jaw (ONJ) is an unpredictable, debilitating adverse effect. Recently, genetic polymorphisms have arisen as promising tools to identify patients with a higher risk of drug-related adverse events. We aimed to examine the association between the aromatase polymorphism g.132810C>T, and the estrogen receptor polymorphisms g.156705T>C and g.156751A>G, and the risk of BP-related ONJ. Eighty-three subjects were included in the study. A clinical and radiological examination was conducted on oncologic subjects treated with zoledronic acid. Subjects with histologically confirmed ONJ were included in the test group (n = 30) whereas subjects with good oral health were included in control group (n = 53). Aromatase and estrogen receptor polymorphisms from blood samples were analyzed. The aromatase g.132810C>T polymorphism displayed an over-representation of the TT genotype in the test group (36.67 vs 16.98%; p < 0.05). There was no significant difference in either estrogen receptor polymorphism genotype frequency between the test and control groups. Our data suggest a role for the g.132810C>T polymorphism in predicting ONJ risk. These results can pave the way to the personalization of BP therapy, based on individual genotype.


Photovoice and empowerment: evaluating the transformative potential of a participatory action research project.
Photovoice is a visual research methodology with the intention to foster social change. Photovoice has been used to investigate change in empowerment in vulnerable communities, However, the individual experience of participants involved in Photovoice projects is seldom scrutinized. Our aim was to explore and describe the individual experiences of the female individuals who participated in a previous Photovoice project. We analyzed a change in the women's empowerment in terms of: 1) gain in knowledge and skills, 2) change in self-perception, and 3) access to and use of resources. This qualitative study took place in the low-income District of Villaverde (Madrid, Spain), from January-June 2016. We conducted 10 semi-structured interviews with the female residents who had participated in the previous Photovoice project. We also collected field notes. We analyzed these data through a direct qualitative content analysis. The three outlined dimensions of empowerment provided guidance for the analysis of the results. We found positive changes in the three dimensions of empowerment: 1) participants acquired new knowledge and developed critical awareness of their community; 2) the social recognition participants received transformed their self-perception; and 3) the project allowed them to expand their social networks and to build new links with different actors (research partners, local decision makers, media and the wider public). Photovoice projects entail the opportunity for empowering participants. Future research using Photovoice should assess the influence it has on participants' empowerment changes and how to sustain these individual and social changes.


Correcting synthetic MRI contrast-weighted images using deep learning.
Synthetic magnetic resonance imaging (MRI) offers a scanning paradigm where a fast multi-contrast sequence can be used to estimate underlying quantitative tissue parameter maps, which are then used to synthesize any desirable clinical contrast by retrospectively changing scan parameters in silico. Two benefits of this approach are the reduced exam time and the ability to generate arbitrary contrasts offline. However, synthetically generated contrasts are known to deviate from the contrast of experimental scans. The reason for contrast mismatch is the necessary exclusion of some unmodeled physical effects such as partial voluming, diffusion, flow, susceptibility, magnetization transfer, and more. The inclusion of these effects in signal encoding would improve the synthetic images, but would make the quantitative imaging protocol impractical due to long scan times. Therefore, in this work, we propose a novel deep learning approach that generates a multiplicative correction term to capture unmodeled effects and correct the synthetic contrast images to better match experimental contrasts for arbitrary scan parameters. The physics inspired deep learning model implicitly accounts for some unmodeled physical effects occurring during the scan. As a proof of principle, we validate our approach on synthesizing arbitrary inversion recovery fast spin-echo scans using a commercially available 2D multi-contrast sequence. We observe that the proposed correction visually and numerically reduces the mismatch with experimentally collected contrasts compared to conventional synthetic MRI. Finally, we show results of a preliminary reader study and find that the proposed method statistically significantly improves in contrast and SNR as compared to synthetic MR images.


Haliea salexigens gen. nov., sp. nov., a member of the Gammaproteobacteria from the Mediterranean Sea.
A novel aerobic, Gram-negative bacterium, designated 3X/A02/235T, was isolated from the surface of coastal waters in the north-western Mediterranean Sea. Cells were motile, straight rods, 1.6 microm long and 0.5 microm wide, and formed cream colonies on marine agar medium. The G+C content of the genomic DNA was 61 mol%. Phylogenetic analysis of the 16S rRNA gene sequence placed the strain in the class Gammaproteobacteria and within the family Alteromonadaceae. On the basis of 16S rRNA gene sequence comparisons and physiological and biochemical characteristics, this isolate represents a novel species of a novel genus, for which the name Haliea salexigens gen. nov., sp. nov. is proposed. The type strain of Haliea salexigens is 3X/A02/235T (=DSM 19537T =CIP 109602T =MOLA 286T).


