Effectiveness of azelastine nasal spray compared with oral cetirizine in patients with seasonal allergic rhinitis.
Azelastine nasal spray and oral cetirizine are selective histamine H(1)-receptor antagonists that are approved in the United States for the treatment of seasonal allergic rhinitis (SAR). The objective of the present study was to compare the efficacy and tolerability of azelastine nasal spray administered at the recommended dosage of 2 sprays per nostril twice daily with those of cetirizine in the treatment of moderate to severe SAR. This multicenter, randomized, double-blind, parallel-group, 2-week comparative study was conducted during the 2004 fall allergy season in patients with moderate to severe SAR. After a 1-week placebo lead-in period, patients were randomized to receive azelastine nasal spray 2 sprays per nostril twice daily plus placebo tablets or cetirizine 10-mg tablets once daily plus a placebo saline nasal spray for the 2-week double-blind treatment period. The primary efficacy variables were (1) change from baseline to day 14 in the 12-hour reflective total nasal symptom score (TNSS), which combines scores for rhinorrhea, sneezing, itchy nose, and nasal congestion, and (2) onset of action, based on the instantaneous TNSS over 4 hours after the first dose of study drug. During the double-blind treatment period, patients recorded their symptom scores on diary cards twice daily (morning and evening). Patients aged > or =18 years also completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) at baseline and on day 14. Three hundred seven patients were randomized to treatment, and 299 completed 2 weeks of study treatment. The age of the population ranged from 12 to 74 years (mean, 35 years), 62.9% were female, and 69.6% were white. Over 2 weeks of treatment, both groups had significant improvements in the TNSS compared with baseline (P < 0.001). The overall change in TNSS was significantly greater with azelastine nasal spray compared with cetirizine (29.3% vs 23.0% improvement, respectively; P = 0.015). In terms of onset of action, azelastine nasal spray significantly improved the instantaneous TNSS compared with cetirizine at 60 and 240 minutes after the initial dose (both, P = 0.040). Scores on each domain of the RQLQ were significantly improved in both groups compared with baseline (P < 0.001); the overall RQLQ score was significantly improved with azelastine nasal spray compared with cetirizine (P = 0.049). Both treatments were well tolerated. In this 2-week study in patients with moderate to severe SAR, azelastine nasal spray was well tolerated and produced significantly greater improvements in TNSS and total RQLQ score compared with cetirizine.


Phagocytic superoxide specifically damages an extracytoplasmic target to inhibit or kill Salmonella.
The phagocytic oxidative burst is a primary effector of innate immunity that protects against bacterial infection. However, the mechanism by which reactive oxygen species (ROS) kill or inhibit bacteria is not known. It is often assumed that DNA is a primary target of oxidative damage, consistent with known effects of endogenously produced ROS in the bacterial cytoplasm. But most studies fail to distinguish between effects of host derived ROS versus damage caused by endogenous bacterial sources. We took advantage of both the ability of Salmonella enterica serovar Typhimurium to survive in macrophages and the genetic tractability of the system to test the hypothesis that phagocytic superoxide damages cytoplasmic targets including DNA. SodCI is a periplasmic Cu-Zn superoxide dismutase (SOD) that contributes to the survival of Salmonella Typhimurium in macrophages. Through competitive virulence assays, we asked if sodCI has a genetic interaction with various cytoplasmic systems. We found that SodCI acts independently of cytoplasmic SODs, SodA and SodB. In addition, SodCI acts independently of the base excision repair system and RuvAB, involved in DNA repair. Although sodCI did show genetic interaction with recA, this was apparently independent of recombination and is presumably due to the pleiotropic effects of a recA mutation. Taken together, these results suggest that bacterial inhibition by phagocytic superoxide is primarily the result of damage to an extracytoplasmic target.


Fungus-host relationship in candidiasis. A brief review.
Candidiasis and its causative agent, Candida albicans, have been under continuous study in our clinics and laboratories for the past 20 years. Cultured cells of C albicans and tissues from natural and experimental infections were used for observations by light microscopy, transmission electron microscopy, scanning electron microscopy and freeze fracture techniques. In cultures, the cells of C albicans revealed a more complex cell wall, plasma membrane, intracellular organelles, and biochemical organization than those described in classic text-books on mycology. In infected tissues, noteworthy characteristics of C albicans were prominent vacuoles and invasion of host cells with subsequent intracellular localization and lysis of tissues surrounding the fungus. These findings are discussed in relation to their importance in the pathogenesis and management of candidiasis and to the mechanism of action of anticandida agents.


Development and interpretation of a pathomics-based model for the prediction of microsatellite instability in Colorectal Cancer.
Microsatellite instability (MSI) has been approved as a pan-cancer biomarker for immune checkpoint blockade (ICB) therapy. However, current MSI identification methods are not available for all patients. We proposed an ensemble multiple instance deep learning model to predict microsatellite status based on histopathology images, and interpreted the pathomics-based model with multi-omics correlation. Methods: Two cohorts of patients were collected, including 429 from The Cancer Genome Atlas (TCGA-COAD) and 785 from an Asian colorectal cancer (CRC) cohort (Asian-CRC). We established the pathomics model, named Ensembled Patch Likelihood Aggregation (EPLA), based on two consecutive stages: patch-level prediction and WSI-level prediction. The initial model was developed and validated in TCGA-COAD, and then generalized in Asian-CRC through transfer learning. The pathological signatures extracted from the model were analyzed with genomic and transcriptomic profiles for model interpretation. Results: The EPLA model achieved an area-under-the-curve (AUC) of 0.8848 (95% CI: 0.8185-0.9512) in the TCGA-COAD test set and an AUC of 0.8504 (95% CI: 0.7591-0.9323) in the external validation set Asian-CRC after transfer learning. Notably, EPLA captured the relationship between pathological phenotype of poor differentiation and MSI (P < 0.001). Furthermore, the five pathological imaging signatures identified from the EPLA model were associated with mutation burden and DNA damage repair related genotype in the genomic profiles, and antitumor immunity activated pathway in the transcriptomic profiles. Conclusions: Our pathomics-based deep learning model can effectively predict MSI from histopathology images and is transferable to a new patient cohort. The interpretability of our model by association with pathological, genomic and transcriptomic phenotypes lays the foundation for prospective clinical trials of the application of this artificial intelligence (AI) platform in ICB therapy.


Left ventricular retraining and anatomic correction in teenage patient with congenitally corrected transposition of the great arteries.
Left ventricular (LV) retraining followed by anatomical repair would be a superior alternative in patients with congenitally corrected transposition (ccTGA) having a deconditioned morphologically left ventricle (MLV); however, LV retraining in older children is a challenging task. A retraining process of the MLV in a teenage patient with ccTGA is reported here. Cardiac catheterization at 7 years of age revealed low pressure of the MLV (33/4 mm Hg) and a LV to right ventricular pressure ratio (LVp/RVp ratio) of 0.32. The first pulmonary artery banding (PAB) was performed at 10 years of age. Although the LVp/RVp ratio reached 0.68, there was no evidence of adequate LV hypertrophy. The second PAB was performed 2 years after the initial PAB, resulting in an increase in the LVp/RVp ratio to 0.93 and an adequate LV hypertrophy. The double switch procedure was successfully performed at 13 years of age. Although the ejection fraction of the MLV mildly decreased, the patient has been doing well during a follow-up period of 4 years. The MLV in the teenage patient with ccTGA was successfully trained using a retraining strategy and has sustained systemic circulation after anatomical repair.


In Situ Observations of Interstellar Pickup Ions from 1 au to the Outer Heliosphere.
Interstellar pickup ions are an ubiquitous and thermodynamically important component of the solar wind plasma in the heliosphere. These PUIs are born from the ionization of the interstellar neutral gas, consisting of hydrogen, helium, and trace amounts of heavier elements, in the solar wind as the heliosphere moves through the local interstellar medium. As cold interstellar neutral atoms become ionized, they form an energetic ring beam distribution comoving with the solar wind. Subsequent scattering in pitch angle by intrinsic and self-generated turbulence and their advection with the radially expanding solar wind leads to the formation of a filled-shell PUI distribution, whose density and pressure relative to the thermal solar wind ions grows with distance from the Sun. This paper reviews the history of in situ measurements of interstellar PUIs in the heliosphere. Starting with the first detection in the 1980s, interstellar PUIs were identified by their highly nonthermal distribution with a cutoff at twice the solar wind speed. Measurements of the PUI distribution shell cutoff and the He focusing cone, a downwind region of increased density formed by the solar gravity, have helped characterize the properties of the interstellar gas from near-Earth vantage points. The preferential heating of interstellar PUIs compared to the core solar wind has become evident in the existence of suprathermal PUI tails, the nonadiabatic cooling index of the PUI distribution, and PUIs' mediation of interplanetary shocks. Unlike the Voyager and Pioneer spacecraft, New Horizon's Solar Wind Around Pluto (SWAP) instrument is taking the only direct measurements of interstellar PUIs in the outer heliosphere, currently out to ∼ 47 au from the Sun or halfway to the heliospheric termination shock.


Waterpipe use in adolescents in Northern Sweden: Association with mental well-being and risk and health behaviours.
There is a lack of studies examining the association between waterpipe smoking and mental well-being among adolescents. This study sought to determine whether waterpipe smoking is associated with mental well-being and other risk and health behaviours in adolescents. A questionnaire was distributed to 1006 adolescents in grades 9-12 (with a response rate of >95%), containing questions on measures of stress, mental energy and sleep. In addition, the questionnaire assessed risk and health behaviours, including use of a waterpipe, cigarettes, e-cigarettes, snus, alcohol, narcotics, gambling and exercise. Logistic regression was used to assess factors associated with waterpipe use. Thirty-seven per cent ( n=371) of the participants had used a waterpipe at some point. Waterpipe use was associated with lower mental energy (odds ratio [OR] = 0.90, 95% confidence interval [CI] 0.81-0.99), higher stress (OR = 1.10, 95% CI 1.02-1.20) and use of cigarettes (OR = 3.82, 95% CI 2.33-6.03), e-cigarettes (OR = 3.26, 95% CI 2.12-4.99), snus (OR = 2.29, 95% CI 2.12-4.99), alcohol (OR = 1.92, 95% CI 1.07-3.44) and narcotics (OR = 3.64, 95% CI 1.75-7.58). Waterpipe use was not significantly associated with gambling, exercise or sleep quality. Waterpipe use in adolescents is associated with worse mental well-being, as well as use of other nicotine products, alcohol and narcotics. Prospective studies are needed to delineate causal and temporal relationships further between waterpipe use and mental well-being and its relationship to other risky behaviours in order to design effective prevention programs.


