Resonance phenomenon for the Galerkin-truncated Burgers and Euler equations.
It is shown that the solutions of inviscid hydrodynamical equations with suppression of all spatial Fourier modes having wave numbers in excess of a threshold K(G) exhibit unexpected features. The study is carried out for both the one-dimensional Burgers equation and the two-dimensional incompressible Euler equation. For large K(G) and smooth initial conditions, the first symptom of truncation, a localized short-wavelength oscillation which we call a "tyger," is caused by a resonant interaction between fluid particle motion and truncation waves generated by small-scale features (shocks, layers with strong vorticity gradients, etc.). These tygers appear when complex-space singularities come within one Galerkin wavelength λ(G)=2π/K(G) from the real domain and typically arise far away from preexisting small-scale structures at locations whose velocities match that of such structures. Tygers are weak and strongly localized at first-in the Burgers case at the time of appearance of the first shock their amplitudes and widths are proportional to K(G)(-2/3) and K(G)(-1/3), respectively-but grow and eventually invade the whole flow. They are thus the first manifestations of the thermalization predicted by T. D. Lee [Q. J. Appl. Math. 10, 69 (1952)]. The sudden dissipative anomaly-the presence of a finite dissipation in the limit of vanishing viscosity after a finite time t(⋆)-which is well known for the Burgers equation and sometimes conjectured for the three-dimensional Euler equation, has as counterpart, in the truncated case, the ability of tygers to store a finite amount of energy in the limit K(G)→∞. This leads to Reynolds stresses acting on scales larger than the Galerkin wavelength and thus prevents the flow from converging to the inviscid-limit solution. There are indications that it may eventually be possible to purge the tygers and thereby to recover the correct inviscid-limit behavior.


Active suppression of early immune response in tobacco by the human pathogen Salmonella Typhimurium.
The persistence of enteric pathogens on plants has been studied extensively, mainly due to the potential hazard of human pathogens such as Salmonella enterica being able to invade and survive in/on plants. Factors involved in the interactions between enteric bacteria and plants have been identified and consequently it was hypothesized that plants may be vectors or alternative hosts for enteric pathogens. To survive, endophytic bacteria have to escape the plant immune systems, which function at different levels through the plant-bacteria interactions. To understand how S. enterica survives endophyticaly we conducted a detailed analysis on its ability to elicit or evade the plant immune response. The models of this study were Nicotiana tabacum plants and cells suspension exposed to S. enterica serovar Typhimurium. The plant immune response was analyzed by looking at tissue damage and by testing oxidative burst and pH changes. It was found that S. Typhimurium did not promote disease symptoms in the contaminated plants. Live S. Typhimurium did not trigger the production of an oxidative burst and pH changes by the plant cells, while heat killed or chloramphenicol treated S. Typhimurium and purified LPS of Salmonella were significant elicitors, indicating that S. Typhimurium actively suppress the plant response. By looking at the plant response to mutants defective in virulence factors we showed that the suppression depends on secreted factors. Deletion of invA reduced the ability of S. Typhimurium to suppress oxidative burst and pH changes, indicating that a functional SPI1 TTSS is required for the suppression. This study demonstrates that plant colonization by S. Typhimurium is indeed an active process. S. Typhimurium utilizes adaptive strategies of altering innate plant perception systems to improve its fitness in the plant habitat. All together these results suggest a complex mechanism for perception of S. Typhimurium by plants.


Multidrug resistance-1 (MDR1) expression and functional dye/drug efflux is highly correlated with the t(8;21) chromosomal translocation in pediatric acute myeloid leukemia.
Resistance to chemotherapy is a major problem in acute myeloid leukemia (AML). An important resistance mechanism in adult AML is active drug efflux mediated by the multidrug resistance protein-1 (MDR1). To determine if MDR1 is important in childhood AML, we examined MDR1 expression and functional dye/drug efflux in 20 pediatric/adolescent AML patients; results were correlated with cytogenetics and clinical outcome. Using flow cytometry, MDR1 protein expression on the leukemic blasts was measured with the antibody MRK16, while efflux was measured by extrusion of the fluorescent dye DiO(C2)3 in the presence/absence of cyclosporin A (CsA). Six of 20 cases expressed MDR1. While all six MDR1+ cases were efflux+, three of 14 MDR1- cases also demonstrated efflux. Both MDR1 and efflux were strongly correlated with the t(8;21). All six MDR1 +/efflux+ cases and 2/3 MDR1 -/efflux+ cases had a t(8;21), while no MDR1-/efflux- cases had a t(8;21) (P < 0.0005). This correlation between MDR1, efflux, and the t(8;21) in pediatric AML was not found in 11 adult t(8;21) cases similarly studied. Although the clinical relevance of MDR1 in pediatric AML awaits larger studies, our results suggest a biologic subset of pediatric AML patients may benefit from regimens which include MDR1-reversing agents or non-MDR1 substrates.