The recovery of some components of the renin angiotensin system in the rat pancreas after chronic exposure to hypoxic condition.
Previous studies have shown that the expression of the major components from a local pancreatic renin-angiotensin system (RAS) was upregulated after chronic exposure to oxygen deprivation (10% oxygen). In the present study, the reversibility of expression for the pancreatic RAS affected by chronic hypoxia was investigated in the pancreas. Rats were first subject to hypoxia for one Month and they were then returned to normoxic conditions for a varying period of time (1, 2, 3 and 4 weeks). The degree of recovery in the expression of RAS components was analyzed with standard curve-quantitative competitive-reverse transcription-polymerase chain reaction (SC-QC-RT-PCR), Western blot analysis and a specific assay for angiotensin-converting enzyme (ACE) activity. Results from SC-QC-RT-PCR showed that the upregulated expression of angiotensin II type 1 (AT(1)) receptor mRNA following chronic hypoxia could be completely restored to the control level after the rats were returned to the normoxic condition for 3 weeks. The reversibility of mRNA expression for angiotensin II type 2 (AT(2)) receptor and angiotensinogen was observed after the return to normoxic conditions for 2 and 3 weeks respectively when compared with that of their respective controls. Results from Western blot analysis further confirmed that the expression of AT(1) receptor protein was also reversible after return to normoxic conditions for 4 weeks. In addition, the activation of ACE activity returned to its normal level in a time-dependent manner. These data indicate that the upregulation of a local pancreatic RAS affected by chronic hypoxia could be recoverable. The significance of its reversibility and adaptability following chronic hypoxia may be of physiological relevance to the pancreas.


Abortion and Infertility.
The purpose of this article is to examine one potential factor that might negatively impact female fertility, namely induced abortion. While there appears to be a general consensus that there is no association between abortion and infertility, amongst the publications that do exist there is nevertheless evidence to the contrary. Moreover, given the variety of reasonable grounds for a link, and the insufficient attention to the subject by researchers, a re-examination of the field is warranted. Abortion, whether surgical or medical, is one of the most common medical procedures undertaken by women, so even a small effect could influence large numbers of women, and therefore couples. If it were known that abortion was an underlying cause of infertility, it would be an ethical and legal requirement for medical professionals to inform women before consent is obtained. A case could even be made that if research were inconclusive, inadequate or preliminary, women should nevertheless be informed.


The genus Cuscuta (Convolvolaceac): An updated review on indigenous uses, phytochemistry, and pharmacology.
Cuscuta, commonly known as dodder, is a genus of family convolvolaceace. Approximately 170 species of Cuscuta are extensively distributed in temperate and subtropical areas of the world. Species of this genus are widely used as essential constituents in functional foods and traditional medicinal systems. Various parts of many members of Cuscuta have been found efficacious against a variety of diseases. Phytochemical investigations have confirmed presence of biologically active moieties such as flavonoids, alkaloids, lignans, saponines, phenolics, tannins, and fatty acids. Pharmacological studies and traditional uses of these plants have proved that they are effective antibacterial, antioxidant, antiostioporotic, hepatoprotective, anti-inflammatory, antitumor, antipyretic, antihypertensive, analgesic, anti hair fall, and antisteriogenic agents.


[Therapeutic-preventive effect of sodium selenite on the course of experimental myocardial infarct].
An occlusion of the left coronary artery in rats tends to signally raise the intensity of free radical oxidation of myocardial-lipids, which is revealed by the chemofluorescent method. A direct correlational link between the intensity of the lipids peroxidation and the extent of the myocardial damage was established. Subcutaneous injection of sodium selenite in a dose of 30 gamma/kg 2 hours prior to ligation and once daily for a space of 7 days produces a distincly reduced intensity of free-radical processes in the myocardium, decreases the extent of infarction and prevents the appearance of gross changes on the ECG.


