Adhesion and activation of platelets from subjects with coronary artery disease and apparently healthy individuals on biomaterials.
On the basis of the clinical studies in patients with coronary artery disease (CAD) presenting an increased percentage of activated platelets, we hypothesized that hemocompatibility testing utilizing platelets from healthy individuals may result in an underestimation of the materials' thrombogenicity. Therefore, we investigated the interaction of polymer-based biomaterials with platelets from CAD patients in comparison to platelets from apparently healthy individuals. In vitro static thrombogenicity tests revealed that adherent platelet densities and total platelet covered areas were significantly increased for the low (polydimethylsiloxane, PDMS) and medium (Collagen) thrombogenic surfaces in the CAD group compared to the healthy subjects group. The area per single platelet-indicating the spreading and activation of the platelets-was markedly increased on PDMS treated with PRP from CAD subjects. This could not be observed for collagen or polytetrafluoroethylene (PTFE). For the latter material, platelet adhesion and surface coverage did not differ between the two groups. Irrespective of the substrate, the variability of these parameters was increased for CAD patients compared to healthy subjects. This indicates a higher reactivity of platelets from CAD patients compared to the healthy individuals. Our results revealed, for the first time, that utilizing platelets from apparently healthy donors bears the risk of underestimating the thrombogenicity of polymer-based biomaterials.


The mechanism of regulation of actomyosin subfragment 1 ATPase.
The mechanism of regulation of actin-subfragment 1 nucleoside triphosphatase is described in terms of the rate and equilibrium constants of a relatively simple kinetic scheme: (Formula: see text) where T, D, and Pi are nucleoside triphosphate, nucleoside diphosphate, and inorganic phosphate, respectively; Ka, Kb, and Kc are association constants; the ki are first-order rate constants; A is regulated actin (actin-tropomyosin-troponin); and M is subfragment 1. Calcium binding to regulated actin had little effect on step 2; k2 was almost unaffected, and k-2 increased, at most, 2-fold. k-1 and k3 increased 10-20-fold for ATP and 3-5-fold for 1-N6-ethenoadenosine triphosphate as substrates. Kb and Kc increased by less than 50%, whereas Ka increased 6-10-fold. The primary effect in regulation is on the rate of a conformational change which determines the rate of dissociation of ligands bound to the active site. The measurements probably underestimate the ratio of rate constants of product dissociation for active and relaxed states of actin because of heterogeneity. The kinetic evidence can be explained by a partial steric blocking mechanism or by a conformational (nonsteric) mechanism.


Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial.
Relationships between plasma morphine concentrations and neonatal responses to endotracheal tube (ETT) suctioning are unknown in preterm neonates. Ventilated preterm neonates (n=898) from 16 centres were randomly assigned to placebo (n=449) or morphine (n=449). After an i.v. loading dose (100 microg kg(-1)), morphine infusions [23-26 weeks postmenstrual age (PMA) 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); and 30-32 weeks 30 microg kg(-1) h(-1)] were established for a maximum of 14 days. Open-label morphine (20-100 microg kg(-1)) was given for pain or agitation. Morphine assay and neonatal response to ETT suctioning was measured at 20-28 and 70-76 h after starting the drug infusion and at 10-14 h after discontinuation of the study drug. The concentration-effect response was investigated using non-linear mixed effects models. A total of 5119 data points (1598 measured morphine concentrations and 3521 effect measures) were available from 875 neonates for analysis. Clearance was 50% that of the mature value at 54.2 weeks PMA (CLmat(50)) and increased from 2.05 litre h(-1) 70 kg(-1) at 24 weeks PMA to 6.04 litre h(-1) 70 kg(-1) at 32 weeks PMA. The volume of distribution in preterm neonates was 190 litre 70 kg(-1) (CV 51%) and did not change with age. There was no relationship between morphine concentrations (range 0-440 microg litre(-1)) and heart rate changes associated with ETT suctioning or with the Premature Infant Pain Profile. A sigmoid curve describing maturation of morphine clearance is moved to the right in preterm neonates and volume of distribution is increased compared with term neonates. Morphine does not alter the neonatal response to ETT suctioning.


Morphological variation in the tropical anole, Anolis casildae (Squamata: Polychrotidae).
We describe morphological variation (scalation and coloration) observed among eight individuals of the Panamanian lizard species Anolis casildae. This variation was not observed in the holotype and aids in identification of this recently described species (originally described on the basis of a single, male specimen). This species occurs only in the Reserva Forestal Fortuna (Chiriquí Province) and the adjacent Bosque Protector Palo Seco (Bocas del Toro Province) in western Panama. Anolis casildae can be distinguished from all other Panamanian anole species via six features: (1) two enlarged superciliary scales (the first larger than the second); (2) an anterior nasal scale in contact with the rostral scale or separated from the rostral by one scale; (3) 6-8 sublabial scales to the center of the eye; (4) 3-4 scales between the supraobital semicircles; (5) unique coloration (4-6 oblique brown bands interspersed by blue-outlined yellow patches; dewlap is a dirty cream color with broad yellow scale rows irregularly interspersed with smaller emerald green scales) and (6) A. casildae occurs from 1,050 to 1,400 m in the Cordillera Central. We also compare our natural history observations of A. casildae to a similar large anole, A. frenatus, a species which we believe A. casildae to be closely related.


Natural killer cells at the forefront of cancer immunotherapy with immune potency, genetic engineering, and nanotechnology.
Natural killer (NK) cells are vital components of the human immune system, acting as innate lymphocytes and playing a crucial role in immune surveillance. Their unique ability to independently eliminate target cells without antigen contact or antibodies has sparked interest in immunological research. This review examines recent NK cell developments and applications, encompassing immune functions, interactions with target cells, genetic engineering techniques, pharmaceutical interventions, and implications in cancers. Insights into NK cell regulation emerge, with a focus on promising genetic engineering like CAR-engineered NK cells, enhancing specificity against tumors. Immune checkpoint inhibitors also enhance NK cells' potential in cancer therapy. Nanotechnology's emergence as a tool for targeted drug delivery to improve NK cell therapies is explored. In conclusion, NK cells are pivotal in immunity, holding exciting potential in cancer immunotherapy. Ongoing research promises novel therapeutic strategies, advancing immunotherapy and medical interventions.


Exploring the formation of focal adhesions on patterned surfaces using super-resolution imaging.
The formation of focal adhesions on various sizes of fibronectin patterns, ranging from 200 μm to 250 nm, was systematically investigated by total internal reflection fluorescence microscopy and super-resolution imaging. It was found that cells adhered to and spread on these micro/nanopatterns, forming focal adhesions. On a micrometer scale the shape of the focal adhesions was elongated. However, on the nanometer scale, the shape of focal adhesions became dotlike. To further explore the distribution of focal adhesion proteins formed on surfaces, a localization-based super-resolution imaging technique was employed in order to determine the position and density of vinculin proteins. A characteristic distance of 50 nm was found between vinculin molecules in the focal adhesions, which did not depend on the size of the fibronectin nanopatterns. This distance was found to be crucial for the formation of focal adhesions. In addition, the density of vinculin at the focal adhesions formed on the nanopatterns increased as the pattern size decreased. The density of the protein was found to be 425 ± 247, 584 ± 302, and 703 ± 305 proteins μm(-2) on the 600, 400, and 250 nm fibronectin patterns respectively. Whereas 226 ± 77 proteins μm(-2) was measured for the matured focal adhesions on homogeneous fibronectin coated substrates. The increase in vinculin density implies that an increase in mechanical load was applied to the focal adhesions formed on the smaller nanopatterns.


Design considerations for patient-specific bone fixation plates: a literature review.
In orthopedic surgery, patient-specific bone plates are used for fixation when conventional bone plates do not fit the specific anatomy of a patient. However, plate failure can occur due to a lack of properly established design parameters that support optimal biomechanical properties of the plate.This review provides an overview of design parameters and biomechanical properties of patient-specific bone plates, which can assist in the design of the optimal plate.A literature search was conducted through PubMed and Embase, resulting in the inclusion of 78 studies, comprising clinical studies using patient-specific bone plates for fracture fixation or experimental studies that evaluated biomechanical properties or design parameters of bone plates. Biomechanical properties of the plates, including elastic stiffness, yield strength, tensile strength, and Poisson's ratio are influenced by various factors, such as material properties, geometry, interface distance, fixation mechanism, screw pattern, working length and manufacturing techniques.Although variations within studies challenge direct translation of experimental results into clinical practice, this review serves as a useful reference guide to determine which parameters must be carefully considered during the design and manufacturing process to achieve the desired biomechanical properties of a plate for fixation of a specific type of fracture.


DC-HIL/glycoprotein Nmb promotes growth of melanoma in mice by inhibiting the activation of tumor-reactive T cells.
DC-HIL/glycoprotein nmb (Gpnmb) expressed on antigen-presenting cells attenuates T-cell activation by binding to syndecan-4 (SD-4) on activated T cells. Because DC-HIL/Gpnmb is expressed abundantly by mouse and human melanoma lines, we posited that melanoma-associated DC-HIL/Gpnmb exerts similar inhibitory function on melanoma-reactive T cells. We generated small interfering RNA-transfected B16F10 melanoma cells to completely knock down DC-HIL/Gpnmb expression, with no alteration in cell morphology, melanin synthesis, or MHC class I expression. This knockdown had no effect on B16F10 proliferation in vitro or entry into the cell cycle following growth stimulation, but it markedly reduced the growth of these cells in vivo following their s.c. injection into syngeneic immunocompetent (but not immunodeficient) mice. This reduction in tumor growth was due most likely to an augmented capacity of DC-HIL-knocked down B16F10 cells (compared with controls) to activate melanoma-reactive T cells as documented in vitro and in mice. Whereas DC-HIL knockdown had no effect on susceptibility of melanoma to killing by cytotoxic T cells, blocking SD-4 function enhanced the reactivity of CD8(+) T cells to melanoma-associated antigens on parental B16F10 cells. Using an assay examining the spread to the lung following i.v. injection, DC-HIL-knocked down cells produced lung foci at similar numbers compared with that produced by control cells, but the size of the former foci was significantly smaller than the latter. We conclude that DC-HIL/Gpnmb confers upon melanoma the ability to downregulate the activation of melanoma-reactive T cells, thereby allowing melanoma to evade immunologic recognition and destruction. As such, the DC-HIL/SD-4 pathway is a potentially useful target for antimelanoma immunotherapy.