Prospects of snap beans (Phaseolus vulgaris L.) production and commercialization in Benin.
Vegetables and fruits are highly recommended in diets because of their nutritional importance. Among those, leguminous vegetables are more important, for low-income countries, because of their protein, mineral contents and potential to increase food security and income. In Benin, snap beans (Phaseolus vulgaris L.) are the most consumed leguminous vegetables; however, their production is declining, driving the need to understand the current status of its industry to propose solutions for the revival of the sector. This paper assessed the production system, market value, marketing channels, seed systems, and the constraints associated with Benin's snap bean production from a gender lens. A semi-structured interview was conducted with 602 bean producers and traders, randomly selected from 12 major vegetable-producing areas across Benin. The study found a drastic decline in the production of snap beans, with more than 60% abandonment over the last decade. As a consequence, Benin gets supplied through importations, with the highest importation flow coming from Togo (51%), followed by Burkina Faso (25%), and Ghana (12%). Only 13% of the beans traded are locally produced. The leading causes of the decline were pests and diseases that affected the crops' yield and quality, causing the local produce to be less valued than the imported ones. Women are heavily involved in marketing but cannot expand their business due to low production and high importation. The study recommends that integrated pest management (IPM) and new varieties with tolerance to major pests and diseases be developed to address market demand and producers trained in agronomic practices.


Development and implementation of a pharmacist-managed clinical pharmacogenetics service.
The development and implementation of a pharmacist-managed clinical pharmacogenetics service are described. A pharmacist-managed clinical pharmacogenetics service was designed and implemented at an academic specialty hospital to provide clinical pharmacogenetic testing for gene products important to the pharmacodynamics of medications used in the hospital's patients. A series of accredited educational seminars were conducted for our pharmacists to establish competencies in providing pharmacogenetic consults for the genes to be tested by the clinical pharmacogenetics service. The service was modeled after and integrated with an already-established clinical pharmacokinetics service. A steering committee was formed to evaluate the use of available tests, new evidence for implementation of additional tests, and other service quality metrics. All clinical pharmacogenetic test results are first reported to one of the pharmacists, who reviews the result and provides a written consultation. The consultation includes an interpretation of the result and recommendations for any indicated changes to therapy. In 2009, 136 clinical pharmacogenetic tests were performed. The service has been met with positive clinician feedback. The successful implementation of this service highlights the leadership role that pharmacists can take in moving pharmacogenetics from research to patient care. The development of and experience with a pharmacist-managed clinical pharmacogenetics service are described. The program's success has depended on collaboration between the clinical laboratory and pharmacists, and pharmacists' pharmacogenetic recommendations have been well accepted by prescribers.


Development of a three-dimensional extracellular matrix synthesized by human diploid fibroblasts in vitro.
Development and maturation of an extracellular matrix, synthesized by human gingival fibroblasts, have been studied microscopically. Pairs of demineralized, fibronectin-coated slices of human tooth root, 300 micron thick, were placed on confluent cell layers, defining a 0.5 mm wide space. The cultures were grown under standard conditions with ascorbic acid (50 micrograms ml-1) added daily. At various times up to 13 weeks, the cultures were fixed and the samples prepared for light and electron microscopy. Cells from the monolayer became attached to, and migrated up, the vertical root surface and, during the time studied, completely filled the space between the root slices with an extracellular matrix. A close association was seen between the cell membrane and collagen fibres in the demineralized surface initially. A thin layer of fibrillar material was deposited between the cell and the vertical surface, and eventually an extracellular matrix surrounding the cells and attaching to the root surface was present. Samples fixed in the presence of Ruthenium Red showed intense staining of the fibrillar material, indicating the presence of anionic molecules. Additional cells migrated onto the newly synthesized matrix and up the root surface. Growth of the fibrillar networks on either side, horizontally and vertically, continued and, eventually, an extracellular matrix attaching to the vertical surfaces completely filled the previously empty space. Immunocytochemical staining showed that the matrix contained hyaluronic acid, chondroitin sulphate, dermatan sulphate and fibronectin at this time. Collagen fibres were observed at 6 weeks, and at later times collagen types I, III and V were the primary matrix components. The fibroblasts attaching to the root slice and those present at the edge of the matrix had an elongated, polar form. The cells within the matrix frequently showed a stellate appearance with numerous extended processes, in contact with fibrillar material or collagen fibres. Fibroblast processes were at later times seen to enclose bundles of collagen fibres and to mediate cell-to-cell contact, occasionally via desmosome-like structures. The structure and composition of the matrix and the appearance and apparent behaviour of the cells were similar to that observed in the healing wound. This system thus could provide a model for studying various aspects of regeneration of extracellular matrix.


Poverty, production, and health: inhibition of erythrocyte cholinesterase via occupational exposure to organophosphate insecticides in Chiapas, Mexico.
Occupational exposure to organophosphate pesticides and its effects on the concentration of erythrocyte cholinesterase in the rural population of Chiapas, Mexico, are described. The authors surveyed agricultural production and pesticide use was surveyed among 199 campesinos (peasants) in three communities that used various agricultural production systems. The authors measured the concentration of the cholinesterase enzyme in blood samples obtained from 65 campesinos before and after exposure to the insecticide. The authors established a comparison value for the population that was not exposed occupationally. The exposure values of the enzyme concentration were significantly lower than preexposure values (p = .00001) and reference group values (p = .0008). Individuals in the community characterized by subsistence production had significantly lower levels of the enzyme than individuals in the other two communities (p = .01). This result suggested that a greater risk of adverse health effects existed among the poorest communities.


Concise reviews: A stem cell apostasy: a tale of four H words.
The field of hematopoietic stem cell (HSC) biology has become increasingly dominated by the pursuit and study of highly purified populations of HSCs. Such HSCs are typically isolated based on their cell surface marker expression patterns and ultimately defined by their multipotency and capacity for self-generation. However, even with progressively more stringent stem cell separation techniques, the resultant HSC population remains heterogeneous with respect to both self-renewal and differentiation capacity. Critical studies on unseparated whole bone marrow have definitively shown that long-term engraftable HSCs are in active cell cycle and thus continually changing phenotype. Therefore, they cannot be purified by current approaches dependent on stable surface epitope expression because the surface markers are continually changing as well. These critical cycling cells are discarded with current stem cell purifications. Despite this, research defining such characteristics as self-renewal capacity, lineage-commitment, bone marrow niches, and proliferative state of HSCs continues to focus predominantly on this small subpopulation of purified marrow cells. This review discusses the research leading to the hierarchical model of hematopoiesis and questions the dogmas pertaining to HSC quiescence and purification.


Extracellular Matrix Secretion Mechanically Reinforces Interlocking Interfaces.
Drawing inspiration for biomaterials from biological systems has led to many biomedical innovations. One notable bioinspired device, Velcro, consists of two substrates with interlocking ability. Generating reversibly interlocking biomaterials is an area of investigation, as such devices can allow for modular tissue engineering, reversibly interlocking biomaterial interfaces, or friction-based coupling devices. Here, a biaxially interlocking interface generated using electrostatic flocking is reported. Two electrostatically flocked substrates are mechanically and reversibly interlocked with the ability to resist shearing and compression forces. An initial high-throughput screen of polyamide flock fibers with varying diameters and fiber lengths is conducted to elucidate the roles of different fiber parameters on scaffold mechanical properties. After determining the most desirable parameters via weight scoring, polylactic acid (PLA) fibers are used to emulate the ideal scaffold for in vitro use. PLA flocked scaffolds are populated with osteoblasts and interlocked. Interlocked flocked scaffolds improved cell survivorship under mechanical compression and sustained cell viability and proliferation. Additionally, the compression and shearing resistance of cell-seeded interlocking interfaces increased with increasing extracellular matrix deposition. The introduction of extracellular matrix-reinforced interlocking interfaces may serve as binders for modular tissue engineering, act as scaffolds for engineering tissue interfaces, or enable friction-based couplers for biomedical applications.


Isolation methods for particle protein corona complexes from protein-rich matrices.
Background: Nanoparticles become rapidly encased by a protein layer when they are in contact with biological fluids. This protein shell is called a corona. The composition of the corona has a strong influence on the surface properties of the nanoparticles. It can affect their cellular interactions, uptake and signaling properties. For this reason, protein coronae are investigated frequently as an important part of particle characterization. Main body of the abstract: The protein corona can be analyzed by different methods, which have their individual advantages and challenges. The separation techniques to isolate corona-bound particles from the surrounding matrices include centrifugation, magnetism and chromatographic methods. Different organic matrices, such as blood, blood serum, plasma or different complex protein mixtures, are used and the approaches vary in parameters such as time, concentration and temperature. Depending on the investigated particle type, the choice of separation method can be crucial for the subsequent results. In addition, it is important to include suitable controls to avoid misinterpretation and false-positive or false-negative results, thus allowing the achievement of a valuable protein corona analysis result. Conclusion: Protein corona studies are an important part of particle characterization in biological matrices. This review gives a comparative overview about separation techniques, experimental parameters and challenges which occur during the investigation of the protein coronae of different particle types.


Introduction to competition between continuous cultures of Phaeodactylum tricornutum and Dunaliella tertiolecta.
When the diatom, Phaeodactylum tricornutum, and the microalga, Dunaliella tertiolecta, are cultured together in a chemostat at dilution factors of approximately 0.5 day-1, the diatom develops the higher population density. At dilution factors above 1.2 day-1 the inability of the diatom to assimilate nutrient as fast as it flows into the chemostat results in the microalga generating the larger population. This change in population densities is accompanied by an increase in the chlorophyll content of the diatom and a decrease in the chlorophyll content of the microalga. Two species of phytoplankton can coexist when they compete for nutrient in a chemostat providing they do not otherwise interact. When the species do interact coexistence in a stable steady state is possible providing intraspecies interactions exceed the interactions between the species. Both species adjust their consumption to minimise the concentration of nutrient in the chemostat and their growth is modified to match the dilution factor of the flow.