Necrotic death but not irradiation abolishes costimulation of T-cell effector functions and survival by CD80-expressing tumor cells.
Tumor vaccination by the use of gene-modified cancer cells that provide costimulatory signals has been successfully applied in preclinical animal models and is currently evaluated in a variety of clinical settings. In previous work, we demonstrated the efficacy of B7.1/CD80 to promote tumor immunity in syngeneic murine models and to prevent deletion of activated T cells by activation-induced cell death (AICD). In clinical trials, tumor cell vaccines are generally inactivated to avoid transfer of live tumor cells, i.e., additional tumor burden. Previous data indicated, however, that inactivation of tumor cells by lethal ionizing irradiation abrogates tumor vaccination by CD80-expressing cells. Here, we compare living and irradiated allogeneic tumor cells regarding their capacity to induce T-cell effector functions and their propensity to interfere with T-cell deletion by apoptosis. Both lethally irradiated and nonirradiated tumor cells facilitated T-cell proliferation, tumor cell lysis, and interfered with T-cell AICD to a similar extent. In contrast, necrotic tumor cells failed to costimulate T-cell effector functions. Thus, irradiation does not seem to hamper tumor cell-mediated costimulation of T-cell effector functions. In contrast, necrosis of gene-modified tumor cells abrogates costimulation of T cells by CD80-expressing cells.


Machine Learning and Natural Language Processing in Mental Health: Systematic Review.
Machine learning systems are part of the field of artificial intelligence that automatically learn models from data to make better decisions. Natural language processing (NLP), by using corpora and learning approaches, provides good performance in statistical tasks, such as text classification or sentiment mining. The primary aim of this systematic review was to summarize and characterize, in methodological and technical terms, studies that used machine learning and NLP techniques for mental health. The secondary aim was to consider the potential use of these methods in mental health clinical practice. This systematic review follows the PRISMA (Preferred Reporting Items for Systematic Review and Meta-analysis) guidelines and is registered with PROSPERO (Prospective Register of Systematic Reviews; number CRD42019107376). The search was conducted using 4 medical databases (PubMed, Scopus, ScienceDirect, and PsycINFO) with the following keywords: machine learning, data mining, psychiatry, mental health, and mental disorder. The exclusion criteria were as follows: languages other than English, anonymization process, case studies, conference papers, and reviews. No limitations on publication dates were imposed. A total of 327 articles were identified, of which 269 (82.3%) were excluded and 58 (17.7%) were included in the review. The results were organized through a qualitative perspective. Although studies had heterogeneous topics and methods, some themes emerged. Population studies could be grouped into 3 categories: patients included in medical databases, patients who came to the emergency room, and social media users. The main objectives were to extract symptoms, classify severity of illness, compare therapy effectiveness, provide psychopathological clues, and challenge the current nosography. Medical records and social media were the 2 major data sources. With regard to the methods used, preprocessing used the standard methods of NLP and unique identifier extraction dedicated to medical texts. Efficient classifiers were preferred rather than transparent functioning classifiers. Python was the most frequently used platform. Machine learning and NLP models have been highly topical issues in medicine in recent years and may be considered a new paradigm in medical research. However, these processes tend to confirm clinical hypotheses rather than developing entirely new information, and only one major category of the population (ie, social media users) is an imprecise cohort. Moreover, some language-specific features can improve the performance of NLP methods, and their extension to other languages should be more closely investigated. However, machine learning and NLP techniques provide useful information from unexplored data (ie, patients' daily habits that are usually inaccessible to care providers). Before considering It as an additional tool of mental health care, ethical issues remain and should be discussed in a timely manner. Machine learning and NLP methods may offer multiple perspectives in mental health research but should also be considered as tools to support clinical practice.


Polyketide genes in the marine sponge Plakortis simplex: a new group of mono-modular type I polyketide synthases from sponge symbionts.
Sponge symbionts are a largely unexplored source of new and unusual metabolic pathways. Insights into the distribution and function of metabolic genes of sponge symbionts are crucial to dissect and exploit their biotechnological potential. Screening of the metagenome of the marine sponge Plakortis simplex led to the discovery of the swf family, a new group of mono-modular type I polyketide synthase/fatty acid synthase (PKS/FAS) specifically associated with sponge symbionts. Two different examples of the swf cluster were present in the metagenome of P. simplex. A third example of the cluster is present in the previously sequenced genome of a poribacterium from the sponge Aplysina aerophoba but was formerly considered orthologous to the wcb/rkp cluster. The swf cluster was also found in six additional species of sponges. Therefore, the swf cluster represents the second group of mono-modular PKS, after the supA family, to be widespread in marine sponges. The putative swf operon consists of swfA (type I PKS/FAS), swfB (reductase and sulphotransferase domains) and swfC (radical S-adenosylmethionine, or radical SAM). Activation of the acyl carrier protein (ACP) domain of the SwfA protein to its holo-form by co-expression with Svp is the first functional proof of swf type genes in marine sponges. However, the precise biosynthetic role of the swf clusters remains unknown.