Stem/Progenitor cells, atherosclerosis and cardiovascular regeneration.
Regenerative cell based therapy has potential to become effective adjuvant treatment for patients with atherosclerotic disease. Although data from animal studies support this notion, clinical studies undertaken in patients with acute and chronic coronary artery disease do not conclusively demonstrate benefits of such therapy. There are many questions on the stem cell translational roadmap. The basic mechanisms of stem cell-dependent tissue regeneration are not well understood. There is a debate regarding characterization of specific cell types conferring therapeutic effects. In particular, the role of endothelial progenitor cells as a specific reparative cell subtype is questioned, and the role of myeloid cell linage in fostering of vasculo- and angiogenesis is being increasingly appreciated. Intense discussions surround the place of stem/progenitor cells in atherosclerosis progression, plaque destabilization and vessel remodeling. This paper summarizes the current knowledge on the regenerative stem/progenitor cell definitions, mechanisms of stem cell trafficking, homing and their involvement in atherosclerosis progression.


Colorimetric phage-based assay for detection of rifampin-resistant Mycobacterium tuberculosis.
Tests based on bacteriophage replication enable rapid screening of Mycobacterium tuberculosis for drug resistance. We describe a novel broth-based colorimetric method for detecting phage replication. When clinical isolates were tested by this novel method, high concordance was observed with both the traditional phage assay and gene mutation analysis for detection of resistance to rifampin.


Balancing Memorization and Generalization in RNNs for High Performance Brain-Machine Interfaces.
Brain-machine interfaces (BMIs) can restore motor function to people with paralysis but are currently limited by the accuracy of real-time decoding algorithms. Recurrent neural networks (RNNs) using modern training techniques have shown promise in accurately predicting movements from neural signals but have yet to be rigorously evaluated against other decoding algorithms in a closed-loop setting. Here we compared RNNs to other neural network architectures in real-time, continuous decoding of finger movements using intracortical signals from nonhuman primates. Across one and two finger online tasks, LSTMs (a type of RNN) outperformed convolutional and transformer-based neural networks, averaging 18% higher throughput than the convolution network. On simplified tasks with a reduced movement set, RNN decoders were allowed to memorize movement patterns and matched able-bodied control. Performance gradually dropped as the number of distinct movements increased but did not go below fully continuous decoder performance. Finally, in a two-finger task where one degree-of-freedom had poor input signals, we recovered functional control using RNNs trained to act both like a movement classifier and continuous decoder. Our results suggest that RNNs can enable functional real-time BMI control by learning and generating accurate movement patterns.


The developmental origins of laterality: fetal handedness.
This paper reviews the evidence for lateralized motor behavior in the fetus around a number of key questions: does the fetus exhibit signs of laterality? when does lateralized motor behavior begin? is the lateralized preference consistently displayed? does prenatal handedness relate to postnatal handedness? and, does prenatal handedness relate to brain functioning? The evidence indicates that the fetus exhibits lateralized behavior from 10 weeks gestation, as soon as it independently moves its arms, and this is the precursor of lateralized motor behavior observed post-natally. Data is presented suggesting that the strength of laterality decreases with advancing gestation and this correlates with more efficient information processing as assessed by habituation. However extreme caution is warranted in attempting to link asymmetric motor behavior and brain function prenatally. The paper concludes that the initial developmental emergence of lateralized behavior is under genetic control and is a fundamental feature of prenatal human development.


[Fragment-based drug discovery: concept and aim].
Fragment-Based Drug Discovery (FBDD) has been recognized as a newly emerging lead discovery methodology that involves biophysical fragment screening and chemistry-driven fragment-to-lead stages. Although fragments, defined as structurally simple and small compounds (typically <300 Da), have not been employed in conventional high-throughput screening (HTS), the recent significant progress in the biophysical screening methods enables fragment screening at a practical level. The intention of FBDD primarily turns our attention to weakly but specifically binding fragments (hit fragments) as the starting point of medicinal chemistry. Hit fragments are then promoted to more potent lead compounds through linking or merging with another hit fragment and/or attaching functional groups. Another positive aspect of FBDD is ligand efficiency. Ligand efficiency is a useful guide in screening hit selection and hit-to-lead phases to achieve lead-likeness. Owing to these features, a number of successful applications of FBDD to "undruggable targets" (where HTS and other lead identification methods failed to identify useful lead compounds) have been reported. As a result, FBDD is now expected to complement more conventional methodologies. This review, as an introduction of the following articles, will summarize the fundamental concepts of FBDD and will discuss its advantages over other conventional drug discovery approaches.


Patterns of blunt use among rural young adult African-American men.
Blunts are hollowed-out cigars or leaf tobacco filled with marijuana. Use of blunts has increased since the 1990s and, in 2005, 3.5% of all American youth were estimated to have used blunts in the past month. Blunt smokers may have greater odds of cannabis and tobacco dependency and are at risk of smoking-related diseases. Previous studies have suggested that blunt use is more common among blacks, older teens, and men. However, data pertaining to blunt use in non-adolescent African-American populations are scarce. To assess patterns of blunt use among young adult African-American men aged 19-30 years residing in five rural Black Belt counties in Alabama and to compare these data with those from tobacco cigarette smokers within the same study population. Verbal, face-to-face interviewer-administered survey of 415 participants collected and analyzed between December 2008 and February 2011. 159 respondents (38.3%) smoked cigarettes and 45 smoked blunts (10.8%). Of blunt smokers, 33 also smoked cigarettes (73.3%). Use of blunts was prevalent among unemployed, single men, and occupational blunt use was uncommon. Factors important in the initiation, maintenance, and cessation of product use were similar for blunt and cigarette smokers, especially product use and acceptance by friends. Legal concerns were an important factor facilitating blunt cessation. Blunt use is relatively common among male African Americans aged 19-30 years and is frequently associated with concomitant cigarette use. Tobacco control efforts in this male African-American population should also address blunt usage.


The TATA-binding protein core domain in solution variably bends TATA sequences via a three-step binding mechanism.
Studies of the binding and bending of the AdMLP TATA sequence (TATAAAAG) by the core domain of yeast TBP allow quantitation of the roles of the N-terminal domains of yeast and human TBP. All three proteins bind DNA via a three-step mechanism with no evidence for an initially bound but unbent DNA. The large enthalpy and entropy of activation for the first step in yTBP binding can now be assigned to movement of the NTD from the DNA binding pocket and not to energetics of DNA bending. The energetic patterns for hTBP and cTBP suggest that the 158-amino acid NTD in hTBP does not initially occupy the DNA binding pocket. Despite the appearance of similar energetics for hTBP and cTBP, order of magnitude differences in rate constants lead to differing populations of intermediates during DNA binding. We find that the NTDs destabilize the three bound forms of DNA for both yTBP and hTBP. For all three proteins, the DNA bend angle (theta) depends on the TATA sequence, with theta for cTBP and hTBP being greater than that for yTBP. For all three proteins, theta for the G6 variant (TATAAGAG) varies with temperature and increases in the presence of osmolyte to be similar to that of AdMLP. Crystallographic studies of cTBP binding to a number of variants had shown no dependence of DNA bending on sequence. The results reported here reveal a clear structural difference for the bound DNA in solution versus the crystal; we attribute the difference to the presence of osmolytes in the crystals.


Serum Cyclosporine Levels: The Influence of the Time Interval Between Interrupting the Infusion and Obtaining the Samples: A Randomized Clinical Trial.
There are controversies regarding the best way to collect blood samples for cyclosporine A (CsA) serum levels when this immunosuppressant is administered continuously through a silicone central venous catheter (CVC) to hematopoietic stem cell transplant recipients. The aim of this study was to verify the effect of the time elapsed between the interruption of a continuous intravenous CsA infusion and the collection of blood samples on CsA serum levels. This randomized 2-group clinical trial involved 32 adults. In group A, blood samples were collected immediately after interrupting the medication from peripheral vein and CVC lines. In group B, the same procedures were performed 5 minutes after interrupting the infusion. We did not observe influence of the time elapsed between interruption of the infusion and collection of the samples, independent of the collection mode and the volume discarded (P > .05). The line used for the infusion maintained a constant high level when compared with different moments of collection (P > .05), whereas in the other lines, there was a significant increase when compared with the levels obtained at 24 hours and 7 days after CsA start (P = .00). The CVC line free from cyclosporine can safely be used to collect blood. The procedure can be performed immediately after interrupting the infusion, and discarding 5 mL is sufficient to obtain accurate levels. The results can help nurses choose how to collect blood samples through the CVC, thus preventing patients from having a painful and stressful procedure such as peripheral venipuncture.


Single-dose actinomycin-D treatment for nonmetastatic gestational trophoblastic disease. A prospective phase II trial of the Gynecologic Oncology Group.
The Gynecologic Oncology Group (GOG) conducted a prospective trial of single-dose Actinomycin-D (ACT-D) given intravenously (IV) at 1.25 mg/m2 every 2 weeks to patients with nonmetastatic gestational trophoblastic disease (NMGTD) in order to determine the efficacy of pulse scheduling and the frequency and severity of associated toxicity. Of 31 evaluable patients, 29 (94%) achieved remission after receiving a median of four courses of therapy. Two patients who failed to respond to pulse therapy were subsequently cured by alternative treatment. There were 93 toxic events in 133 cycles of therapy. Ninety-two percent of adverse effects were graded as mild or moderate, and 8% were graded as severe. No life-threatening toxicity occurred. Although single-dose ACT-D efficacy and toxicity is comparable to conventional therapy for NMGTD, the advantages of easier administration, greater patient convenience, and improved cost-effectiveness make it superior to other alternatives. On this basis it is recommended as the treatment of choice for NMGTD.


Combined methods to evaluate human cells in muscle xenografts.
Xenotransplantation of human cells into immunodeficient mouse models is a very powerful tool and an essential step for the pre-clinical evaluation of therapeutic cell- and gene- based strategies. Here we describe an optimized protocol combining immunofluorescence and real-time quantitative PCR to both quantify and visualize the fate and localization of human myogenic cells after injection in regenerating muscles of immunodeficient mice. Whereas real-time quantitative PCR-based method provides an accurate quantification of human cells, it does not document their specific localization. The addition of an immunofluorescence approach using human-specific antibodies recognizing engrafted human cells gives information on the localization of the human cells within the host muscle fibres, in the stem cell niche or in the interstitial space. These two combined approaches offer an accurate evaluation of human engraftment including cell number and localization and should provide a gold standard to compare results obtained either using different types of human stem cells or comparing healthy and pathological muscle stem cells between different research laboratories worldwide.