The parietal sheet of Bowman's capsule of rat renal glomerulus: a target of endothelin and PAF.
On the basis of intracellular calcium concentration ([Ca2+]i) measurements, we have previously reported that the parietal sheet of Bowman's capsule was sensitive to cholinergic agonists. The aim of the present work was to investigate whether this structure could be also a target of endothelin and platelet-activating factor (PAF), since we observed [Ca2+]i increases in response to both agonists in the glomerulus, but which were very different from that induced by carbachol. For this purpose, we measured [Ca2+]i on single microdissected parietal sheets, using a fura 2 microfluorescence technique and compared the effects of maximal concentrations of the three agonists (10(-7), 10(-8), and 10(-4) M for endothelin, PAF, and carbachol, respectively) under various experimental conditions. We observed that, like in the glomerulus, endothelin and PAF induced, in the parietal sheet, [Ca2+]i responses that differed in many respects from those found with carbachol. Thus, in the presence of 2 mM external calcium, 1) endothelin and PAF responses spontaneously declined to basal level, whereas a stationary plateau was observed after a sharp peak of [Ca2+]i with carbachol; 2) the magnitude of [Ca2+]i peak was smaller with endothelin and PAF than with carbachol; and 3) endothelin and PAF, but not carbachol, induced a homologous dose-dependent desensitization. Moreover, in the absence of external calcium, endothelin and PAF responses were smaller than carbachol response, although all three responses apparently resulted from release of calcium ions from the same internal pool. In additional experiments, we observed that, like carbachol, endothelin and PAF contracted the parietal sheet, which is only composed of myoepithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Detection and localization of pectin methylesterase isoforms in pollen tubes of Nicotiana tabacum L.
Pectin methylesterases (PMEs) were detected in tobacco ( Nicotiana tabacum) pollen tubes grown in vitro. Seven PME isoforms exhibiting a wide isoelectric-point (pI) range (5.3-9.1) were found in crude extracts of pollen tubes. These isoforms were mainly retrieved in supernatants after low- and high-speed separation of the crude extract. Two isoforms, with pIs 5.5 and 7.3 and molecular weight about 158 kDa, were detected by immunoblotting with anti-flax PME antiserum. Localization of pectins and PME isoforms in pollen tubes was investigated by immunogold labelling with JIM5 monoclonal antibodies and anti-flax PME antiserum, respectively. In germinated pollen grains, two PME isoforms were mainly detected in the exine, Golgi apparatus and secretory vesicles. In pollen tubes the same two PME isoforms were distributed along the outer face of the plasma membrane in the vicinity of the inner layer of the cell wall, in the Golgi and around secretory vesicles. In pollen grains, PME isoforms were, in some cases, mixed with acidic pectins in proximity to the outer surface of the plasma membrane. In pollen tubes the presence of PMEs inside secretory vesicles carrying esterified pectins supports the hypothesis that, during pollen tube growth, PMEs could be transferred by secretory vesicles in a precursor form and be activated at the tip where exocytosis takes place.


A newly introduced salt bridge cluster improves structural and biophysical properties of de novo TIM barrels.
Protein stability can be fine-tuned by modifying different structural features such as hydrogen-bond networks, salt bridges, hydrophobic cores, or disulfide bridges. Among these, stabilization by salt bridges is a major challenge in protein design and engineering since their stabilizing effects show a high dependence on the structural environment in the protein, and therefore are difficult to predict and model. In this work, we explore the effects on structure and stability of an introduced salt bridge cluster in the context of three different de novo TIM barrels. The salt bridge variants exhibit similar thermostability in comparison with their parental designs but important differences in the conformational stability at 25°C can be observed such as a highly stabilizing effect for two of the proteins but a destabilizing effect to the third. Analysis of the formed geometries of the salt bridge cluster in the crystal structures show either highly ordered salt bridge clusters or only single salt bridges. Rosetta modeling of the salt bridge clusters results in a good prediction of the tendency on stability changes but not the geometries observed in the three-dimensional structures. The results show that despite the similarities in protein fold, the salt bridge clusters differently influence the structural and stability properties of the de novo TIM barrel variants depending on the structural background where they are introduced.


Succinylcholine and atropine for premedication of the newborn infant before nasotracheal intubation: a randomized, controlled trial.
Twenty preterm newborn infants were randomized to receive either atropine alone (20 micrograms/kg) or atropine plus succinylcholine (2 mg/kg) before nasotracheal intubation. Heart rate, BP, transcutaneous PO2, and intracranial pressure were monitored continuously before, during, and after intubation. No infants developed bradycardia or hypoxia. Intracranial hypertension developed during intubation in the infants receiving atropine alone, but was prevented by premedication with succinylcholine and atropine (p less than .01). A 41% increase in systemic BP occurred immediately after the administration of succinylcholine (p less than .01). BP increased during intubation in both groups, and the overall peak BP was not significantly different between the groups. Intubation was significantly shorter in the infants receiving succinylcholine. Premedication with succinylcholine and atropine will facilitate intubation of neonates, and ameliorate the adverse physiologic consequences of this procedure.


A conserved Swi2/Snf2 ATPase motif couples ATP hydrolysis to chromatin remodeling.
Yeast (Saccharomyces cerevisiae) SWI/SNF is a prototype for a large family of ATP-dependent chromatin-remodeling enzymes that facilitate numerous DNA-mediated processes. Swi2/Snf2 is the catalytic subunit of SWI/SNF, and it is the founding member of a novel subfamily of the SF2 superfamily of DNA helicase/ATPases. Here we present a functional analysis of the diagnostic set of helicase/ATPase sequence motifs found within all Swi2p/Snf2p family members. Whereas many of these motifs play key roles in ATP binding and/or hydrolysis, we identify residues within conserved motif V that are specifically required to couple ATP hydrolysis to chromatin-remodeling activity. Interestingly, motif V of the human Swi2p/Snf2p homolog, Brg1p, has been shown to be a possible hot spot for mutational alterations associated with cancers.


Clinical outcomes and prognostic factors in triple-negative invasive lobular carcinoma of the breast.
Triple-negative invasive lobular carcinoma (TN-ILC) of breast cancer is a rare disease and the clinical outcomes and prognostic factors are not well-defined. Women with stage I-III TN-ILC or triple-negative invasive ductal carcinoma (TN-IDC) of the breast undergoing mastectomy or breast-conserving surgery between 2010 and 2018 in the National Cancer Database were included. Kaplan-Meier curves and multivariate Cox proportional hazard regression were used to compare overall survival (OS) and evaluate prognostic factors. Multivariate logistic regression was performed to analyze the factors associated with pathological response to neoadjuvant chemotherapy. The median age at diagnosis for women with TN-ILC was 67 years compared to 58 years in TN-IDC (p < 0.001). There was no significant difference in the OS between TN-ILC and TN-IDC in multivariate analysis (HR 0.96, p = 0.44). Black race and higher TNM stage were associated with worse OS, whereas receipt of chemotherapy or radiation was associated with better OS in TN-ILC. Among women with TN-ILC receiving neoadjuvant chemotherapy, the 5-year OS was 77.3% in women with a complete pathological response (pCR) compared to 39.8% in women without any response. The odds of achieving pCR following neoadjuvant chemotherapy were significantly lower in women with TN-ILC compared to TN-IDC (OR 0.53, p < 0.001). Women with TN-ILC are older at diagnosis but have similar OS compared to TN-IDC after adjusting for tumor and demographic characteristics. Administration of chemotherapy was associated with improved OS in TN-ILC, but women with TN-ILC were less likely to achieve complete response to neoadjuvant therapy compared to TN-IDC.


Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure.
The pathophysiologic and potential therapeutic role of selectins in renal ischemia-reperfusion injury (IRI) is not fully understood, due in part to redundancy in the roles of individual selectins. We hypothesized that blockade of ligands for all three selectins using a novel small molecule (TBC-1269) would improve the course of renal IRI by overcoming redundancy issues. This was investigated in a rat model of renal IRI. Rats were treated with TBC-1269 either during or post-IRI. The effects of TBC-1269 were investigated in two models of renal IRI: moderate IRI (30 minutes bilateral renal artery clamping) and severe IRI (45 minutes clamping). The combination of anti-E- and anti-P-selectin antibodies also was investigated in rats subjected to moderate IRI. Renal function, histological injury and mortality were assessed. Rats treated with TBC-1269 during moderate IRI showed significantly reduced serum creatinine (SCr) and tubular necrosis post-ischemia compared to control animals. By contrast, delayed treatment (post-IRI) did not show a reduction in SCr. In rats with severe IRI, TBC-1269 treatment during IRI significantly reduced mortality at 48 hours post-ischemia. Rats with moderate IRI and treated with the combination of anti-E- and anti-P-selectin antibodies showed significantly reduced SCr compared to control rats at 24 hours post-ischemia. Small molecule selectin ligand inhibition provides a novel and effective approach to attenuate ischemic acute renal failure. Timing of treatment is crucial to success.


Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention.
Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases. With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (complex I) induce isolated complex I deficiency and Leigh syndrome. This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA-encoded NDUFS4 gene, encoding the NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4) of complex I, induce 'mitochondrial complex I deficiency, nuclear type 1' (MC1DN1) and Leigh syndrome in paediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the Leigh syndrome pathomechanism and intervention testing. Here, we review and discuss the role of complex I and NDUFS4 mutations in human mitochondrial disease, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/Leigh syndrome pathomechanism and its therapeutic targeting.


Young children who abandon error behaviourally still have to free themselves mentally: a retrospective test for inhibition in intuitive physics.
When preschoolers overcome persistent error, subsequent patterns of correct choices may identify how the error had been overcome. Children who no longer misrepresented a ball rolling down a bent tube as though it could only fall vertically, were asked sometimes to approach and sometimes to avoid where the ball landed. All children showed requisite task-switching flexibility. The pattern of 4-year-olds' correct choices among different places showed unnecessary avoidance of any place that would previously have tempted them into a vertical-approach error, 5-year-olds rebounded into a reversal, and 7-year-olds were flexible. The data attest to an inhibition mechanism, ruling out competing possibilities.