Inhibition of Bacillus anthracis growth and virulence-gene expression by inhibitors of quorum-sensing.
Density-dependent gene expression, quorum sensing (QS), involves the synthesis and detection of low-molecular-weight molecules known as autoinducers. Inhibitors of bacterial QS systems offer potential treatment of infections with highly virulent or multidrug-resistant agents. We studied the effects on Bacillus anthracis growth and the virulence gene (pagA, lef, and cya) expression of the QS inhibitor (5Z)-4-bromo-5-(bromomethylene)-3-butyl-2(5H)-furanone, which is naturally synthesized by the marine alga Delisea pulchra, as well as a related compound and synthetic derivatives. Growth of B. anthracis Sterne strain was substantially reduced in the presence of each furanone in a dose-dependent manner. When furanones were added to midlog-phase cultures of B. anthracis strains with LacZ reporters in pagA, lef, or cya, growth was inhibited, and expression of these virulence genes was inhibited to a proportionately greater extent. These data suggest that use of QS inhibitors could represent novel therapies for anthrax.


Low tumor cell content predicts favorable prognosis in germinoma patients.
Germinoma preferentially occurs in pediatric and young adult age groups. Although they are responsive to treatment with chemotherapy and radiation, the treatment may cause long-term sequelae in their later lives. Here, we searched for clinical and histopathological features to predict the prognosis of germinoma and affect treatment response. A total of 114 germinoma cases were included in the analysis. We investigated the association between clinical factors, tumor cell content, and progression-free survival (PFS). The tumor cell content was widely distributed from <5% to 90% in the specimens, with a median value of 50%. Female patients showed higher tumor cell content in the specimens (P = .002). Cases with lesions at atypical sites showed shorter PFS than those with lesions at other sites (P = .03). Patients with a higher tumor cell content (≥50%) showed shorter PFS than those with a lower tumor cell content (<50%) (P = .03). In multivariate analysis, tumor cell content was the only statistically significant prognostic factor (P = .04). Among the 7 cases treated with local radiation and chemotherapy, all 3 cases that recurred (2 outside of the radiation field, 1 unknown) had tumor cell content of ≥50% in the original specimen, whereas all 4 cases without recurrence had tumor cell contents of <50%. We found that tumor cell content significantly affected the prognosis of germinomas. Although validation of these results using an independent and larger cohort is necessary, this potentially opens the possibility of leveraging this pathological factor in future clinical trials when stratifying the treatment intensity.


Alcohol dehydrogenase polymorphism in the seaweed fly, Coelopa frigida.
Seaweed flies (Coelopa frigida) inhabit piles of decaying seaweed on the seashore. All populations so far studied have been found to be polymorphic at the alcohol dehydrogenase locus (Adh). This article reports an attempt to identify some of the forces of natural selection that may be maintaining this polymorphism First, the genetic determination of the rather complex isozyme system is described. Several inbred lines homozygous at the Adh locus were derived and the biochemical properties of their allozymes compared. Significant differences in both specific activities and thermal stabilities were found between ADH allozymes. A simple experiment is reported in which individuals with different Adh genotypes were cultured in competition with each other in the presence of elevated levels of ethanol. Although the presence of ethanol resulted in greater mortality, there is no evidence that it was selective with respect to the Adh genotypes. The possible relevance of these results to the maintenance of the Adh polymorphism is discussed.