Development of interlimb movement synchrony in the rat fetus.
In the fetal rat, interlimb synchrony is a prominent form of temporally organized spontaneous motor activity in which movement of different limbs occurs at nearly the same instant. In the present study, synchrony profiles were created for different pairwise combinations of limbs over the last 5 days of gestation. Observed rates of synchrony differentiated from randomized time series from Gestational Day 19 to Day 21 (E19-E21), with forelimb synchrony emerging earlier than that of other limb pairs. Synchrony profiles were elevated at the shortest intervals between successive limb movements, indicating that movements became more tightly coupled toward the end of gestation. Interlimb synchrony appears to be a robust method of quantifying fetal movement and may prove useful as a tool for assessing prenatal nervous system functioning.


Changes in serum levels of pain mediators in hemiplegic shoulder pain.
To provide a new insight into the diagnosis and treatment of hemiplegic shoulder pain (HSP) by investigating changes in serum pain mediators. Cross-sectional study. Shoulder pain group (n = 34) and control group (n = 21). Pain-free shoulder mobility, anxiety status, depression status, and shoulder pain were measured by passive range of motion (PROM), self-rating anxiety scale, self-rating depression scale (SDS), and visual analog scale, respectively. The enzyme-linked immunosorbent assay was used to test the serum pain mediators, including interleukin (IL)-1β, IL-2, IL-6, IL-10, nerve growth factor (NGF), tumor necrosis factor-α (TNF-α), substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), 5-hydroxytryptamine (5-HT), prostaglandin E2 (PGE2), and lysophosphatidic acid (LPA). Shoulder pain group pain-free PROM significantly lower than control (p < .01), and SDS index score of shoulder pain group was significantly higher than control (p < .05). The rate of spasticity in the flexor elbow muscles is higher in shoulder pain group (p < .01). CGRP, IL-10, and IL-2 were significantly upregulated in shoulder pain group compared with control (p < .01), whereas NGF, TNF-α, IL-6, 5-HT, PGE2, SP, LPA, BK, and IL-1β were significantly decreased (p < .01). Patients with HSP have a higher risk of joint mobility disorders and depression; spasticity may be an important factor in the development of shoulder pain; CGRP is thought to be the major pain mediator in HSP, and HSP may not be inflammatory.


Multimedia-enhanced Radiology Reports: Concept, Components, and Challenges.
Multimedia-enhanced radiology report (MERR) development is defined and described from an informatics perspective, in which the MERR is seen as a superior information-communicating entity. Recent technical advances, such as the hyperlinking of report text directly to annotated images, improve MERR information content and accessibility compared with text-only reports. The MERR is analyzed by its components, which include hypertext, tables, graphs, embedded images, and their interconnections. The authors highlight the advantages of each component for improving the radiologist's communication of report content information and the user's ability to extract information. Requirements for MERR implementation (eg, integration of picture archiving and communication systems, radiology information systems, and electronic medical record systems) and the authors' initial experiences and challenges in MERR implementation at the National Institutes of Health are reviewed. The transition to MERRs has provided advantages over use of traditional text-only radiology reports because of the capacity to include hyperlinked report text that directs clinicians to image annotations, images, tables, and graphs. A framework is provided for thinking about the MERR from the user's perspective. Additional applications of emerging technologies (eg, artificial intelligence and machine learning) are described in the crafting of what the authors believe is the radiology report of the future. ©RSNA, 2018.


Residential churn moderates the relationship between economic deprivation and psychiatric admission: evidence from Wales.
There is a well-established link between area-level socioeconomic deprivation and psychiatric admission rates. Social capital has been proposed as a possible protective factor that may buffer economically deprived communities, but it may be disrupted in areas with high population turnover. This study aims to test whether population turnover, hereafter called churn, moderates the social gradient of psychiatric admissions. Population churn rates, low income rates and psychiatric admission rates for 1909 lower super output areas in Wales were analysed using Poisson generalised linear mixed-effects models. Additional analyses explored the impact of deprivation measured more generally and the potential confound of population density. Population churn moderated the association between socioeconomic deprivation and psychiatric admission rates, such that greater social gradients in admission rates were found in areas with greater churn. Economic deprivation and churn were also found to be independently positively associated with admission rates. These relationships remained significant when using a broader measure of deprivation and after adjusting for population density. High churn appears to exacerbate the detrimental effects of economic deprivation on mental health as well as being a risk factor in its own right. Residential stability rates should be considered when designing and implementing policies which aim to understand, prevent and treat mental health problems in at-risk communities.


Assessment and Models of Insect Damage to Cones and Seeds of Pinus strobiformis in the Sierra Madre Occidental, Mexico.
Insect damage to cones and seeds has a strong impact on the regeneration of conifer forest ecosystems, with broader implications for ecological and economic services. Lack of control of insect populations can lead to important economic and environmental losses. Pinus strobiformis is the most widespread of the white pines in Mexico and is widely distributed throughout the mountains of northern Mexico. Relatively few studies have examined insect damage to the cones and seeds of these pines, especially in Mexico. In this study, we therefore analyzed insect damage to cones and seeds of P. strobiformis in Mexico by using X-ray and stereomicroscopic analysis. The specific objectives of the study were (a) to characterize insect damage by measuring external and internal cone traits, (b) to assess the health of seeds and cones of P. strobiformis in the Sierra Madre Occidental, Mexico, and (c) to estimate the relative importance of the effects of different environmental variables on cone and seed damage caused by insects. We found that 80% of P. strobiformis seeds and 100% of the tree populations studied had damage caused by insects. Most seeds were affected by Leptoglossus occidentalis, Tetyra bipunctata, Megastigmus albifrons, and the Lepidoptera complex (which includes Apolychrosis synchysis, Cydia latisigna, Eucosma bobana, and Dioryctria abietivorella). The cones of all tree populations were affected by some type of insect damage, with Lepidoptera causing most of the damage (72%), followed by Conophthorus ponderosae (15%), the hemipteran L. occidentalis (7%), and the wasp M. albifrons (6%). The proportion of incomplete seeds in P. strobiformis at the tree level, cone damage by M. albifrons and seed damage in L. occidentalis were associated with various climate and soil variables and with crown dieback. Thus, cone and seed insect damage can be severe and potentially impact seed production in P. strobiformis and the reforestation potential of the species. The study findings will enable managers to better identify insects that cause damage to cone and seeds. In addition, identification of factors associated with damage may be useful for predicting the levels of insect predation on seeds and cones.


Prevalence and Predictive Value of Microvascular Flow Abnormalities after Successful Contemporary Percutaneous Coronary Intervention in Acute ST-Segment Elevation Myocardial Infarction.
Although microvascular flow abnormalities have been observed following epicardial recanalization in acute ST-segment elevation myocardial infarction (STEMI), the prevalence and severity of these abnormalities in the current era of rapid percutaneous coronary intervention (PCI) has not been evaluated. The objective of this study was to assess microvascular perfusion (MVP) following successful primary PCI in patients with STEMI and how it affects clinical outcome. In this single-center, retrospective study, 170 patients who successfully underwent emergent PCI for STEMI were assessed using real-time myocardial contrast echocardiography using a continuous infusion of intravenous commercial microbubbles (3% Definity). Three patterns of myocardial contrast replenishment were observed following intermittent high-mechanical index impulses: infarct zone replenishment within 4 sec (normal MVP), delays in contrast replenishment but normal plateau intensity (delayed MVP [dMVP]), and both delays in replenishment and reduced plateau intensity (microvascular obstruction [MVO]). Changes in left ventricular ejection fraction at 6 months and clinical event rate at 12 months (death, recurrent infarction, need for defibrillator placement, or heart failure admission) were compared. Normal MVP was seen in 62 patients (36%), dMVP in 49 (29%), and MVO in 59 (35%). Left anterior descending coronary artery infarct location was the only parameter independently associated with dMVP or MVO, independent of age, cardiac risk factors, door-to-dilation time, pre-PCI Thrombolysis In Myocardial Infarction flow grade, and thrombus burden. A dMVP pattern had a similar reduction in left ventricular ejection fraction as MVO at hospital discharge but had recovery of left ventricular ejection fraction at 6 months and a greater than fourfold lower event rate than the MVO group (P < .001). MVO and dMVP are frequently seen following contemporary successful PCI for STEMI, especially following left anterior descending coronary artery infarction. Despite a similar area at risk, a dMVP pattern has better functional recovery and clinical outcome than MVO.


Metalloprotease inhibitors GM6001 and TAPI-0 inhibit the obligate intracellular human pathogen Chlamydia trachomatis by targeting peptide deformylase of the bacterium.
Chlamydia trachomatis is an obligate intracellular bacterium responsible for a number of human diseases. The mechanism underlying the intracellular parasitology of Chlamydiae remains poorly understood. In searching for host factors required for chlamydial infection, we discovered that C. trachomatis growth was effectively inhibited with GM6001 and TAPI-0, two compounds known as specific inhibitors of matrix metalloproteases. The inhibition was independent of chlamydial entry of the cell, suggesting that the loss of extracellular metalloprotease activities of the host cell is unlikely to be the mechanism for the growth suppression. Nucleotide sequences of candidate metalloprotease genes remained unchanged in a chlamydial variant designated GR10, which had been selected for resistance to the inhibitors. Nevertheless, GR10 displayed a single base mutation in the presumable promoter region of the gene for peptide deformylase (PDF), a metal-dependent enzyme that removes the N-formyl group from newly synthesized bacterial proteins. The mutation correlated with an increased PDF expression level and resistance to actinonin, a known PDF inhibitor with antibacterial activity, as compared with the parental strain. Recombinant chlamydial PDF was covalently labeled with a hydroxamate-based molecular probe designated AspR1, which was developed for the detection of metalloproteases. The AspR1 labeling of the chlamydial PDF became significantly less efficient in the presence of excessive amounts of GM6001 and TAPI-0. Finally, the PDF enzyme activity was efficiently inhibited with GM6001 and TAPI-0. Taken together, our results suggest that the metalloprotease inhibitors suppress chlamydial growth by targeting the bacterial PDF. These findings have important biochemical and medical implications.