Induced endothelial cells from peripheral arterial disease patients and neonatal fibroblasts have comparable angiogenic properties.
Induced endothelial cells (iECs) generated from neonatal fibroblasts via transdifferentiation have been shown to have pro-angiogenic properties and are a potential therapy for peripheral arterial disease (PAD). It is unknown if iECs can be generated from fibroblasts collected from PAD patients and whether these cells are pro-angiogenic. In this study fibroblasts were collected from four PAD patients undergoing carotid endarterectomies. These cells, and neonatal fibroblasts, were transdifferentiated into iECs using modified mRNA. Endothelial phenotype and pro-angiogenic cytokine secretion were investigated. NOD-SCID mice underwent surgery to induce hindlimb ischaemia in a murine model of PAD. Mice received intramuscular injections with either control vehicle, or 1 × 106 neonatal-derived or 1 × 106 patient-derived iECs. Recovery in perfusion to the affected limb was measured using laser Doppler scanning. Perfusion recovery was enhanced in mice treated with neonatal-derived iECs and in two of the three patient-derived iEC lines investigated in vivo. Patient-derived iECs can be successfully generated from PAD patients and for specific patients display comparable pro-angiogenic properties to neonatal-derived iECs.


Making non-drug interventions easier to find and use.
Patients with heart failure are often anxious about any exertion as it brings on the shortness of breath that characterises their condition. But exercise for heart failure appears to be as good as the medications we use, and may be better for symptoms and quality of life. The 10 year follow up of an Italian randomised trial found that patients allocated to supervised exercise had significantly better quality of life, and around a one-third reduction in hospital readmission and cardiac mortality. A Cochrane review of shorter term studies supports these overall findings. Despite this, exercise for heart failure appears to be underprescribed, but also getting the 'prescription' correct - dose, duration, monitoring - is not straightforward. A non-pharmacopeia might be helpful.


Cloning and characterization of SRP1, a suppressor of temperature-sensitive RNA polymerase I mutations, in Saccharomyces cerevisiae.
The SRP1-1 mutation is an allele-specific dominant suppressor of temperature-sensitive mutations in the zinc-binding domain of the A190 subunit of Saccharomyces cerevisiae RNA polymerase I (Pol I). We found that it also suppresses temperature-sensitive mutations in the zinc-binding domain of the Pol I A135 subunit. This domain had been suggested to be in physical proximity to the A190 zinc-binding domain. We have cloned the SRP1 gene and determined its nucleotide sequence. The gene encodes a protein of 542 amino acids consisting of three domains: the central domain, which is composed of eight (degenerate) 42-amino-acid contiguous tandem repeats, and the surrounding N-terminal and C-terminal domains, both of which contain clusters of acidic and basic amino acids and are very hydrophilic. The mutational alteration (P219Q) responsible for the suppression was found to be in the central domain. Using antibody against the SRP1 protein, we have found that SRP1 is mainly localized at the periphery of the nucleus, apparently more concentrated in certain regions, as suggested by a punctate pattern in immunofluorescence microscopy. We suggest that SRP1 is a component of a larger macromolecular complex associated with the nuclear envelope and interacts with Pol I either directly or indirectly through other components in the structure containing SRP1.


[Use of the indirect hemagglutination test for the study of ornithosis. Report 2. Preparation and approbation of the dry ornithosis erythrocyte diagnostic agent].
An original preparation--dry ornithosis erythrocytic diagnostic agent for the indirect hemagglutination test was prepared on the basis of formalinized tannin-treated sheep red blood cells and group-specific phospholipid antigen of the causative agent of ornithosis. This diagnostic agent retained its specific activity for 18 months (observation period). The use of this preparation considerably facilitated the method of performance of this test, this offering a possibility of its wide application in practice. A sufficiently high sensitivity and specificity of the indirect hemagglutination test with the suggested diagnostic agent, in comparison with the complement fixation test was demonstrated.


Advantages of having a lateralized brain.
Brain lateralization is common among vertebrates. However, despite its implications for higher-order cognitive functions, almost no empirical evidence has been provided to show that it may confer any advantage to the functioning of the brain. Here, we show in the domestic chick (Gallus gallus domesticus) that cerebral lateralization is associated with an enhanced ability to perform two tasks simultaneously: finding food and being vigilant for predators. This finding suggests that cerebral lateralization enhances brain efficiency in cognitive tasks that demand the simultaneous but different use of both hemispheres.


A prosencephalic neuronal circuit possibly involved in modulation of pain.
Both anatomical and physiological studies in cats substantiated the existence of a thalamus-cortex-thalamus neuronal circuit in which neurons in the centre median send fibers to wide areas of the cerebral cortex and the cerebral cortex, the motor cortex in particular, may send the fibers back to the parafascicular nucleus. The cortical neurons concerned tend to discharge spontaneously and constantly. These spontaneous discharges can be readily inhibited by the corticopetal impulses from the centre median, which itself can be activated by general afferent impulses. On the basis of this observation it is assumed that constantly discharging corticothalamic neurons may exert a tonic excitatory influence on the pain-receiving center, parafascicular nucleus, so as to keep it in a state of constant alertness to the tissue-damaging danger signals and that the inhibitory action of the ascending fibers from centre median would serve to suspend the excitatory action of the cortex on the parafascicular nucleus, resulting in relief of pain. The corticofugal fibers in this forebrain circuit terminating in the centromedian nucleus may reinforce the inhibitory action of the centromedian neurons so as to inhibit the spontaneous discharges of the cortical neurons . A self-regulating mechanism is thus formed by which a stabilized state of brain excitability can be maintained.


Remote Access Therapy for Veterans With Psychological Problems: Current State of the Art.
The past decade has seen both an increase in use and research into ways in which psychological therapy might be delivered remotely. Remote access therapy uses technology to deliver talking therapies. It is important to understand how remote technologies are being used as part of the therapeutic process and consider what effect this has on the success of therapeutic interventions. This review discusses what is currently known about the use of remote access therapy with a veteran population. Moreover, the review summarizes potential benefits and barriers to conducting therapy remotely. This review was conducted to explore the use of remote access therapies with veterans. All available literature identified for this review focused on veteran cohorts from the US and UK. To meet search criteria, studies had to include veteran participants engaging with any form of talking therapy delivered remotely. A total of 15 studies met the inclusion criteria: two from the UK and 13 from the US. Searches were carried out during June and July 2019. A number of potential benefits to remote therapy delivery were observed in the research reviewed, including improved accessibility to therapy for people living in remote locations (providing infrastructure existed to facilitate the remote access technologies), increased flexibility of timing, and being able to undergo therapy alongside other life commitments. The studies also suggested that those involved in remote therapy found the technology accessible and easy to operate. Digital technologies could generally be relied upon and although there were some technical difficulties reported that these were generally not seen as a barrier to the use of remote technologies as a whole. Some limitations to using remote therapies were observed, such as the acceptability of remote therapy, particularly in the UK, and the willingness of practitioners to engage with digital technologies to facilitate remote therapy. There was also caution raised that the apparent cost effectiveness of delivering therapy remotely needs to be further investigated, particularly in relation to costs involved in enabling remote access technologies in locations where poor infrastructure exists. Overall, studies reported largely positive outcomes for veterans undergoing remote access therapy and in general participants did not find the therapeutic process compromised by remote delivery. Studies showed that remote access therapy is being conducted successfully in both the US and UK. There is, however, a need for more research into the use of remote access therapies to treat a wider range of psychological difficulties in veterans.


Characterization of the TGN exit signal of the human mannose 6-phosphate uncovering enzyme.
The human mannose 6-phosphate uncovering enzyme participates in the uncovering of the mannose 6-phosphate recognition tag on lysosomal enzymes, a process that facilitates recognition of those enzymes by mannose 6-phosphate receptors to ensure delivery to lysosomes. Uncovering enzyme has been identified on the trans-Golgi network at steady state. It has been shown to traffic to the plasma membrane from where it is rapidly internalized via endosomal structures, the process being mediated by a tyrosine-based internalization motif, Y488HPL, in its cytoplasmic tail. Using immunogold electron microscopy a GFP-uncovering enzyme fusion construct was found to be colocalized with the cation-dependent mannose 6-phosphate receptor in regions of the trans-Golgi network, suggesting that uncovering enzyme might follow a similar pathway of exit from the trans-Golgi network as that of the cation-dependent mannose 6-phosphate receptor. In this study, we identified the signal sequence in the cytoplasmic tail of uncovering enzyme responsible for its exit from the trans-Golgi network. Using GFP fusion constructs of the transmembrane and cytoplasmic domains of uncovering enzyme, we could show, by automated analysis of confocal immunofluorescence images, that residues Q492EMN in the cytoplasmic tail of uncovering enzyme are involved in its exit from the trans-Golgi network. Detailed characterization of the exit signal revealed that residue Q492 is the most important to the exit function while M494 and N495 also contribute. The cytoplasmic tail of the uncovering enzyme does not possess any of the known canonical signal sequences for interaction with Golgi-associated gamma ear-containing adaptor proteins. The identification of a trans-Golgi network exit signal in its cytoplasmic tail elucidates the trafficking pathway of uncovering enzyme, a crucial player in the process of lysosomal biogenesis.


Neurosteroid enhances glutamate release in rat prelimbic cortex via activation of alpha1-adrenergic and sigma1 receptors.
The present paper studied the effect and mechanism of neurosteroid pregnenolone sulfate (PREGS) on spontaneous glutamate release using electrophysiological and biochemical methods combined with a pharmacological approach. The results suggested that PREGS had a selective enhancing effect on spontaneous glutamate release in the prelimbic cortex and the hippocampus but not in the striatum. The effect of PREGS in the prelimbic cortex appeared to be via modulation of alpha1-adrenergic and sigma1 receptors, but in the hippocampus it might be dependent on sigma1 receptors only. The activation of alpha1-adrenergic receptors synergized sigma1 receptor activation in the prelimbic cortex. Intracellular calcium released from the endoplasmic reticulum, protein kinase C, adenylyl cyclase and protein kinase A played a key role in the effect of PREGS. Intracellular calcium, protein kinase C and adenylyl cyclase might be upstream events in the activation of protein kinase A after PREGS.