Downregulation of microRNA‑199a‑5p protects cardiomyocytes in cyanotic congenital heart disease by attenuating endoplasmic reticulum stress.
Chronic hypoxia is a key pathological change in patients with cyanotic congenital heart defect (CCHD). It has been demonstrated that enhanced myocardial unfolded protein response (UPR) increases the capacity to buffer endoplasmic reticulum (ER) stress and to avoid subsequent apoptosis caused by the hypoxia that underlies CCHD. The present study was performed to determine the regulatory role of microRNAs (miRNAs) in this cytoprotective UPR process. The results revealed that miR‑199a‑5p was markedly downregulated in the cardiac tissue of patients with CCHD and in human myocardial cells cultured in hypoxic conditions. The two major UPR modulators, 78 kDa glucose‑regulated protein (GRP78) and activating transcription factor 6 (ATF6), were potential target genes of miR‑199a‑5p in CCHD myocardial specimens. In addition, the miR‑199a‑5p mimic and inhibitor were evidently able to change GRP78 and ATF6 gene expression and ER stress‑associated apoptosis in hypoxia‑treated cardiomyocytes. The interaction between miR‑199a‑5p and the ATF6 and GRP78 3'‑UTR binding sites in myocardial cells was also confirmed by luciferase assay. Thus, it is concluded that myocardial downregulation of miR‑199a‑5p favors the UPR against hypoxia‑induced ER stress in CCHD, which contributes to myocardial protection.


Novel mechanisms of action of the biologicals in rheumatic diseases.
Biological drugs targeting pro-inflammatory or co-stimulatory molecules or depleting lymphocyte subsets made a revolution in rheumatoid arthritis (RA) treatment. Their comparable efficacy in clinical trials raised the point of the heterogeneity of RA pathogenesis, suggesting that we are dealing with a syndrome rather than with a single disease. Several tumor necrosis factor-alpha (TNF-α) blockers are available, and a burning question is whether they are biosimilar or not. The evidence of diverse biological effects in vitro is in line with the fact that a lack of efficacy to one TNF-α agent does not imply a non-response to another one. As proteins, biologicals are potentially immunogenic. It has been recently raised that anti-drug antibodies (ADA) may affect their bioavailability and eventually the clinical efficacy through local formation of immune complexes and directly by preventing the interaction between the drug and TNF-α. Regular monitoring of drug and ADA levels appears the best way to tailor anti-TNF-α therapies. Owing to the pleiotropic characteristics of the target, anti-TNF-α blockers may affect several mechanisms beyond rheumatoid synovitis. As TNF-α plays a pivotal role in the induction of early atherosclerosis, treatment with TNF-inhibitors may modulate cholesterol handling, in particular, cholesterol efflux from macrophages. Side effects are a major issue because of the systemic TNF-α blocking action. The efficacy of an anti-C5 monoclonal antibody fused to a peptide targeting inflamed synovia in experimental arthritis opened the way for new strategies: Homing to the synovium of molecules neutralizing TNF would allow to maximize the therapeutic action avoiding the side effects.


Convergent evolution of an extreme dietary specialisation, the olfactory system of worm-eating rodents.
Turbinal bones are key components of the mammalian rostrum that contribute to three critical functions: (1) homeothermy, (2) water conservation and (3) olfaction. With over 700 extant species, murine rodents (Murinae) are the most species-rich mammalian subfamily, with most of that diversity residing in the Indo-Australian Archipelago. Their evolutionary history includes several cases of putative, but untested ecomorphological convergence, especially with traits related to diet. Among the most spectacular rodent ecomorphs are the vermivores which independently evolved in several island systems. We used 3D CT-scans (N = 87) of murine turbinal bones to quantify olfactory capacities as well as heat or water conservation adaptations. We obtained similar results from an existing 2D complexity method and two new 3D methodologies that quantify bone complexity. Using comparative phylogenetic methods, we identified a significant convergent signal in the rostral morphology within the highly specialised vermivores. Vermivorous species have significantly larger and more complex olfactory turbinals than do carnivores and omnivores. Increased olfactory capacities may be a major adaptive feature facilitating rats' capacity to prey on elusive earthworms. The narrow snout that characterises vermivores exhibits significantly reduced respiratory turbinals, which may reduce their heat and water conservation capacities.