Sketching algorithms for genomic data analysis and querying in a secure enclave.
Genome-wide association studies (GWAS), especially on rare diseases, may necessitate exchange of sensitive genomic data between multiple institutions. Since genomic data sharing is often infeasible due to privacy concerns, cryptographic methods, such as secure multiparty computation (SMC) protocols, have been developed with the aim of offering privacy-preserving collaborative GWAS. Unfortunately, the computational overhead of these methods remain prohibitive for human-genome-scale data. Here we introduce SkSES (https://github.com/ndokmai/sgx-genome-variants-search), a hardware-software hybrid approach for privacy-preserving collaborative GWAS, which improves the running time of the most advanced cryptographic protocols by two orders of magnitude. The SkSES approach is based on trusted execution environments (TEEs) offered by current-generation microprocessors-in particular, Intel's SGX. To overcome the severe memory limitation of the TEEs, SkSES employs novel 'sketching' algorithms that maintain essential statistical information on genomic variants in input VCF files. By additionally incorporating efficient data compression and population stratification reduction methods, SkSES identifies the top k genomic variants in a cohort quickly, accurately and in a privacy-preserving manner.


Diffraction-limited circular single spot from phased array lasers.
Anamorphic prism optics makes it possible to obtain a diffraction-limited (lambda/8) circular single spot from index guided phased array lasers. It served not only for beam shaping but also for astigmatism correction and spatial filtering. The optical path analysis based on the interferometric fringe scanning phase measurements both in the near and far fields indicates that the phased array lasers can be applied to such diffraction-limited precise optical systems as optical disk recording, laser beam printing, or second harmonics generation.


Lack of an association of BDNF Val66Met polymorphism and plasma BDNF with hippocampal volume and memory.
Brain-derived neurotrophic factor (BDNF) has been shown to be important for neuronal survival and synaptic plasticity in the hippocampus in nonhuman animals. The Val66Met polymorphism in the BDNF gene, involving a valine (Val) to methionine (Met) substitution at codon 66, has been associated with lower BDNF secretion in vitro. However, there have been mixed results regarding associations between either circulating BDNF or the BDNF Val66Met polymorphism with hippocampal volume and memory in humans. The current study examined the association of BDNF genotype and plasma BDNF with hippocampal volume and memory in two large independent cohorts of middle-aged and older adults (both cognitively normal and early-stage dementia). Sample sizes ranged from 123 to 649. Measures of the BDNF genotype, plasma BDNF, MRI-based hippocampal volume, and memory performance were obtained from the Knight Alzheimer Disease Research Center (ADRC) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). There were no significant differences between BDNF Met+ and Met- groups on either hippocampal volume or memory in either cohort. In addition, plasma BDNF was not significantly associated with either hippocampal volume or memory in either cohort. Neither age, cognitive status, nor gender moderated any of the relationships. Overall, current findings suggest that BDNF genotype and plasma BDNF may not be robust predictors for variance in hippocampal volume and memory in middle age and older adult cohorts.


Chitinase 1 is a biomarker for and therapeutic target in scleroderma-associated interstitial lung disease that augments TGF-β1 signaling.
Interstitial lung disease (ILD) with pulmonary fibrosis is an important manifestation in systemic sclerosis (SSc, scleroderma) where it portends a poor prognosis. However, biomarkers that predict the development and or severity of SSc-ILD have not been validated, and the pathogenetic mechanisms that engender this pulmonary response are poorly understood. In this study, we demonstrate in two different patient cohorts that the levels of chitotriosidase (Chit1) bioactivity and protein are significantly increased in the circulation and lungs of SSc patients compared with demographically matched controls. We also demonstrate that, compared with patients without lung involvement, patients with ILD show high levels of circulating Chit1 activity that correlate with disease severity. Murine modeling shows that in comparison with wild-type mice, bleomycin-induced pulmonary fibrosis was significantly reduced in Chit1⁻/⁻ mice and significantly enhanced in lungs from Chit1 overexpressing transgenic animals. In vitro studies also demonstrated that Chit1 interacts with TGF-β1 to augment fibroblast TGF-β receptors 1 and 2 expression and TGF-β-induced Smad and MAPK/ERK activation. These studies indicate that Chit1 is potential biomarker for ILD in SSc and a therapeutic target in SSc-associated lung fibrosis and demonstrate that Chit1 augments TGF-β1 effects by increasing receptor expression and canonical and noncanonical TGF-β1 signaling.


Persons with chronic hip joint pain exhibit reduced hip muscle strength.
Controlled laboratory cross-sectional study. Objectives To assess strength differences of the hip rotator and abductor muscle groups in young adults with chronic hip joint pain (CHJP) and asymptomatic controls. A secondary objective was to determine if strength in the uninvolved hip of those with unilateral CHJP differs from that in asymptomatic controls. Little is known about the relationship between hip muscle strength and CHJP in young adults. Thirty-five participants with CHJP and 35 matched controls (18 to 40 years of age) participated. Using handheld dynamometry, strength of the hip external rotators and internal rotators was assessed with the hip flexed to 90° and 0°. To assess external rotator and internal rotator strength, the hip was placed at the end range of external rotation and internal rotation, respectively. Strength of the hip abductors was assessed in sidelying, with the hip in 15° of abduction. Break tests were performed to determine maximum muscle force, and the average torque was calculated using the corresponding moment arm. Independent-sample t tests were used to compare strength values between (1) the involved limb in participants with CHJP and the corresponding limb in the matched controls, and (2) the uninvolved limb in participants with unilateral CHJP and the corresponding limb in the matched controls. Compared to controls, participants with CHJP demonstrated weakness of 16% to 28% (P<.01) in all muscle groups tested in the involved hip. The uninvolved hip of 22 subjects with unilateral CHJP demonstrated weakness of 18% and 16% (P<.05) in the external rotators (0°) and abductors, respectively, when compared to the corresponding limb of the matched controls. The results of the present study demonstrate that persons with CHJP have weakness in the hip rotator and hip abductor muscles. Weakness also was found in the uninvolved hip of persons with CHJP.


[Glucocorticoid-induced osteoporosis treatment algorithm].
An excess amount of glucocorticoids represents the primary and most frequent etiological factor influencing secondary osteoporosis. The patients receiving glucocorticoids, but also those with the endogenous form of hypercorticism are at high risk for the loss of bone density, with the subsequent occurrence of pathological fractures. In this review, we summarize the currently available methods of prevention and the treatment of glucocorticoid-induced osteoporosis (GIO). We also include a proposal for both prophylactic and therapeutic approach that takes into account the risk factors typical for long-term users of glucocorticoids.


The Non-Recurrent Laryngeal Nerve: a meta-analysis and clinical considerations.
The Non-Recurrent Laryngeal Nerve (NRLN) is a rare embryologically-derived variant of the Recurrent Laryngeal Nerve (RLN). The presence of an NRLN significantly increases the risk of iatrogenic injury and operative complications. Our aim was to provide a comprehensive meta-analysis of the overall prevalence of the NRLN, its origin, and its association with an aberrant subclavian artery. Through March 2016, a database search was performed of PubMed, CNKI, ScienceDirect, EMBASE, BIOSIS, SciELO, and Web of Science. The references in the included articles were also extensively searched. At least two reviewers judged eligibility and assessed and extracted articles. MetaXL was used for analysis, with all pooled prevalence rates calculated using a random effects model. Heterogeneity among the included studies was assessed using the Chi2 test and the I2 statistic. Fifty-three studies (33,571 right RLNs) reported data on the prevalence of a right NRLN. The pooled prevalence estimate was 0.7% (95% CI [0.6-0.9]). The NRLN was found to originate from the vagus nerve at or above the laryngotracheal junction in 58.3% and below it in 41.7%. A right NRLN was associated with an aberrant subclavian artery in 86.7% of cases. The NRLN is a rare yet very clinically relevant structure for surgeons and is associated with increased risk of iatrogenic injury, most often leading to temporary or permanent vocal cord paralysis. A thorough understanding of the prevalence, origin, and associated pathologies is vital for preventing injuries and complications.


Racial/ethnic disparities in PM2.5-attributable cardiovascular mortality burden in the United States.
Average ambient fine particulate matter (PM2.5) concentrations have decreased in the US in recent years, but the health benefits of this improvement among different racial/ethnic groups are unknown. We estimate the associations between long-term exposure to ambient PM2.5 and cause-specific cardiovascular disease (CVD) mortality rate and assess the PM2.5-attributable CVD deaths by race/ethnicity across 3,103 US counties during 2001-2016 (n = 595,776 county-months). A 1 µg m-3 increase in PM2.5 concentration was associated with increases of 7.16 (95% confidence interval (CI): 3.81, 10.51) CVD deaths per 1,000,000 Black people per month, significantly higher than the estimates for non-Hispanic white people (1.76 (95% CI: 1.37, 2.15); difference in coefficients: 5.40 (95% CI: 2.03, 8.77), P = 0.001). No significant difference in this association was observed between Hispanic (2.66 (95% CI: -0.03, 5.35)) and non-Hispanic white people (difference in coefficients: 0.90 (95% CI: -1.81, 3.61), P = 0.523). From 2001 to 2016, the absolute disparity in PM2.5-attributable CVD mortality burden was reduced by 44.04% between non-Hispanic Black and white people and by 2.61% between Hispanic and non-Hispanic white people. However, in 2016, the burden remained 3.47 times higher for non-Hispanic Black people and 0.45 times higher for Hispanic people than for non-Hispanic white people. We call for policies that aim to reduce both exposure and vulnerability to PM2.5 for racial/ethnic minorities.


Proteinase trapping: screening for viral proteinase mutants by alpha complementation.
Many virally encoded proteinases cleave themselves out of a polyprotein, with cleavage occurring usually at their own N terminus. This property was used to develop an in vivo screening system using the lacZ gene fragment of M13mp18. When a fusion protein of the alpha fragment of beta-galactosidase and an active 2A proteinase of human rhinovirus 2 was expressed, alpha complementation was not affected, as the 2A proteinase cleaved itself off the alpha fragment. However, fusion of an inactive 2A prevented alpha complementation, as the 2A polypeptide remained fused to the alpha fragment. After random mutation of the 2A gene by PCR amplification, mutants were screened; M13 phage defective in alpha complementation were obtained at an efficiency of 5% and were shown to contain mutated 2A genes. Intermolecular cleavage was then examined by expressing an alpha fragment-inactive proteinase fusion protein as substrate for an active 2A proteinase expressed from an M13 vector. alpha complementation indicated intermolecular processing of the 2A cleavage site on the alpha fragment-inactive proteinase fusion protein. This versatile system thus allows the high-density screening of both active and inactive proteinase mutants, cleaving either intramolecularly or intermolecularly, and should be applicable to other proteinases of high specificity.