Expression of the alpha4 isoform of the nicotinic acetylcholine receptor in the fetal human cerebral cortex.
Nicotinic acetylcholine receptors are likely to play an important role in neuronal migration during development. Furthermore, the alpha4 receptor subunit gene is related to a hereditary juvenile form of epilepsy. Only little information is available, however, on the expression of cerebrocortical nicotinic acetylcholine receptors during human fetal development. Using non-isotopic in situ hybridization and immunohistochemistry, we have studied the distribution of the alpha4 subunit of the nicotinic acetylcholine receptor mRNA and protein in the human frontal cortex at middle (17-24 weeks of gestation) and late (34-42 weeks of gestation) fetal stages. Both, alpha4 receptor mRNA and alpha4 receptor protein were observed beginning during week 17-18 of gestation. At this time of development, a few weakly labeled mRNA-containing cells were present mainly in the ventricular zone, the subplate and the cortical plate. A similar distribution pattern was found for the receptor protein. Around week 38 of gestation, the distribution in the cerebral cortex of alpha4 subunit-containing cells was similar to that of adult human cortices with the highest densities of labeled neurons found in layers II/III, followed by layers V and VI. Nicotinic acetylcholine receptor-containing neurons appear rather early in human fetal development. Given functional maturity, they may interact during cortical development with acetylcholine released from corticopetal fibers or other yet unknown sources subserving the process of neuronal migration and pathfinding.


Amyotrophic lateral sclerosis: Correlations between fluid biomarkers of NfL, TDP-43, and tau, and clinical characteristics.
We previously reported the diagnostic and prognostic performance of neurofilament light chain (NfL), TAR DNA-binding protein 43 (TDP-43), and total tau (t-tau) in cerebrospinal fluid (CSF) and plasma as amyotrophic lateral sclerosis (ALS) biomarkers. The present study aimed to elucidate associations between clinical characteristics and the markers as well as mutual associations of the markers in ALS patients using the same dataset. NfL, TDP-43, and t-tau levels in CSF and plasma in 75 ALS patients were analyzed. The associations between those markers and clinical details were investigated by uni- and multivariate analyses. Correlations between the markers were analyzed univariately. In multivariate analysis of CSF proteins, the disease progression rate (DPR) was positively correlated with NfL (β: 0.51, p = 0.007) and t-tau (β: 0.37, p = 0.03). Plasma NfL was correlated with age (β: 0.53, p = 0.005) and diagnostic grade (β: -0.42, p = 0.02) in multivariate analysis. Plasma TDP-43 was correlated negatively with split hand index (β: -0.48, p = 0.04) and positively with % vital capacity (β: 0.64, p = 0.03) in multivariate analysis. Regarding mutual biomarker analysis, a negative correlation between CSF-NfL and TDP-43 was identified (r: -0.36, p = 0.002). Elevated NfL and t-tau levels in CSF may be biomarkers to predict rapid DPR from onset to sample collection. The negative relationship between CSF NfL and TDP-43 suggests that elevation of CSF TDP-43 in ALS is not a simple consequence of its release into CSF during neurodegeneration. The negative correlation between plasma TDP-43 and split hand index may support the pathophysiological association between plasma TDP-43 and ALS.


Thyrotropin-stimulated recruitment of free monoribosomes on to membrane-bound thyroglobulin-synthesizing polyribosomes.
Treatment of ox and dog thyroid slices in vitro with either thyrotropin or dibutyryl cyclic AMP elicited a variety of changes in polyribosome distribution. The most marked and consistent responses were decreases in both free and membrane-bound monoribosomes with a concomitant increase in the specific peak of thyroglobulin-synthesizing polyribosomes. On some occasions there was a shift towards heavier aggregates in the free polyribosomes. The increase in the amount of thyroglobulin-synthesizing polyribosomes was not accompanied by a shift in its location on the gradients. These changes were apparent within 30 min of thyrotropin addition and within 60 min of the addition of dibutyryl cyclic AMP. It is suggested that the major initial effect on translation of both thyrotropin and dibutyryl cyclic AMP is to stimulate the recruitment of pre-existing free monoribosomes on to pre-existing unloaded or under-loaded thyroglobulin mRNA molecules.


Evaluation of similar dietary roughage equivalency fed to beef steers during the growing and finishing phase.
The objective of this experiment was to determine the influence that similar dietary roughage equivalency offered in a single or two-diet system during a 210-d growing-finishing period has on growth performance, the efficiency of dietary net energy (NE) utilization, and carcass traits in beef steers. Beef steers (n = 46; initial shrunk [4%]; body weight [BW] = 281 ± 40.4 kg) were fed once daily, and bunks were managed according to a slick bunk management system across all 10 pens. Treatments included the following: 1) A single diet program that was formulated to provide 16% (dry matter [DM] basis) dietary roughage equivalency; SD) or 2) multiple diet programs (formulated to provide a dietary roughage equivalency (DM basis) of 25% for 98 d, 16% for 14 d, and 7% for 98 d; MD). Day 1 to 112 was considered the growing period, and day 113 to 210 (the day of harvest) was considered the finishing period, all steers were implanted on day 1 with a 100 mg trenbolone acetate (TBA) and 14 mg estradiol benzoate (EB) implant and implanted with a 200 mg TBA and 28 mg EB implant on day 112. Average daily gain tended (P = 0.06) to be 9.5% greater for SD compared to MD during the growing portion, and average daily gain (ADG) was greater by 11.3% (P = 0.01) for MD compared to SD during the finishing phase of the experiment. Cumulative ADG did not differ (P ≥ 0.86) between treatments (1.61 vs. 1.62 ± 0.046 kg) for SD and MD, respectively. Cumulative dietary NEm and NEg calculated based on performance did not differ (P ≥ 0.96) between treatments. There were no differences (P ≥ 0.18) detected between treatments for hot carcass weight, dressing percent, longissimus muscle area, rib fat, United States Department of Agriculture (USDA) marbling score, kidney, pelvic, heart fat, yield grade, retail yield, empty body fat, or body weight at 28% estimated empty body fat. These data indicate that feedlot producers can feed a single growing-finishing diet to beef steers with minimal effects on overall growth performance or carcass traits.


Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
Few studies have been conducted to compare the efficacies of stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA). Thus, in this multinational study, we compared the effectiveness of SBRT and RFA in patients with unresectable HCC. The retrospective study cohort included 2,064 patients treated in 7 hospitals: 1,568 and 496 in the RFA and SBRT groups, respectively. More than half of the patients (56.5%) developed recurrent tumors, mainly after transarterial chemoembolization (44.8%). Propensity score matching was performed to adjust for clinical factors (n = 313 in each group). At baseline, the SBRT group had unfavorable clinical features compared to the RFA group, including BCLC stage (B-C 65% vs. 16%), tumor size (median 3.0 cm vs. 1.9 cm), and frequent history of liver-directed treatment (81% vs. 49%, all p <0.001). With a median follow-up of 27.7 months, the 3-year cumulative local recurrence rates in the SBRT and RFA groups were 21.2% and 27.9%, respectively (p <0.001). After adjusting for clinical factors, SBRT was related to a significantly lower risk of local recurrence than RFA in both the entire (hazard ratio [HR] 0.45, p <0.001) and matched (HR 0.36, p <0.001) cohorts. In subgroup analysis, SBRT was associated with superior local control in small tumors (≤3 cm) irrespective of location, large tumors located in the subphrenic region, and those that progressed after transarterial chemoembolization. Acute grade ≥3 toxicities occurred in 1.6% and 2.6% of the SBRT and RFA patients, respectively (p = 0.268). SBRT could be an effective alternative to RFA for unresectable HCC, particularly for larger tumors (>3 cm) in a subphrenic location and tumors that have progressed after transarterial chemoembolization. It is currently not known what the best treatment option is for patients with unresectable hepatocellular carcinoma. Here, we show that stereotactic body radiation therapy provides better local control than radiofrequency ablation, with comparable toxicities. Stereotactic body radiation therapy appears to be an effective alternative to radiofrequency ablation that should be considered when there is a higher risk of local recurrence or toxicity after radiofrequency ablation.


Implementation of Automated Blood Culture With Quality Assurance in a Resource-Limited Setting.
Background: Blood cultures (BC) have a high clinical relevance and are a priority specimen for surveillance of antimicrobial resistance. Manual BC are still most frequently used in resource-limited settings. Data on automated BC performance in Africa are scarce. We implemented automated BC at a surveillance site of the African Network for improved Diagnostics, Epidemiology and Management of Common Infectious Agents (ANDEMIA). Methods: Between June 2017 and January 2018, pairs of automated BC (BacT/ALERT®FA Plus) and manual BC (brain-heart infusion broth) were compared at a University hospital in Bouaké, Côte d'Ivoire. BC were inoculated each with a target blood volume of 10 ml from the same venipuncture. Automated BC were incubated for up to 5 days, manual BC for up to 10 days. Terminal subcultures were performed for manual BC only. The two systems were compared regarding yield, contamination, and turnaround time. For quality assurance, isolates were retested in a German routine microbiological laboratory. Results: BC sampling was increased from on average 24 BC to 63 BC per month. A total of 337 matched pairs of BC were included. Automated BC was positive in 36.5%, manual BC in 24.0% (p-value < 0.01), proportion of contamination was 47.9 and 43.8%, respectively (p-value = 1.0). Turnaround time of positive BC was shortened by 2.5 days with automated compared to manual BC (p < 0.01). Most common detected pathogens in both systems were Klebsiella spp. (26.0%) and Staphylococcus aureus (18.2%). Most contaminants were members of the skin flora. Retesting of 162 isolates was concordant in 79.6% on family level. Conclusions: Implementing automated BC in a resource-limited setting is possible and improves microbiological diagnostic performance. Automated BC increased yield and shortened turnaround times. Regular training and mentorship of clinicians has to be intensified to increase number and quality of BC. Pre-analytical training to improve diagnostic stewardship is essential when implementing a new microbiological method. Retesting highlighted that manual identification and antimicrobial susceptibility testing can be of good quality and sustainable. The implementation of automated tools should be decided individually according to economic considerations, number of samples, stable supply chain of consumables, and technical sustainability.