Screening and Validation of Novel Biomarkers in Osteoarticular Pathologies by Comprehensive Combination of Protein Array Technologies.
Osteoarthritis (OA) is one of the most prevalent articular diseases. The identification of proteins closely associated with the diagnosis, progression, prognosis, and treatment response is dramatically required for this pathology. In this work, differential serum protein profiles have been identified in OA and rheumatoid arthritis (RA) by antibody arrays containing 151 antibodies against 121 antigens in a cohort of 36 samples. Then the identified differential serum protein profiles have been validated in a larger cohort of 282 samples. The overall immunoreactivity is higher in the pathological situations in comparison with the controls. Several proteins have been identified as biomarker candidates for OA and RA. Most of these biomarker candidates are proteins related to inflammatory response, lipid metabolism, or bone and extracellular matrix formation, degradation, or remodeling.


Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes.
The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30-40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO-L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption.


The units of selection and measures of fitness.
This paper presents a unified account of the properties of the measures, Malthusian parameter and entropy in predicting evolutionary change in populations of macromolecules, cells and individuals. The Malthusian parameter describes the intrinsic rate of increase of the population. The entropy describes the intrinsic variability in populations: it characterizes the variability in mutation and replication rates in populations of macromolecules; the rate of decay of synchrony in populations of cells; and the degree of iteroparity in populations of individuals. The Malthusian parameter determines ultimate population numbers: under constant environmental conditions, it is the rate of increase when equilibrium conditions are attained. Entropy determines population stability: the gain in the Malthusian parameter due to small fluctuations in the life-cycle variables is determined by entropy. These properties, which are valid for populations of macromolecules, cells and individuals, show that the Malthusian parameter and entropy act as complimentary fitness indices in understanding evolutionary change in populations.


Lack of correlation between bronchoconstrictor response and bronchodilator response in a population-based study.
Bronchodilator and bronchoconstrictor responsiveness have been considered physiological opposites in patients with obstructive airways disease. Provocation challenges have been replaced by bronchodilator tests in the assessment of cases of severe airways obstruction. The aim of this study was to examine the relationship between bronchoconstrictor and bronchodilator responsiveness, and their supposed interchangeability, in a general population. From the Vlagtwedde-Vlaardingen follow-up study, 101 adults were recruited (mean (SD) age 55 (11) yrs, 67 males and 34 females, and 31 were smokers). All completed a questionnaire on airways symptoms. Bronchoconstrictor and bronchodilator responsiveness were assessed with cumulative dose-response curves, using histamine and terbutaline, respectively. Thus, it was possible to relate histamine sensitivity of the airways (the concentration of histamine, at which forced expiratory volume in one second (FEV1) falls by 10% (PC10)) to the maximal bronchodilator response (delta FEV1) and the sensitivity to the bronchodilator (cumulative dose of inhaled terbutaline at which FEV1 increases by 10% (RD10)). Subjects with a bronchoconstrictor response (PC10 < or = 16 mg x mL(-1); n=38) had more respiratory symptoms than those without (n=63) (40 versus 21%) and also lower baseline FEV1 values (90 versus 96% predicted), but had comparable bronchodilator responsiveness. Subjects with a bronchodilator response (delta FEV1 > or = 9% of the predicted value; n=13) did not differ from those without (n=88) for all parameters, including symptoms, allergy and pulmonary function. In those with a bronchoconstrictor response, there was a weak but significant correlation between the PC10 and RD10 (rho=-0.32), but not between PC10 and delta FEV1. This study suggests that bronchoconstrictor and bronchodilator responsiveness are not highly correlated, even in subjects with airways obstruction. Symptoms were associated with the presence of a bronchoconstrictor, but not a bronchodilator, response. We conclude that bronchoconstrictor and bronchodilator responsiveness are two different phenotypic markers that are not interchangeable in epidemiological studies.