Multilocus variable-number tandem repeat analysis distinguishes outbreak and sporadic Escherichia coli O157:H7 isolates.
Escherichia coli O157:H7 is a major cause of food-borne illness in the United States. Outbreak detection involves traditional epidemiological methods and routine molecular subtyping by pulsed-field gel electrophoresis (PFGE). PFGE is labor-intensive, and the results are difficult to analyze and not easily transferable between laboratories. Multilocus variable-number tandem repeat (VNTR) analysis (MLVA) is a fast, portable method that analyzes multiple VNTR loci, which are areas of the bacterial genome that evolve quickly. Eighty isolates, including 21 isolates from five epidemiologically well-characterized outbreaks from Pennsylvania and Minnesota, were analyzed by PFGE and MLVA. Strains in PFGE clusters were defined as strains that differed by less than or equal to one band by using XbaI and the confirmatory enzyme SpeI. MLVA was performed by comparing the number of tandem repeats at seven loci. From 6 to 30 alleles were found at the seven loci, resulting in 64 MLVA types among the 80 isolates. MLVA correctly identified the isolates from all five outbreaks if only a single-locus variant was allowed. MLVA differentiated strains with unique PFGE types. Additionally, MLVA discriminated strains within PFGE-defined clusters that were not known to be part of an outbreak. In addition to being a simple and validated method for E. coli O157:H7 outbreak detection, MLVA appears to have a sensitivity equal to that of PFGE and a specificity superior to that of PFGE.


Morphologic and molecular characterization of Salmonella typhimurium infection in neonatal calves.
The host response to Salmonella plays a major role in the outcome of infection. The present study was undertaken to further characterize Salmonella typhimurium infection in neonatal calves at both the morphologic and the molecular level using the ligated ileal loop model. Eight 4-5-week-old male Holstein calves underwent laparotomy, and loops were prepared in the ileum. The loops were either inoculated with an S. typhimurium strain pathogenic for cattle or injected with sterile LB broth as control. Samples for histology, transmission and scanning electron microscopy, and RNA extraction were collected at various time points between 5 minutes and 12 hours postinfection. Invasion of both M cells and enterocytes began at 15 minutes postinfection. No specific cell type was the main target for invasion. Intracellular bacteria were observed in the lamina propria after 1 hour postinfection. A severe acute neutrophilic response was associated with invasion of the Peyer's patches. Upregulated expression of CXC chemokines (interleukin [IL]-8, growth-related oncogenes, [GRO] alpha and gamma, and granulocyte chemotactic protein [GCP]2) was detected by reverse transcription polymerase chain reaction beginning at 1 hour postinfection. Expression of proinflammatory (IL-1beta, IL-18, and tumor necrosis factor [TNF]alpha) and anti-inflammatory (IL-10, IL-IRa, and IL-4) cytokines was also assessed. A marked increase in expression of IL-1beta was observed, whereas the profile of expression of IL-18 and TNFalpha did not change after infection. Upregulation of IL-1Ra and IL-4 but not of IL-10 was observed. These findings indicate that infection of bovine ligated ileal loops with S. typhimurium results in an acute neutrophilic inflammatory response that is associated with the upregulation of CXC chemokines (IL-8, GROalpha and gamma, and GCP2), IL-1beta, IL-IRa, and IL-4.


A Stability-Indicating HPLC Method for the Determination of Nitrosylcobalamin (NO-Cbl), a Novel Vitamin B12 Analog.
Nitrosylcobalamin (NO-Cbl), a novel vitamin B12 analog and anti-tumor agent, functions as a biologic 'Trojan horse', utilizing the vitamin B12 transcobalamin II transport protein and cell surface receptor to specifically target cancer cells. a stability-indicating HPLC method was developed for the detection of NO-Cbl during forced degradation studies. This method utilized an ascentis® RP-amide (150 mm × 4.6 mm, 5 μm) column at 35 °C with a mobile phase (1.0 mL min-1) combining a gradient of methanol and an acetate buffer at pH 6.0. Detection wavelengths of 450 and 254 nm were used to detect corrin and non-corrin-based products, respectively. NO-Cbl, synthesized from hydroxocobalamin and pure nitric oxide gas, was subjected to degradative stress conditions including oxidation, hydrolysis and thermal and radiant energy challenge. The method was validated by assessing linearity, accuracy, precision, detection and quantitation limits and robustness. The method was applied successfully for purity assessment of synthesized NO-Cbl and for the determination of NO-Cbl during kinetic studies in aqueous solution and in solid-state degradation assessments. This HPLC method is suitable for the separation of cobalamins in aqueous and methanolic solutions, for routine detection of NO-Cbl and for purity assessment of synthesized NO-Cbl. additionally, this method has potential application in identification and monitoring of diseases involving altered nitric oxide homeostasis where vitamin B12 therapy is utilized to scavenge excess nitric oxide, subsequently resulting in the in vivo production of NO-Cbl.


Shear Wave Elastography of Focal Liver Lesion: Intraobserver Reproducibility and Elasticity Characterization.
The aim of the study was to evaluate the intraobserver reproducibility and to determine the elasticity characteristics of focal liver lesions (FLLs) by shear wave elastography (SWE). One hundred thirty-six FLLs in 118 patients were examined with SWE for quantitative and qualitative assessment of stiffness. Three SWE images were obtained for each lesion and liver parenchyma by 1 radiologist. Intraobserver reproducibility was assessed by intraclass correlation coefficients (ICCs). Patient and lesion factors that can affect the reproducibility were evaluated. For characterization of the lesion elasticity, the difference in stiffness between the groups of lesions was evaluated. The mean (SD) diameter and depth of the lesions were 3.98 (2.07) and 4.4 (1.59) cm, respectively. The ICC of intraobserver reproducibility was 0.763. Deep-seated lesions (≥6 cm; ICC, 0.621) showed significantly lower intraobserver reproducibility compared with superficial lesions (ICC, 0.793; P = 0.047). Stiffness values of malignant lesions (n = 85, 60.41 [47.81] kPa) were significantly higher than those of benign lesions (n = 51, 22.05 [17.24] kPa, P < 0.0001). Mean (SD) stiffness of hepatocellular carcinoma (45.72 [35.65] kPa) was significantly lower than that of metastasis (67.43 [43.39] kPa) and was significantly higher than benign FLLs (22.05 [17.24] kPa). However, mean (SD) lesion-parenchyma ratio of hepatocellular carcinoma (3.76 [4]) was not significantly different from that of benign FLLs (3.7 [3.77]). Overall, intraobserver reproducibility of SWE in evaluation of FLLs was excellent, but it can be affected by lesion depth. In addition, SWE is helpful in elasticity characterization of FLLs.


An Experimental Study of a Zeolite Membrane Reactor for Reverse Water Gas Shift.
Reverse water gas shift (RWGS) is attracting attention as one of the promising technologies for CO2 conversion. Selective removal of H2O from the reaction system can improve the CO2 conversion beyond the equilibrium conversion of RWGS in a conventional reactor. In this study, a conventional plug-flow reactor without membrane, and two types of RWGS membrane reactors using ZSM-5 membranes, were developed. The yield of CO without membrane (Case 1) was almost the same as the equilibrium conversion. A membrane reactor (Case 2) showed a CO yield 2-3% above that of a conventional reactor. From the results, the effectiveness of the dehydration membrane reactor for RWGS was verified. In addition, CO yield was further increased in the reactor made up of the combination of conventional reactor and membrane reactor (Case 3). For example, the CO yields in Cases 1, 2, and 3 at 560 K were 21.8, 24.9, and 29.0%, respectively. Although the CO yield increased in Case 2, a large amount of raw materials penetrated through the membrane to the permeation side, and was lost. In Case 3, H2 and CO2 permeation through the membrane were suppressed because of the existence of H2O, resulting in the prevention of the leakage of raw material, and contributing to the high CO yield.


Ambivalent role of the innate immune response in rabies virus pathogenesis.
The neurotropic rabies virus (RABV) has developed several evasive strategies, including immunoevasion, to successfully infect the nervous system (NS) and trigger a fatal encephalomyelitis. Here we show that expression of LGP2, a protein known as either a positive or negative regulator of the RIG-I-mediated innate immune response, is restricted in the NS. We used a new transgenic mouse model (LGP2 TG) overexpressing LGP2 to impair the innate immune response to RABV and thus revealed the role of the RIG-I-mediated innate immune response in RABV pathogenesis. After infection, LGP2 TG mice exhibited reduced expression of inflammatory/chemoattractive molecules, beta interferon (IFN-β), and IFN-stimulated genes in their NS compared to wild-type (WT) mice, demonstrating the inhibitory function of LGP2 in the innate immune response to RABV. Surprisingly, LGP2 TG mice showed more viral clearance in the brain and lower morbidity than WT mice, indicating that the host innate immune response, paradoxically, favors RABV neuroinvasiveness and morbidity. LGP2 TG mice exhibited similar neutralizing antibodies and microglia activation to those of WT mice but showed a reduction of infiltrating CD4(+) T cells and less disappearance of infiltrating CD8(+) T cells. This occurred concomitantly with reduced neural expression of the IFN-inducible protein B7-H1, an immunoevasive protein involved in the elimination of infiltrated CD8(+) T cells. Our study shows that the host innate immune response favors the infiltration of T cells and, at the same time, promotes CD8(+) T cell elimination. Thus, to a certain extent, RABV exploits the innate immune response to develop its immunoevasive strategy.


[Two cold legs].
Bilateral acute lower limb ischaemia is rare. Usually the diagnosis is based on clinical findings. In four patients, three women aged 51, 48, and 72 and a man aged 64 years, bilateral acute ischaemia of the lower limbs was diagnosed, due to different causes: arterial cardiac myxoma embolism, arterial thrombosis probably due to paraneoplastic coagulopathy, aortic dissection, and arterial thrombosis due to cardiac insufficiency, respectively. The management of these conditions includes restoring the circulation as soon as possible. Reperfusion can be achieved by thromboembolectomy or thrombolysis. In patients with underlying atherosclerosis angiography is useful, but time loss must be avoided. The outcome in patients with bilateral ischaemia of the lower limbs depends on the preoperative ischaemia time and the cardiac situation. The mortality varies between 20 and 50%.