Effects of thymopoietin pentapeptide (TP-5) on in vitro and in vivo IgE production by atopic dermatitis cell subsets.
Atopic dermatitis (AD) patients exhibit multiple immune abnormalities, including T-cell defects that may be partially correctable by the administration of thymic hormones. Our investigations confirmed that peripheral blood mononuclear leukocytes obtained from patients with AD spontaneously synthesized markedly elevated amounts of IgE in vitro. The thymic hormone thymopoietin pentapeptide (TP-5) greatly inhibited this synthesis. An antihuman pan-T cell monoclonal antibody (Lyt3) was used to separate T-cell marker-positive (T+) T cells from marker-negative (T-) B-enriched cells. TP-5 pretreatment of T+ cells resulted in significant reduction of in vitro IgE synthesis by recombined T+ and T- cells, whereas pretreatment of T- B-enriched cells resulted in a nonsignificant reduction in in vitro IgE synthesis. Thus, although pretreatment of both subsets resulted in some degree of reduction, TP-5-induced inhibition of in vitro IgE synthesis was primarily mediated via T cells. The majority of patients' untreated T+ and T4+ cells showed enhanced IgE synthesis, but only one patient's T8+ cells were capable of suppressing IgE synthesis. Thus TP-5 may either induce suppressor T-cell activity or reduce helper T-cell activity. A six-week double-blind clinical trial of TP-5 produced evidence of clinical improvement and alterations of abnormalities of OKT8+ cells, although no significant effects on serum IgE were seen.


Gastrointestinal stromal tumor of unusual phenotype after imatinib treatment: A case report and diagnostic utility of ETV1 mRNA in situ hybridization.
Gastrointestinal stromal tumor (GIST) is the most common tumor of mesenchymal origin in gastrointestinal tract. Immunohistochemical (IHC) staining combined with a typical morphology is used for the diagnosis of GIST. Typically, IHC staining for v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene (KIT) and discovered on GIST-1(DOG1) is positive in almost all GISTs. However, imatinib mesylate, a specific inhibitor of KIT tyrosine kinase, frequently involves changes in the morphology and IHC staining of GIST, impeding the diagnosis. Recently, in situ hybridization (ISH) for E26 transformation-specific sequence variant 1 (ETV1) mRNA was introduced as a useful marker to diagnose GIST. We report 2 cases of gastric GIST, which expressed unusual phenotypes after imatinib therapy. The first patient was found to have a gastric subepithelial tumor in gastroduodenoscopy done for regular checkup. In biopsy of the tumor, it showed homogenous spindle cells that were positive to standard IHC markers for GIST. The second patient visited our hospital because of a palpable mass in the abdomen. In abdominal computed tomography (CT), a tumor arising from the stomach was found. A needle biopsy was done and the patient was diagnosed of gastric GIST because the biopsy showed spindle cells positive to typical IHC markers for GIST. After imatinib treatment, in both patients, the resected tumors were composed of heterogeneous spindle cells negative to KIT, DOG1, and CD34 IHC staining, which was unusual for GIST. However, ISH for ETV1 mRNA done for both biopsied and resected tumors was positive, even after imatinib treatment. A molecular analysis found a mutation in exon 11 of KIT gene before and after imatinib therapy in both patients, confirming the diagnosis of GIST. Both patients took neoadjuvant imatinib treatment, and afterwards, underwent a surgical resection. The patients remain on imatinib treatment and no progression or recurrence has been detected to date. ISH for ETV1 mRNA is a useful technique in diagnosing GIST when IHC with KIT, DOG1, or CD34 fail to stain positive after imatinib therapy.


Impact of the First SARS-CoV-2 Lockdown on Adherence to Biological Treatment in Patients with Immune-Mediated Inflammatory Diseases in the Netherlands.
During the SARS-CoV-2 pandemic, national and international societies have recommended continuing biological agents in patients with immune-mediated inflammatory diseases (IMID) in the absence of SARS-CoV-2 symptoms. However, adherence to biological treatment might decrease, because these recommendations contradict patients' beliefs. Especially an increased concern about side effects could have influenced the adherence to biological treatment during the first lockdown. The primary objective was to investigate the impact of the first SARS-CoV-2 lockdown on adherence to biological treatment in IMID patients. In this prospective cohort study, IMID patients who received a biological agent before and during the first SARS-CoV-2 lockdown (March 2020- June 2020) were included. Patients were excluded if they did not complete the medication adherence report scale-5 (MARS-5) questionnaire at ≥1 visit before the lockdown and ≥1 visit during the lockdown. Adherence to biological treatment was measured with the MARS-5 and Medication Possession Ratio (MPR). We included 157 IMID patients. The percentage of adherent patients, defined as MARS-5 score >21, was significantly lower during the lockdown compared to the period before the lockdown (88.5% vs 84.1%, p<0.001). Additionally, the overall percentage of adherent patients during the lockdown based on the MPR ≥90% was significantly lower compared to adherence based upon the MARS-5 (65.1% vs 84.1%, p<0.001). This study showed that the first SARS-CoV-2 lockdown negatively impacts adherence to biological treatment in IMID patients. Therefore, treating physicians should be aware of this problem to minimize the potential harmful effects of non-adherence.


Increased erythropoietin levels as a biomarker of pancreatic adenocarcinoma: A case report.
Pancreatic cancer is one of the deadliest cancers commonly diagnosed at an advanced stage. Early diagnosis is crucial for the timely and potentially curative treatment of this highly fatal disease. Although screening tests have improved the survival rate in malignancies such as colon, breast, cervical and prostate cancer, there is currently no effective screening method available for the early detection of pancreatic cancer. As the sensitivity and specificity of existing biomarkers, such as carbohydrate antigen 19-9, for the early detection of pancreatic cancer is low, there is a pressing need for the identification of novel cancer markers. An increase in erythropoietin (EPO) levels has been observed in several cases of pancreatic neoplasms. However, the potential role of EPO as a biomarker of pancreatic cancer or malignant transformation requires further investigation. We herein present a case of increased EPO levels in an adult male patient with stage IV pancreatic cancer.


Wsp1 is downstream of Cin1 and regulates vesicle transport and actin cytoskeleton as an effector of Cdc42 and Rac1 in Cryptococcus neoformans.
Human Wiskott-Aldrich syndrome protein (WASP) is a scaffold linking upstream signals to the actin cytoskeleton. In response to intersectin ITSN1 and Rho GTPase Cdc42, WASP activates the Arp2/3 complex to promote actin polymerization. The human pathogen Cryptococcus neoformans contains the ITSN1 homolog Cin1 and the WASP homolog Wsp1, which share more homology with human proteins than those of other fungi. Here we demonstrate that Cin1, Cdc42/Rac1, and Wsp1 function in an effector pathway similar to that of mammalian models. In the cin1 mutant, expression of the autoactivated Wsp1-B-GBD allele partially suppressed the mutant defect in endocytosis, and expression of the constitutively active CDC42(Q61L) allele restored normal actin cytoskeleton structures. Similar phenotypic suppression can be obtained by the expression of a Cdc42-green fluorescent protein (GFP)-Wsp1 fusion protein. In addition, Rac1, which was found to exhibit a role in early endocytosis, activates Wsp1 to regulate vacuole fusion. Rac1 interacted with Wsp1 and depended on Wsp1 for its vacuolar membrane localization. Expression of the Wsp1-B-GBD allele restored vacuolar membrane fusion in the rac1 mutant. Collectively, our studies suggest novel ways in which this pathogenic fungus has adapted conserved signaling pathways to control vesicle transport and actin organization, likely benefiting survival within infected hosts.


Enhanced alcohol self-administration and reinstatement in a highly impulsive, inattentive recombinant inbred mouse strain.
Deficits in executive control have frequently been associated with alcohol use disorder. Here we investigated to what extent pre-existing genetically encoded levels of impulsive/inattentive behavior associate with motivation to take alcohol and vulnerability to cue-induced reinstatement of alcohol seeking in an operant self-administration paradigm. We took advantage of BXD16, a recombinant inbred strain previously shown to have enhanced impulsivity and poor attentional control. We compared BXD16 with C57BL/6J mice in a simple choice reaction time task (SCRTT) and confirmed its impulsive/inattentive phenotype. BXD16 mice were less active in a novel open field (OF), and were equally active in an automated home cage environment, showing that increased impulsive responding of BXD16 mice could not be explained by enhanced general activity compared to C57BL/6J mice. After training in a sucrose/alcohol fading self-administration procedure, BXD16 showed increased motivation to earn 10% alcohol solution, both under fixed ratio (FR1) and progressive ratio (PR2) schedules of reinforcement. Responding on the active lever readily decreased during extinction training with no apparent differences between strains. However, upon re-exposure to alcohol-associated cues, alcohol seeking was reinstated to a larger extent in BXD16 than in C57BL/6J mice. Although further studies are needed to determine whether impulsivity/inattention and alcohol seeking depend on common or separate genetic loci, these data show that in mice enhanced impulsivity coincides with increased motivation to take alcohol, as well as relapse vulnerability.


The Solanum pimpinellifolium Cf-ECP1 and Cf-ECP4 genes for resistance to Cladosporium fulvum are located at the Milky Way locus on the short arm of chromosome 1.
The interaction between tomato and the leaf mould pathogen Cladosporium fulvum is an excellent model to study gene-for-gene interactions and plant disease resistance gene evolution. Most Cf genes were introgressed into cultivated tomato (Solanum lycopersicum) from wild relatives such as S. pimpinellifolium and novel Cf-ECP genes were recently identified in this species. Our objective is to isolate Cf-ECP1, Cf-ECP2, Cf-ECP4 and Cf-ECP5 to increase our understanding of Cf gene evolution, and the molecular basis for recognition specificity in Cf proteins. The map locations of Cf-ECP2 and Cf-ECP5 have been reported previously and we report here that Cf-ECP1 and Cf-ECP4 map to a different locus on the short arm of chromosome 1. The analysis of selected recombinants and allelism tests showed both genes are located at Milky Way together with Cf-9 and Cf-4. Our results emphasise the importance of this locus in generating novel Cf genes for resistance to C. fulvum. Candidate genes for Cf-ECP1 and Cf-ECP4 were also identified by DNA gel blot analysis of bulked segregant pools. In addition, we generated functional cassettes for expression of the C. fulvum ECP1, ECP2, ECP4 and ECP5 proteins using recombinant Potato Virus X, and three ECPs were also expressed in stable transformed plants. Using marker-assisted selection we have also identified recombinants containing Cf-ECP1, Cf-ECP2, Cf-ECP4 or Cf-ECP5 in cis with a linked T-DNA carrying the non-autonomous Zea mays transposon Dissociation. Using these resources it should now be possible to isolate all four Cf-ECPs using transposon tagging, or a candidate gene strategy.