Differential variability analysis of gene expression and its application to human diseases.
Current microarray analyses focus on identifying sets of genes that are differentially expressed (DE) or differentially coexpressed (DC) in different biological states (e.g. diseased versus non-diseased). We observed that in many human diseases, some genes have a significant increase or decrease in expression variability (variance). As these observed changes in expression variability may be caused by alteration of the underlying expression dynamics, such differential variability (DV) patterns are also biologically interesting. Here we propose a novel analysis for changes in gene expression variability between groups of samples, which we call differential variability analysis. We introduce the concept of differential variability (DV), and present a simple procedure for identifying DV genes from microarray data. Our procedure is evaluated with simulated and real microarray datasets. The effect of data preprocessing methods on identification of DV gene is investigated. The biological significance of DV analysis is demonstrated with four human disease datasets. The relationships among DV, DE and DC genes are investigated. The results suggest that changes in expression variability are associated with changes in coexpression pattern, which imply that DV is not merely stochastic noise, but informative signal. The R source code for differential variability analysis is available from the contact authors upon request.


Nonalcoholic Fatty Liver is Contributing to the Increase in Cases of Liver Disease in US Emergency Departments.
We aimed to assess temporal changes in the different types of liver disease (LD) cases and outcomes from emergency departments (EDs) across the United States. We used data from the National Inpatient Survey database from 2005 to 2011. The International Classification of Diseases, Ninth Revision (ICD-9) clinical modification codes identified hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and other LDs including autoimmune hepatitis. We excluded cases without LD, nonhepatocellular carcinoma-related cancers, human immunodeficiency virus infection, or those with missing information. Logistic regression was used to estimate odds ratios with 95% confidence intervals. Controls were matched to cases without LD. During the study period, 20,641,839 cases were seen in EDs. Of these, 1,080,008 cases were related to LD and were matched to controls without LD (N=19,557,585). The number of cases with LD increased from 123,873 (2005) to 188,501 (2011) (P<0.0001). Among cases with LD, diagnosis of HCV, HBV, and ALD remained stable during the study years (41.60% vs. 38.20%, 3.70% vs. 2.80%, and 41.4% vs. 38.5%, respectively), whereas NAFLD doubled [6.00% of all LD (2005) to 11.90% of all LD (2011) (P<0.0001)]. Diagnosis of LD in the ED independently predicted increased patient mortality [odds ratio, 1.20 (1.17 to 1.22)]. The number of LD cases presenting to EDs is increasing, and a diagnosis of LD is associated with a higher patient mortality for those admitted through the ED. There is a dramatic increase of NAFLD diagnoses in the ED.


Mathematical Analysis and Physical Profile of Blalock-Taussig Shunt and Sano Modification Procedure in Hypoplastic Left Heart Syndrome: Review of the Literature and Implications for the Anesthesiologist.
The first stage of surgical treatment for hypoplastic left heart syndrome (HLHS) includes the creation of artificial systemic-to-pulmonary connections to provide pulmonary blood flow. The modified Blalock-Taussig (mBT) shunt has been the technique of choice for this procedure; however, a right ventricle-pulmonary artery (RV-PA) shunt has been introduced into clinical practice with encouraging but still conflicting outcomes when compared with the mBT shunt. The aim of this study is to explore mathematical modeling as a tool for describing physical profiles that could assist the surgical team in predicting complications related to stenosis and malfunction of grafts in an attempt to find correlations with clinical outcomes from clinical studies that compared both surgical techniques and to assist the anesthesiologist in making decisions to manage patients with this complex cardiac anatomy. Mathematical modeling to display the physical characteristics of the chosen surgical shunt is a valuable tool to predict flow patterns, shear stress, and rate distribution as well as energetic performance at the graft level and relative to ventricular efficiency. Such predictions will enable the surgical team to refine the technique so that hemodynamic complications be anticipated and prevented, and are also important for perioperative management by the anesthesia team.


[Ultrastructure of the cell walls and septa in glucuronate-positive species of Candida].
According to the ultrastructure of cell walls, glucuronate-positive species of the genus Candida include both ascomycetous organisms (C. ciferrii, C. incommunis, C. steatolytica) and basidiomycetous organisms (C. bogoriensis, C. curiosa, C. diffluens, C. javanica, C. marina). The character of budding and the structure of septa suggest that the perfect forms of glucuronate-positive ascomycetous Candida species should be looked for within the family Ascoideaceae.


Dual-wavelength passively mode-locked Nd:LuYSiO5 laser with SESAM.
A diode-end-pumped dual-wavelength mode-locked laser based on Nd:LuYSiO5 crystal is demonstrated. With a SESAM, simultaneous mode locking at the 1075.8 nm and 1078.1 nm is achieved and the dual-wavelength mode locked pulses have a pulse width of 8.9 ps. Due to frequency beating, ultrahigh repetition rate ultrafast pulses with 997 fs pulse width and 0.59 THz repetition rate are further formed. Under 12.7 W absorbed pump power 1.7 W mode-locked output power was obtained, the slope efficiency of the mode locked laser was 24.3%.


Tissue expression of glutathione S transferase isoenzymes in vitiligo.
The association of glutathione S-transferase (GST) enzymes with vitiligo is inconclusive. To evaluate tissue expressions of GST isoenzymes in vitiligo patients and to compare these expressions with healthy controls, we used 26 active depigmented patches on the trunk of vitiligo patients and 20 healthy sex and age matched controls. Punch biopsies were taken from the lesioned or normal skin. Tissue expression of GST isoenzymes were analyzed immunohistochemically. Tissue expression of GSTT1, GSTA1 and GSTP1 was significantly higher in the patient group than controls. Tissue expression of GSTM1 was not significantly different between the two groups. The increased tissue expression of GSTT1, GSTA1 and GSTP1 may represent a response to excess free radical formation in vitiligo and may support the role of oxidative stress in the pathogenesis of vitiligo.


Clinical characteristics of inflammation-associated depression: Monocyte gene expression is age-related in major depressive disorder.
Increased inflammatory activation might only be present in a subgroup of depressed individuals in which immune processes are especially relevant to disease development. We aimed to analyze demographic, depression, and trauma characteristics of major depressive disorder (MDD) patients with regard to inflammatory monocyte gene expression. Fifty-six naturalistically treated MDD patients (32 ± 12 years) and 57 healthy controls (HC; 31 ± 11 years) were analyzed by the Inventory of Depressive Symptomatology (IDS) and by the Childhood Trauma Questionnaire (CTQ). We determined the expression of 38 inflammatory and immune activation genes including the glucocorticoid receptor (GR)α and GRβ genes in purified CD14(+) monocytes using quantitative-polymerase chain reaction (RT-qPCR). Monocyte gene expression was age-dependent, particularly in MDD patients. Increased monocyte gene expression and decreased GRα/β ratio were only present in MDD patients aged ⩾ 28 years. Post hoc analyses of monocyte immune activation in patients <28 years showed two subgroups: a subgroup with a severe course of depression (recurrent type, onset <15 years) - additionally characterized by panic/arousal symptoms and childhood trauma - that had a monocyte gene expression similar to HC, and a second subgroup with a milder course of the disorder (73% first episode depression, onset ⩾15 years) - additionally characterized by the absence of panic symptoms - that exhibited a strongly reduced inflammatory monocyte activation compared to HC. In conclusion, monocyte immune activation was not uniformly raised in MDD patients but was increased only in patients of 28 years and older.


The management of congenital aortic stenosis.
The progress of 128 patients with congenital aortic stenosis has been followed from one to 28 (mean 14) years. Fifty-eight underwent cardiac catheterisation, and 46 (36% of the total) required surgical treatment. Of these, 42 were under 20 years old. Additional cardiac lesions were noted in five. Infective endocarditis was encountered in four. The onset of symptoms or increasing evidence of left ventricular hypertrophy on the electrocardiogram were the principal indications for catheterisation. Two-dimensional echocardiography is now important in this context. There were four deaths in the 46 surgically treated patients; three of these were early and the fourth was a late death three years after operation due to a massive cerebral embolus complicating infective endocarditis. The 42 survivors of operation and the 82 unoperated patients have remained under long-term supervision. Further surgery was necessary in 12 of the 42 surgically treated patients--valve replacement in seven of them two to eight years after valvotomy, replacement of a calcified xenograft valve in three, and repeat operation in two because of recurrence of subvalvar obstruction. Aortic stenosis is not a benign condition in childhood and adolescence. Close supervision is necessary and when any deterioration is detected further investigation as a prelude to probable surgery is mandatory. This should not be embarked on lightly in childhood unless there are pressing indications, particularly in view of the serious disadvantages of valve replacement in childhood.


Biomechanical evaluation of proximally placed femoral less-invasive stabilization system plates.
Loss of fixation of the Synthes 13-hole femoral Less-Invasive Stabilization System (LISS) plate has been noted. The biomechanical stability of this plate may be affected by improper proximal placement. We conducted a study to determine if there is any difference in fixation failure, deformation, or stiffness based on proximal placement. Using synthetic composite bones, we created a comminuted supracondylar distal femur fracture, AO/OTA (Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association) 33-A3. Three groups of 9 femurs each were created: 1 correctly positioned group and 2 incorrectly positioned groups, 1 with the proximal aspect of the plate 1 cm anterior and 1 with the proximal aspect of the plate 1 cm posterior. The constructs were tested in axial, torsional, and cyclical axial modes to assess plastic and total deformation and stiffness. Under axial loading, the posteriorly placed plate showed a 16.4% increase in stiffness. There was a significant increase of 12% in torsional stiffness in the anteriorly placed plate. Under cyclical axial loading, there was a significant increase of 14% in total deformation in the anteriorly placed plate. No fixation failure was observed. One-centimeter variation in proximal placement of a 13-hole LISS plate in a synthetic composite fracture model had little effect on the overall construct.


High vitamin C intake is associated with lower 4-year bone loss in elderly men.
Vitamin C is essential for collagen formation and normal bone development. We evaluated associations of total, supplemental, and dietary vitamin C intake with bone mineral density (BMD) at the hip [femoral neck, trochanter], spine, and radial shaft and 4-y BMD change in elderly participants from the Framingham Osteoporosis Study. Energy-adjusted vitamin C intakes were estimated from the Willett FFQ in 1988-89. Mean BMD and 4-y BMD change was estimated, for men and women, by tertile/category of vitamin C intake, adjusting for covariates. We tested for interaction with smoking, calcium, and vitamin E intake. Among 334 men and 540 women, the mean age was 75 y and mean vitamin D intake was 8.25 mug/d (women) and 8.05 mug/d (men). We observed negative associations between total and supplemental vitamin C intake and trochanter-BMD among current male smokers (P-trend = 0.01). Among male nonsmokers, total vitamin C intake was positively associated with femoral neck BMD (P-trend = 0.04). Higher total vitamin C intake was associated with less femoral neck and trochanter-BMD loss in men with low calcium (all P-trend </= 0.03) or vitamin E intakes (all P-trend = 0.03). Higher dietary vitamin C intake tended to be associated with lower femoral neck-BMD loss (P-trend = 0.09). These associations were attenuated but retained borderline significance (P-trend < 0.1) after adjusting for potassium intake (a marker of fruit and vegetable intake), suggesting that vitamin C effects may not be separated from other protective factors in fruit and vegetables. Null associations were observed among women. These results suggest a possible protective role of vitamin C for bone health in older men.


Transurethral endoscopic approach for large bladder diverticula: Evaluation of a large series.
To present the results of the largest series of patients with bladder diverticula > 4 cm managed with an endoscopic approach and give tips about the execution of the procedure. Data of male patients undergone the endoscopic approach for an acquired bladder diverticula > 4 cm from December 2004 to August 2018 were prospectively collected and retrospectively analyzed. The description of the monopolar and bipolar techniques are provided. The success of the procedure was defined as the reduction of the diverticula for more of the 80% of its initial diameter documented at the 3- months follow-up imaging. Continuous variables with nonparametric distribution were compared using the Mann-Whitney test, while frequencies of categorical variables were compared between groups by Fisher's exact test with significance level set at 0.05. Thirty-nine patients with a mean (+/- SD) age at surgery of 69.4 ± 8.8 years were enrolled, for an equal number of diverticula managed. The mean diverticular size was 75.1 ± 24.5 millimeters. The mean operative time was 65 ± 21.9 minutes including the prostate surgery. Twelve patients (30.8%) were managed with bipolar energy, the others with monopolar. The success of the procedure was achieved in 30 patients (76.9% - 7 bipolar and 23 monopolar - p = 0.66). The endoscopic approach might be considered as a useful option for patients with a large bladder diverticulum who are at risk for major or laparoscopic procedure.


Radioiodine treatment of non-toxic multinodular goitre: effects of combination with lithium.
This study aimed to evaluate the effects of radioiodine ((131)I), alone or in combination with lithium, on thyroid volume and the prevention of radioiodine-induced thyrotoxicosis. This is the first clinical trial including only patients with multinodular goitre, normal TSH values and negative anti-thyroid auto-antibodies at baseline. Eighty consecutive patients were randomised to receive (131)I plus lithium (group I+L) or (131)I alone (group I). Thyroid ultrasonography and biochemical analyses were performed at baseline and at 1, 3, 6, 12 and 24 months after treatment. At 1-4 weeks after treatment, (131)I-induced hyperthyroidism was observed in 58.8% of patients and was prevented by lithium administration. A low incidence of hypothyroidism (19%) was recorded at 24 months, whereas up to 44% of patients developed anti-thyroid antibodies. A significant reduction in thyroid volume was observed after (131)I, with a mean decrease of 47.2% (median 48.2%) at 24 months, without differences between the groups. Moreover, it was shown that the decrease in thyroid volume after (131)I was also due to the significant shrinkage of thyroid nodules. This demonstrates that adjunctive lithium is able to reduce radioiodine-induced hyperthyroidism. Therefore, such treatment appears to be safe in older patients and those with underlying cardiovascular disease. In the present large series, (131)I therapy was demonstrated to be highly effective in reducing thyroid and nodular volume even in patients treated with low (131)I doses (2.5 MBq/ml of thyroid tissue), further supporting the view that radioiodine therapy represents a real alternative to surgery.


[Peculiarities of epidemiology of chronic tonsillitis under current conditions of providing specialized aid to the patients presenting with ENT diseases].
The objective of he present works was to analyse epidemiological parameters characterizing the prevalence of chronic tonsillitis morbidity and specific features of its local and systemic complications (the former included paratonsillar abscess, PA, while the latter acute rheumatic fever, ARF, and acute post-streptococcal glomerulonephritis, APSGN). The data subjected to the analysis comprised information collected by the Statistical Department of the Clinical Infectious Hospital No 1 for the past 10 years about the number of hospitalized patients having the diagnosis of tonsillitis in combination with PA and the data on the number of peritonsillar abscess drainage procedures performed between 2008 and 2010 (Statistical Department of S.P. Botkin City Clinical Hospital), the number of tonsillectomies, the prevalence of ARF and APSGN during the last 10 years (Medical Statistics Bureau of the Moscow Health Department), and the results of monitoring regular medical check-ups of the patients presenting with the above pathologies. The number of the patients hospitalized at the Clinical Infectious Hospital No 1 for the diagnosis of tonsillitis in combination with PA was shown to increase as well as the number of autopsies of the patients with PA performed at S.P. Botkin City Clinical Hospital. Simultaneously, the number of tonsillectomies in the clinics of Moscow Health Department decreased whereas the prevalence of ARF and APSGN and the number of the patients with chronic tonsillitis under dispensary observation for over 2 years increased. It is concluded that otorhinolaryngologists working in outpatient facilities must promptly identify indications for radical surgical sanitation of the pockets of chronic infection by means of bilateral tonsillectomy.


A pro-inflammatory diet is associated with increased risk of developing hypertension among middle-aged women.
A pro-inflammatory diet is thought to lead to hypertension through oxidative stress and vessel wall inflammation. We therefore investigated the association between the dietary inflammatory index (DII) and developing hypertension in a population-based cohort of middle-aged women. The Australian Longitudinal Study on Women's Health included 7169 Australian women, aged 52 years (SD 1 year) at baseline in 2001, who were followed up through 4 surveys until 2013. The DII, a literature-derived dietary index that has been validated against several inflammatory markers, was calculated based on data collected via a validated food-frequency questionnaire administered at baseline. Hypertension was defined as new onset of doctor-diagnosed hypertension, ascertained through self-report between 2001 and 2013. Generalised Estimating Equation analyses were used to investigate the association between the DII and incident hypertension. The analyses were adjusted for demographic and hypertension risk factors. During 12-years follow-up we identified 1680 incident cases of hypertension. A more pro-inflammatory diet was associated with higher risk of hypertension in dichotomised analyses with an ORfully adjusted of 1.24, 95% CI: 1.06-1.45. A pro-inflammatory diet might lead to a higher risk of developing hypertension. These results need to be replicated in other studies.


The Potential of Glycyrrhiza from "Medicine Food Homology" in the Fight against Digestive System Tumors.
Glycyrrhiza has a long history of applications and a wide range of pharmacological effects. It is known as the "king of all herbs". Glycyrrhiza is effective in clearing heat, detoxifying, relieving cough, and tonifying qi and has good bioactivity in multiple inflammatory, immune, and tumor diseases. This review aims to summarize the origin, distribution, and anti-digestive system tumor mechanism of glycyrrhiza and its homologous applications in medicine and food. The active compounds include triterpenoids, flavonoids, and coumarins, which are widely used in clinical treatments, disease prevention, and daily foods because of their "enhancement of efficacy" and "reduction of toxicity" against digestive system tumors. This paper reviews the use of glycyrrhiza in digestive system tumors and provides an outlook on future research and clinical applications.


[Cycloferon in the complex therapy of patients with widespread forms of pulmonary tuberculosis].
Research performed at the Grodno Regional Clinical Center "Phthisiology" was aimed at studying the dynamics of IFN-gamma and IL-4 in serum of patients with widespread forms of pulmonary tuberculosis, treated by polychemotherapy with the use of cycloferon. Results of the clinical and laboratory evaluation of the effectiveness of the basic course of treatment are presented. A total of 238 patients, including 32 patients with limited forms of the pulmonary tuberculosis and 206 patients had widespread forms of pulmonary tuberculosis, were randomized into the basic group (BG) and comparison group (CG), where 95 CG patients received only polychemotherapy and 111 BG patients received polychemotherapy with the use of cycloferon. Data on the initial levels of cytokines (IFN-gamma and IL-4) in healthy persons and patients with various spread ofa tubercular inflammation in lungs are presented and compared. It is established that, in patients with widespread forms, initially low level of IFN-gamma and high concentration IL-4 (in comparison with the limited forms) shows a severe disbalance between Th1- and Th2-mediated immune response. The administration of cycloferon in the complex therapy of patients with widespread forms leads to an increase in the IFN-gamma concentration at initially low levels (below median level of this cytokine in healthy humans). Activation of the Th1-mediated immune response upon using cycloferon leads to an early elimination of clinical manifestations of the intoxication syndrome, positive roentgenological dynamics, conversion of sputum smear, and successful outcomes of treatment.


Self-Helical Fiber for Glucose-Responsive Artificial Muscle.
A helical configuration confers a great advantage in artificial muscle due to great movement potential. However, most helical fibers are exposed to a high temperature to produce the coiled helical structure. Hence, thermoset polymer-composed hydrogels are difficult to fabricate as helical fibers due to their thermal degeneration. Here, we describe a self-helical hydrogel fiber that is produced without thermal exposure as a glucose-responsive artificial muscle. The sheath-core fiber was spontaneously transformed into the helical structure during the swelling state by balancing the forces between the untwisting force of the twisted nylon fiber core and the recovery force of the hydrogel sheath. To induce controllable actuation, we also applied a reversible interaction between phenylboronic acid and glucose to the self-helical hydrogel. Consequently, the maximum tensile stroke was 2.3%, and the performance was six times greater than that of the nonhelical fiber. The fiber also exhibited tensile stroke with load and a maximum work density of 130 kJ/m3. Furthermore, we showed a reversible tensile stroke in response to the change in glucose level. Therefore, these results indicate that the self-helical hydrogel fiber has a high potential for use in artificial muscles, glucose sensors, and drug delivery systems.


Dexamethasone-regulated expression of pancreatic lipase and two related proteins in AR42J cells.
The pancreas makes two pancreatic proteins [pancreatic lipase-related protein-1 (PLRP-1) and PLRP-2] with marked homology to pancreatic lipase (PL). To determine if a pancreatic acinar cell line, AR42J, also expresses PLRP-1 and PLRP-2, we examined the cells for the presence of PL, PLRP-1, and PLRP-2. RNA blot analysis with specific probes and immunoblot analysis with antipeptide antibodies demonstrated the presence of mRNA and protein for all three homologues in AR42J cells. Additionally, we showed that dexamethasone decreased PLRP-1 mRNA levels twofold and increased PLRP-2 mRNA 20-fold but had little effect on PL or colipase mRNA. Extracellular PLRP-2 protein levels increased threefold, and intracellular PLRP-2 protein levels increased about fourfold. The characteristics of the dexamethasone-induced increase in PLRP-2 mRNA, a rapid change requiring new protein synthesis independent of mRNA turnover, suggested that dexamethasone regulated transcription. We conclude that AR42J cells synthesize and secrete PL, PLRP-1, and PLRP-2 and that dexamethasone discoordinately regulates the expression of the three genes.