Overexpression of the prostaglandin E2 receptor EP2 results in enhanced skin tumor development.
We previously showed that the EP2 knockout mice were resistant to chemically induced skin carcinogenesis. The purpose of this study was to investigate the role of the overexpression of the EP2 receptor in mouse skin carcinogenesis. To determine the effect of overexpression of EP2, we used EP2 transgenic (TG) mice and wild-type (WT) mice in a DMBA (7,12-dimethylbenz[alpha]anthracene)/TPA (12-O-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis protocol. EP2 TG mice developed significantly more tumors compared with WT mice. Overexpression of the EP2 receptor increased TPA-induced keratinocyte proliferation both in vivo and in vitro. In addition, the epidermis of EP2 TG mice 48 h after topical TPA treatment was significantly thicker compared to that of WT mice. EP2 TG mice showed significantly increased cyclic adenosine monophosphate levels in the epidermis after prostaglandin E2 (PGE2) treatment. The inflammatory response to TPA was increased in EP2 TG mice, as demonstrated by an increased number of macrophages in the dermis. Tumors and 7 x TPA-treated and DMBA-TPA-treated (6 weeks) skins from EP2 TG mice produced more blood vessels than those of WT mice as determined by CD-31 immunostaining. Vascular endothelial growth factor (VEGF) protein expression was significantly increased in squamous cell carcinoma (SCC) samples from EP2 TG mice compared that of WT mice. There was, however, no difference in the number of apoptotic cells in tumors from WT and EP2 TG mice. Together, our results suggest that the overexpression of the EP2 receptor plays a significant role in the protumorigenic action of PGE2 in mouse skin.


Case Report: CD19 CAR T-cell therapy following autologous stem cell transplantation: a successful treatment for R/R CD20-negative transformed follicular lymphoma with TP53 mutation.
Follicular lymphoma (FL), a common indolent B-cell lymphoma, has the potential to transform into an aggressive lymphoma, such as diffuse large B-cell lymphoma (DLBCL). The outcome of patients with transformed follicular lymphoma (tFL) is poor, especially in patients with transformed lymphoma after chemotherapy and patients with progression within 24 months (POD24). Chimeric antigen receptor (CAR) T-cell therapy combined with autologous stem cell transplantation (ASCT) has promising antitumor efficacy. Here, we described a 39-year-old male patient who was initially diagnosed with FL that transformed into DLBCL with POD24, CD20 negativity, TP53 mutation, and a bulky mass after 3 lines of therapy, all of which were adverse prognostic factors. We applied a combination approach: CD19 CAR T-cell infusion following ASCT. Ibrutinib was administered continuously to enhance efficacy, DHAP was administered as a salvage chemotherapy, and ICE was administered as a bridging regimen. The patient underwent BEAM conditioning on days -7~ -1, a total of 3.8 × 106/kg CD34+ stem cells were infused on days 01~02, and a total of 108 CAR T cells (relmacabtagene autoleucel, relma-cel, JWCAR029) were infused on day 03. The patient experienced grade 2 cytokine release syndrome (CRS), manifesting as fever and hypotension according to institutional standards. There was no immune effector cell-associated neurotoxicity syndrome (ICANS) after CAR T-cell infusion. Finally, the patient achieved CMR at +1 month, which has been maintained without any other adverse effects. This case highlights the amazing efficacy of CD19 CAR T-cell therapy following ASCT for R/R tFL, thus providing new insight on therapeutic strategies for the future.


The N-terminal region of CXCL11 as structural template for CXCR3 molecular recognition: synthesis, conformational analysis, and binding studies.
The chemokines and their receptors play a key role in immune and inflammatory responses by promoting recruitment and activation of different subpopulations of leukocytes. The membrane receptor CXCR3 binds three chemokines, CXCL9, CXCL10, and CXCL11, and its involvement is recognized in many inflammatory diseases and cancers. Therefore, the inhibition of CXCR3 pathway through interactions with three ligands was indicated as putative therapeutic target for the treatment of these diseases, and some inhibitory compounds have already been described in the literature. Recently, we studied the interaction between CXCR3 and its three natural ligands and showed that three CXCR3 ligands bound the receptor mainly by their N-terminal regions using aromatic and electrostatic interactions, and, in particular, CXCL11 had the highest affinity for CXCR3. In light of these results, we focused our attention on what structural region(s) of CXCL11 interacted with CXCR3 and what were the structural features. Therefore, we have synthesized three peptides, corresponding to the N-terminal region of CXCL11, but with different aromatic amino acids, analyzed their conformations by circular dichroism, NMR, and molecular dynamics simulations, simulated their complexes with CXCR3 by docking methods, and validated these data by in vitro studies. The results showed that two peptides were able to bind CXCR3 and to mimic the molecular recognition of CXCL11 and demonstrated that N-terminal region of CXCL11 can be used as template and starting point to obtain new molecules by de novo design approaches.


PDTC inhibits picornavirus polyprotein processing and RNA replication by transporting zinc ions into cells.
Previously, it was shown that pyrrolidine dithiocarbamate (PDTC) inhibits proteolytic polyprotein processing and replication of human rhinovirus by transporting metal ions into cells. Here, it is shown that PDTC also inhibits replication of two other picornaviruses: coxsackievirus B3 (CVB3), a closely related virus that belongs to the genus Enterovirus, and mengovirus, an encephalomyocarditis virus strain that belongs to the genus Cardiovirus, and that this inhibition is due to the dithiocarbamate moiety of the compound. Making use of subgenomic replicons, evidence is provided that PDTC inhibits replication of these two viruses by disturbing viral RNA synthesis. Furthermore, it is shown that PDTC transports zinc ions into cells and that these zinc ions play an important role in the antiviral activity mediated by PDTC. Finally, it is shown that PDTC interferes with proteolytic processing of the polyproteins of both CVB3 and mengovirus, but that the underlying mechanism between these two viruses differs. In CVB3-infected cells, PDTC interferes strongly with the proteolytic activity of 3CD(pro), as shown by the impaired production of the mature capsid proteins as well as the autocleavage of 3CD(pro) into 3C(pro) and 3D(pol). In mengovirus-infected cells, however, PDTC had no effect on the proteolytic production of capsid proteins or the autocleavage of 3CD(pro). Instead, PDTC caused the accumulation of a high-molecular-mass precursor protein, due to an impairment in the primary 'break' that normally occurs at the 2A-2B junction. Thus, PDTC disturbs polyprotein processing and replication of two groups of picornaviruses, enteroviruses and cardioviruses, but the underlying mechanism is different.


Early dental intervention in the Redpath Ptolemaic Theban Male.
A computed tomography study of the remains of a Ptolemaic male mummy from Thebes (RM2718; 350-60 BCE), one of three ancient Egyptian human mummies curated at McGill University's Redpath Museum, demonstrates the packing of a large interproximal carious lesion with a protective linen barrier. The dental packing described here is unique among ancient Egyptian mummies studied to date, and represents one of only a few recorded dental interventions in ancient Egypt. Such a finding lends further support for the existence of a group of dental specialists practicing interventional medicine in ancient Egypt. While the physical evidence, to date for other interventions, may be scarce, the findings presented here should underline the need to continue to look for evidence of dental packing as well as other therapeutic dental interventions in the ancient world.


Psychological Science within a Three-Dimensional Ontology.
The present paper outlines the nature of a three-dimensional ontology and the place of psychological science within this ontology, in a way that is partly similar to and partly different from that of Pérez-Álvarez. The first dimension is the material realities, and involves different levels (physical, chemical, biological, psychological, etc.), where each level builds on a lower level but also involves the development of new emergent properties, in accordance with Bunge's emergent materialism. Each level involves systems, with components, structures and mechanisms, and an environment. This dimension can be studied with natural scientific methods. The second dimension is the subjective-experiential realities, and refers to our subjective perspective on the world. In accordance with Husserl's phenomenology, it is argued that this subjectivity does not exist in the world (i.e., should not be reified as an object among other objects), but represents a perspective on the world that we enter in our capacity as conscious human beings. Essential characteristics of this subjectivity (such as intentionality, temporality, embodiment, and intersubjectivity) can be explored by phenomenological methods. The third dimension is the social-constructional realities, and includes social institutions, norms, categories, theories, and techniques. It is argued that psychological science spans over all three dimensions. Although almost all psychological research by necessity starts from a problem formulation where the subjective-experiential dimension plays an essential role (either explicitly or implicitly), most of present-day psychological research clearly emphasizes the material dimension. It is argued that a mature psychological science needs to integrate all three dimensions.


Corticosteroid and platelet-rich plasma injection therapy in tennis elbow (lateral epicondylalgia): a survey of current U.K. specialist practice and a call for clinical guidelines.
Tennis elbow is a common condition with a variety of treatment options, but little is known about which of these options specialists choose most commonly. Corticosteroid injections in tennis elbow may reduce pain in the short-term but delay long-term recovery. We have undertaken a UK-wide survey of upper limb specialists to assess current practice. Cross-sectional electronic survey of current members of the British Elbow and Shoulder Society (BESS) and the British Society for Surgery of the Hand (BSSH). 271 of 1047 eligible members responded (25.9%); consultant surgeons constituted the largest group (232/271, 85%). 131 respondents (48%) use corticosteroid injections as their first-line treatment for tennis elbow. 206 respondents (77%) believed that corticosteroid injections are not potentially harmful in the treatment of tennis elbow, while 31 (11%) did not use them in their current practice. In light of recent evidence of the potential harmful effects of corticosteroid therapy, 136 (50%) had not changed their practice while 108 (40.1%) had reduced or discontinued their use. 43 respondents (16%) reported having used platelet-rich plasma injections. Recent high-quality evidence that corticosteroids may delay recovery in tennis elbow appears to have had a limited effect on current practice. Treatment is not uniform among specialists and a proportion of them use platelet-rich plasma injections.


Liquid biopsy by NGS: differential presence of exons (DPE) in cell-free DNA reveals different patterns in metastatic and nonmetastatic colorectal cancer.
Next-generation sequencing (NGS) has been proposed as a suitable tool for liquid biopsy in colorectal cancer (CRC), although most studies to date have focused almost exclusively on sequencing of panels of potential clinically actionable genes. We evaluated the clinical value of whole-exome sequencing (WES) of cell-free DNA (cfDNA) circulating in plasma, with the goal of identifying differential clinical profiles in patients with CRC. To this end, we applied an original concept, "differential presence of exons" (DPE). We determined differences in levels of 379 exons in plasma cfDNA and used DPE analysis to cluster and classify patients with disseminated and localized disease. The resultant bioinformatics analysis pipeline allowed us to design a predictive DPE algorithm in a small subset of patients that could not be initially classified based on the selection criteria. This DPE suggests that these nucleic acids could be actively released by both tumor and nontumor cells as a means of intercellular communication and might thus play a role in the process of malignant transformation. DPE is a new technique for the study of plasma cfDNA by WES that might have predictive and prognostic value in patients with CRC.


Pest management programmes in vineyards using male mating disruption.
Israeli vine growers have been reluctant to adopt the mating disruption technique for control of the European vine moth, Lobesia botrana Den. & Schiff. Since the chemically controlled honeydew moth, Cryptoblabes gnidiella Mill., coexists with the European vine moth, growers have maintained that the use of mating disruption would fail to bring about a significant reduction in pesticide use. In this study, the efficacy of mating disruption techniques against C. gnidiella was tested, as well as the effect of these methods on pesticide use and damage to clusters when the method was employed against both of the pests in wine grapes. Comparisons were made between plots treated with (1) L. botrana mating disruption pheromone, (2) L. botrana and C. gnidiella mating disruption pheromones and (3) control plots. A significant difference in the number of clusters infested with the developmental stages of the moths was seen between pheromone-treated plots and controls, while no such difference was observed between plots treated with one versus two pheromones. A similar pattern was observed in the number of insecticide applications; the greatest number of applications was used in control plots, followed by plots treated with L. botrana mating disruption pheromone and by plots treated with pheromones against both pests, in which no pesticides were applied.


Surgery for mitral valvar disease in childhood: should we choose reconstruction or repair?
Modern surgical techniques now offer the potential for reconstructing rather than replacing the mitral valve in those patients who require an operation during childhood. The purpose of this study was to assess the outcome in our centre following mitral valvar surgery in children. Between 1992 and 2002, 51 consecutive children, with a mean age of 12.5 +/- 3.5 years, underwent surgical treatment of mitral valvar stenosis and/or insufficiency in the Cardiovascular Surgical Department of Istanbul University. Of the children, 20 underwent repair, whilst we replaced the valve in 31 patients. In one, we inserted a pulmonary valvar autograft in mitral position. There were neither early nor late deaths in those who underwent mitral valvar repair. Similarly, there were no early deaths in those in whom the valve was replaced, but two patients died late, while six outgrew their prosthetic valves and required insertion of a further valve within 10 years of their first operations. Our experience shows that procedures designed to repair the mitral valve are effective and reliable when performed in children, with low mortality, and a lower incidence of reoperation when compared with those having replacement of the mitral valve.


WHAT IS THE FUNDAMENTAL NATURE OF PATHOLOGIC MYOPIA?
Despite being a major cause of visual impairment worldwide, pathologic myopia has not been clearly and consistently defined. This lack of a standardized definition has made comparisons among epidemiological studies difficult. Therefore, the purpose of this review was to summarize the definitions of pathologic myopia. A literature search was conducted of Pubmed to identify reports presenting definitions of pathologic myopia. Although cut-off values for refractive error and increased axial length have been used in some studies, a definition based solely on such values is considered to just show a 'high degree of myopia'. Similarly, the presence of myopic fundus lesions in addition to a high degree of myopia has been used to define pathologic myopia; however, such lesions often develop with age and they are not characteristic of pathologic myopia. So, what is pathologic myopia? This review covers the various proposed definitions for pathologic myopia, and describes its major features such as posterior staphyloma, variation in axial length, and the presence of myopic maculopathy. Some unanswered questions that serve as signposts to areas of interest for future research have also been discussed.


Adaptive Capacities and Complexity of Heart Rate Variability in Patients With Chronic Obstructive Pulmonary Disease Throughout Pulmonary Rehabilitation.
The complexity of bio-signals, like R-R intervals, is considered a reflection of the organism's capacity to adapt. However, this association still remains to be consolidated. We investigated whether the complexity of R-R intervals at rest and during perturbation [6-minute walking test (6MWT)], yielded information regarding adaptive capacities in Chronic Obstructive Pulmonary Disease (COPD) patients during pulmonary rehabilitation (PR). In total, 23 COPD patients (64 ± 8 years, with forced expiratory volume in 1 s of 55 ± 19% predicted) were tested three times at the start (T1), middle (T2), and end (T3) of 4 weeks PR. Each time, R-R intervals were measured at rest and during 6MWT. The complexity of R-R intervals was assessed by evenly spaced Detrended Fluctuations Analysis and evaluated by the fractal exponent α and deviation from maximal complexity |1-α|. The 6MWT distance was significantly increased at T2 and T3 compared to T1. Neither α nor |1-α| at rest and during perturbation significantly changed throughout PR, nor were they consistently associated with 6MWT distances at each time. Throughout the PR program, complexity during the 6MWT was significantly lower compared to the rest. The level of α during 6MWT at T1 was positively correlated with the improvement of the 6MWT distance throughout the PR program. Reduced complexity in COPD patients during acute perturbation at the beginning of PR supports a decreased improvement of the 6MWT distance throughout PR. This result seems consistent with the notion that the complexity reflects the patients' adaptive capacities and could therefore become a clinical indicator in an applied perspective.


Reproduction of influenza viruses; quantitative investigations with particle enumeration procedures on the dynamics of influenza A and B virus reproduction.
Influenza A and B virus reproduction in the allantoic membrane of the intact chicken embryo was studied quantitatively with particle enumeration procedures. Virus particles were enumerated on the basis of two independent properties; capacity to infect and to cause hemagglutination. The infective property of influenza B virus (Lee) was even more unstable than that of influenza A virus (PR8). Inactivation occurred at a constant logarithmic rate which was independent of the concentration of particles and corresponded with first order reaction kinetics. In allantoic fluid at 35 degrees C. either in vitro or in vivo, Lee virus had a half-life for infectivity of only 85 minutes. In contrast, the hemagglutinating property, like that of PR8, was relatively stable and was not appreciably affected by 12 hours at 35 degrees C. On the basis that the number of non-infective particles is equal to the number of hemagglutinating particles minus the number of infective particles and that the number of cells lining the allnatoic membrane is 1.8 x 10(7), the effects of various particle-cell ratios on the reproductive process were analyzed. Adsorption of infective and non-infective Lee particles occurred at the same logarithmic rate, i.e. about 50 per cent in 72 minutes, and the rate was nearly independent of the particle-cell ratio up to a value of 55. The adsorption capacity of an allantoic cell was at least 44 Lee or 89 PR8 particles. The interval before new particles appeared in the allantoic fluid increased as the particle-cell ratio was decreased with both Lee and PR8. At ratios of 0.2 or less, the appearance time for infective particles was nearly identical to that for hemagglutinating particles with both viruses. At ratios of about 1.0, the "latent period" in the allantoic membrane per se was computed to be 150 to 160 minutes for both Lee and PR8. The number of particles, both infective and hemagglutinating, increased at a constant logarithmic rate for 6 hours or more after the adsorptive period. With Lee virus, at a particle-cell ratio of 5 or less, the doubling time was constant and had a value of 43 minutes. The dynamics of the logarithmic increase period suggest that reproduction corresponds to an autocatalytic reaction in which the rate is proportional to the amount of material produced. When the particle-cell ratio was increased to 10 or more, either with infective or non-infective (inactivated at 35 degrees C. or 22 degrees C.) particles, the doubling time increased to 65 minutes. Comparable effects from high ratios were found with PR8. Non-infective particles accumulated at a rapid rate after the interval of constant logarithmic increase regardless of the particle-cell ratio. This accumulation was even more striking with Lee than with PR8 as was expected because of the shorter half-life of the infective property. With both viruses at particle-cell ratios of 4 or more, a large proportion of the particles were non-infective within a few hours after new particles appeared. At particle-cell ratios of 0.2 or less, the maximal yield was relatively constant, i.e., about 900 to 1400 hemagglutinating particles per cell with Lee and 500 to 900 with PR8. However, even with very low ratios, i.e. 0.001 or less, it was not possible to obtain more than about 160 infective particles per cell with either virus regardless of the interval. As was expected, the lower the ratio, the longer was the interval before maximal yields were produced. At ratios of about 10, the maximal yield was reduced by 50 per cent or more with both viruses. Comparable reductions in yield were obtained whether the high particle-cell ratio was due to infective or non-infective (inactivated at 35 degrees C. or 22 degrees C.) particles. These findings indicate that there is a critical particle-cell ratio above which alterations appear in the dynamics of reproduction of influenza viruses. This ratio has a value of approximately 3. The observed alterations in the reproductive process are discussed in relation to the hypothesis that adsorption of 3 or more infective or non-infective particles per cell induces cell damage.


Chemically modified carbon nanostructures and 2D nanomaterials for fabrics performing under operational tension and extreme environmental conditions.
The extensive research on carbon nanostructures and 2D nanomaterials will come to fruition once these materials steadily join everyday-life applications. Their chemical functionalization unlocks their potential as carriers of customized properties and counterparts to fabric fibers. The scope of the current review covers the chemical modification of carbon nanostructures and 2D nanomaterials for hybrid fabrics with enhanced qualities against critical operational and weather conditions, such as antibacterial, flame retardant, UV resistant, water repellent and high air and water vapor permeability activities.


Event frequency modulates the processing of daily life activities in human medial prefrontal cortex.
Event sequence knowledge is necessary to learn, plan, and perform activities of daily life. Clinical observations suggest that the prefrontal cortex (PFC) is crucial for goal-directed behavior such as carrying out plans, controlling a course of actions, or organizing everyday life routines. Functional neuroimaging studies provide further evidence that the PFC is involved in processing event sequence knowledge, with the medial PFC (Brodmann area 10) primarily engaged in mediating predictable event sequences. However, the exact role of the medial PFC in processing event sequence knowledge depending on the frequency of corresponding daily life activities remains obscure. We used event-related functional magnetic resonance imaging while healthy volunteers judged whether event sequences from high- (HF), moderate- (MF), and low-frequency (LF) daily life activities were correctly ordered. The results demonstrated that different medial PFC subregions were activated depending on frequency. The anterior medial Area 10 was differentially activated for LF and the posterior medial Area 10 for HF activities. We conclude that subregions of the medial PFC are differentially engaged in processing event sequence knowledge depending on how often the activity was reportedly performed in daily life.