[Immunohistochemical differential diagnosis of 60 cases of rhabdomyosarcoma].
Using the avidin-biotin complex immunoperoxidase technique and antibodies to myoglobin, desmin, CLA, NSE, GFAP, keratin, fibronectin, alpha 1AT, lysozyme, S-100 protein, vimentin, cytokeratin, actin, the authors studied 60 cases of rhabdomyosarcoma (RMS) histopathologically diagnosed previously. Thirty-six cases showed both myoglobin and desmin positive stain, an objective evidence of the origin from skeletal muscles. The other 24 cases were identified as of non-skeletal muscle origin, including MFH, lymphoma, melanoma, neuroblastoma, malignant neurilemmoma, leiomyosarcoma etc. This study strongly suggests that histologic examination of RMS may lead to incorrect diagnosis. Histologically MFH and other types of spindle cell sarcomas invading normal skeletal muscles may be confused with pleomorphic RMS, lymphoma and neuroblastoma may be confused with embryonic RMS. Our findings indicate that myoglobin is a highly sensitive and specific tumor marker for RMS.


Altered heart rate control in transgenic mice carrying the KCNJ6 gene of the human chromosome 21.
Congenital heart defects (CHD) are common in Down syndrome (DS, trisomy 21). Recently, cardiac sympathetic-parasympathetic imbalance has also been documented in DS adults free of any CHD. The KCNJ6 gene located on human chromosome 21 encodes for the Kir3.2/GIRK2 protein subunits of G protein-regulated K(+) (K(G)) channels and could contribute to this altered cardiac regulation. To elucidate the role of its overexpression, we used homozygous transgenic (Tg(+/+)) mice carrying copies of human KCNJ6. These mice showed human Kir3.2 mRNA expression in the heart and a 2.5-fold increased translation in the atria. Phenotypic alterations were assessed by recording electrocardiogram of urethane anesthetized mice. Chronotropic responses to direct (carbachol) and indirect (methoxamine) muscarinic stimulation were enhanced in Tg(+/+) mice with respect to wild-type (WT) mice. Alternating periods of slow and fast rhythm induced by CCPA (2-chloro-N-cyclopentyl-adenosine) were amplified in Tg(+/+) mice, resulting in a reduced negative chronotropic effect. These drugs reduced the atrial P wave amplitude and area. P wave variations induced by methoxamine and CCPA were respectively increased and reduced in the Tg(+/+) mice, while PR interval and ventricular wave showed no difference between Tg(+/+) and WT. These results indicate that Tg(+/+) mice incorporating the human KCNJ6 exhibit altered Kir3.2 expression and responses to drugs that would activate K(G) channels. Moreover, these altered expression and responses are limited to sino-atrial node and atria that normally express large amounts of K(G) channels. These data suggest that KCNJ6 could play an important role in altered cardiac regulation in DS patients.


A simple hierarchical approach to modeling distributions of substitution rates.
Genetic sequence data typically exhibit variability in substitution rates across sites. In practice, there is often too little variation to fit a different rate for each site in the alignment, but the distribution of rates across sites may not be well modeled using simple parametric families. Mixtures of different distributions can capture more complex patterns of rate variation, but are often parameter-rich and difficult to fit. We present a simple hierarchical model in which a baseline rate distribution, such as a gamma distribution, is discretized into several categories, the quantiles of which are estimated using a discretized beta distribution. Although this approach involves adding only two extra parameters to a standard distribution, a wide range of rate distributions can be captured. Using simulated data, we demonstrate that a "beta-" model can reproduce the moments of the rate distribution more accurately than the distribution used to simulate the data, even when the baseline rate distribution is misspecified. Using hepatitis C virus and mammalian mitochondrial sequences, we show that a beta- model can fit as well or better than a model with multiple discrete rate categories, and compares favorably with a model which fits a separate rate category to each site. We also demonstrate this discretization scheme in the context of codon models specifically aimed at identifying individual sites undergoing adaptive or purifying evolution.


Direct voltammetric determination of redox-active iron in carbon nanotubes.
With the advances in nanotechnology over the past decade, consumer products are increasingly being incorporated with carbon nanotubes (CNTs). As the harmful effects of CNTs are suggested to be primarily due to the bioavailable amounts of metallic impurities, it is vital to detect and quantify these species using sensitive and facile methods. Therefore, in this study, we investigated the possibility of quantifying the amount of redox-available iron-containing impurities in CNTs with voltammetric techniques such as cyclic voltammetry. We examined the electrochemistry of Fe3 O4 nanoparticles in phosphate buffer solution and discovered that its electrochemical behavior could be affected by pH of the electrolyte. By utilizing the unique redox reaction between the iron and phosphate species, the redox available iron content in CNTs was determined successfully using voltammetry.


Care of the older person and the value of human dignity.
As the world population is rapidly aging, stakeholders must address the care of the elderly with great concern. Also, loss of dignity is often associated with aging due to dementia, mobility problems and diminished functional autonomy. However, dignity is a polysemic term that is deemed useless by some ethicists. To counter this claim, we propose four concepts to define it better and make use accurately of this notion. These are human dignity, dignity of identity, dignities of excellence and attributed dignities. Finally, we explain the importance of solicitude and human dignity in the care of the elderly. This will ensure the respect, friendship and dignity of the elderly in providing geriatric ethical care.


Glycogen synthase kinase 3β promotes osteogenic differentiation of murine adipose-derived stromal cells.
Although the role of glycogen synthase kinase 3β (GSK3β) in osteogenic differentiation of bone marrow-derived mesenchymal stromal cells (BMSCs) is well-characterized as a negative regulator of β-catenin, its effect on osteogenesis of adipose-derived stromal cells (ADSCs) is poorly understood. Here, we show that GSK3β positively regulates osteogenic differentiation of murine ADSCs. Gain-of-function studies showed that GSK3β promotes in vitro osteogenesis of ADSCs. Regulation of GSK3β activity in ADSCs, either by small interfering RNA (siRNA)-mediated GSK3β silencing or by pharmacological inhibitors, blunted osteogenesis and the expression of osteogenic markers. Importantly, we demonstrated that transgenic mice, engineered to overexpress the constitutively active GSK3β (GSK3β-S9A) mutant, exhibited a marked increase in osteogenesis, whereas expression of the catalytically inactive GSK3β (GSK3β-K85A) in mice inhibits osteogenic differentiation. Molecular analyses showed that the enhanced osteoblast differentiation induced by GSK3β was mediated by downregulation of β-catenin. Remarkably, β-catenin silencing enhances osteogenesis and osteoblast marker gene expression such as alkaline phosphatase (ALP) and osterix. Taken together, these findings demonstrate a novel role for GSK3β in the regulation of osteogenic differentiation in ADSCs.


Transmural distribution of intramyocardial pressure measured by micropipette technique.
A technique is presented for measuring intramyocardial pressure (IMP) in beating hearts using the servo-nulling pressure transducer equipped with polyethylene micropipettes (ID less than 12 micron). The static and dynamic response characteristics of the system were tested in a pressurized, saline-filled container as well as in a pressurized, hollow, gelatin cylinder. The system was then used to measure IMP in vivo in the hearts of 12 dogs during stable cardiac performance and with aortic constriction. In vitro response characteristics were found to be satisfactory for accurate reproduction of cardiovascular waveforms. Peak systolic IMP was not found to exceed the simultaneously recorded left intraventricular pressure (LVP). Furthermore, the slope of the regression line relating the IMP to LVP during systole is linearly related (slope 0.98) to the depth of the micropipette tip in the ventricular wall, as normalized to total wall thickness. Diastolic IMP ranged between 1 +/- 1 (minimum during the cardiac cycle) and 4 +/- 2 mmHg (end diastolic) at associated LVP of 2 +/- 2 and 5 +/- 2 mmHg (mean +/- SD), respectively.


[Etiologic and epidemiologic questions posed by erythema chronicum migrans and Lyme disease. Apropos of 4 cases at the Regional Hospital Center, Rennes].
The authors give 4 observations, made in Rennes (France), of 3 cases contracted in France and 1 in Canada, cases they think to be related, for 3 at least, to the infectious entity described by American authors under the name of Lyme disease. If 1 of these cases was limited to an erythema chronicum migrans, the 3 others showed a beginning evolution towards a classical Lyme disease. In 2 of these 3 last cases, the infection was perhaps cut short by a quickly applied therapy by antibiotics. They discuss the different hypotheses about the negative Borrelia serologic reactions in 3 of the 4 cases. A possible arboviral aetiology is evocked. In only one of the 4 cases, a tick-bite can be asserted, the role in the the transmission of this kind of arthropods being strictly excluded in 2 of the 3 other cases (transmission likely by a mosquito and by a biting fly (tabanid?)). The authors put the question of the possibility of transmission, for erythema chronicum migrans and Lyme disease, by arthropods other than ticks.


Perspectives on implementing Individual Placement and Support (IPS) within primary health care settings for adults living in British Columbia, Canada.
Individual placement and support (IPS) is an evidence-based practice (EBP) designed to help people with severe mental illness re-enter the labour market. Implementing an IPS program within a new context (e.g., primary health care setting) to support populations that are complex and multi-barriered presents a set of unique challenges and considerations. This paper provides community-based perspectives that identify implementation strengths and challenges and highlights potential strategies aimed at addressing emergent barriers. A case study was conducted across three community health centres in British Columbia (BC), Canada, where a novel IPS program was embedded within primary care services. Data collection consisted of open-ended surveys and focus groups with service providers directly involved in program implementation and their associated clinical and managerial support teams (n = 15). Using the updated Consolidated Framework for Implementation Research (CFIR) as a guide, we performed deductive thematic analysis to identify key areas impacting IPS implementation. Integration with existing health care systems and primary health care teams and support from leadership across all levels were identified as both key facilitators and barriers to implementation. Facilitators and barriers were identified across all domains, with those within innovation and process most easily addressed. Four cross-cutting themes emerged for promoting more integrated and sustainable program implementation: investing in pre-implementation activities, supporting a dynamic and flexible program, building from community experiences, and developing a system for shared knowledge. Implementing an IPS program embedded within primary health care settings is complex and requires extensive planning and consultation with community-based service providers and decision-makers to achieve full integration. Future practice and policy decisions aimed at supporting employment and well-being should be made in collaboration with communities.