Effect of lipopolysaccharide on mitogen-activated protein kinases and cytosolic phospholipase A2.
The addition of platelet-activating factor (PAF) to human neutrophils increases phosphorylation on tyrosine residues and stimulates the activity of p42erk2 mitogen-activated protein kinase (MAP kinase). This action is rapid and transient. In contrast, p42erk2, p44erk1 and the p40hera MAP kinase isoforms are all not tyrosine phosphorylated or activated in human neutrophils stimulated with low concentrations of lipopolysaccharide (LPS) in combination with serum. In spite of this, the PAF-induced tyrosine phosphorylation and activation of the p42erk2 MAP kinase are greatly potentiated in cells pretreated with LPS. More interestingly, although low concentrations of LPS do not affect MAP kinase isoforms in these cells, they cause the phosphorylation of cytosolic phospholipase A2 (cPLA2), as evidenced by a decrease in the electrophoretic mobility of the enzyme. In addition, this stimulus-induced upward shift in the mobility of the enzyme is not inhibited by the tyrosine kinase inhibitor, genistein. Furthermore, LPS increases the release of arachidonic acid in control and PAF-stimulated human neutrophils. These observations clearly show that cPLA2 can be phosphorylated and activated by kinases other than the currently known MAP kinases. It is proposed that there are MAP kinase-dependent and -independent mechanisms for the phosphorylation of cPLA2.


S100B in schizophrenia: an update.
Recent research has supported a potential role of immune pathology in the etiopathogenesis of schizophrenic. In the CNS various viruses were identified in the brains of schizophrenic patients. Pro-inflammatory cytokines were found to be associated with the stage of disease. Microglial cells were reported to be activated in a subgroup of schizophrenic patients in post mortem as well as imaging studies. New research has demonstrated that astrocytes together with microglial cells are the major immunocompetent cells of the brain and play an important role in the regulation of neuronal proliferation and differentiation. S100B, a calcium binding astrocyte-specific cytokine, presents a marker of astrocytic activation. Scientific evidence for increased S100B in acute schizophrenia is very consistent. The picture is not as clear regarding schizophrenia subtypes in acute states but patients with persistent negative symptoms or deficit syndrome show constant high S100B concentrations. There is an association between high S100B and poor therapeutic response. The increased S100B concentrations appear to be functionally relevant since they are reflected by poor cognitive performance and cross validation with other methods make it unlikely that the findings are merely an epiphenomenon. These findings suggest that the activation of astrocytes might be an important pathogenic factor for the development of schizophrenia.


Hypervascular floor of mouth tumor: Rare presentation of oral cavity squamous cell carcinoma.
Oral squamous cell carcinoma (OSCC) is the most common malignancy affecting the oral cavity and commonly presents as an exophytic lesion with red or white granular ulcerations. Most diagnoses are confirmed by biopsy and clinical features; however, early SCC has been shown to hide within benign appearing lesions, such as vascular tumors, resulting in missed diagnoses and delay in treatment. The following case report will discuss a patient who presented with a mass in the floor of the mouth which appeared as a vascular tumor on exam and imaging. This was originally thought to be benign based on FNA findings however was found to harbor invasive squamous cell carcinoma on final pathology. The goal of this case report is to provide a background on the variable presentations of OSCC, vascular tumors, and uncommon presentations for which specialists should be aware of in their practice.


Overcoming the Gas-Liquid Mass Transfer of Oxygen by Coupling Photosynthetic Water Oxidation with Biocatalytic Oxyfunctionalization.
Gas-liquid mass transfer of gaseous reactants is a major limitation for high space-time yields, especially for O2 -dependent (bio)catalytic reactions in aqueous solutions. Herein, oxygenic photosynthesis was used for homogeneous O2 supply via in situ generation in the liquid phase to overcome this limitation. The phototrophic cyanobacterium Synechocystis sp. PCC6803 was engineered to synthesize the alkane monooxygenase AlkBGT from Pseudomonas putida GPo1. With light, but without external addition of O2 , the chemo- and regioselective hydroxylation of nonanoic acid methyl ester to ω-hydroxynonanoic acid methyl ester was driven by O2 generated through photosynthetic water oxidation. Photosynthesis also delivered the necessary reduction equivalents to regenerate the Fe2+ center in AlkB for oxygen transfer to the terminal methyl group. The in situ coupling of oxygenic photosynthesis to O2 -transferring enzymes now enables the design of fast hydrocarbon oxyfunctionalization reactions.


First principles computational study on the electrochemical stability of Pt-Co nanocatalysts.
Using density functional theory (DFT) calculations, we identify the thermodynamically stable configurations of Pt-Co alloy nanoparticles of varying Co compositions and particle sizes. Our results indicate that the most thermodynamically stable structure is a shell-by-shell configuration where the Pt atom only shell and the Co only shell alternately stack and the outermost shell consists of a Pt skin layer. DFT calculations show that the structure has substantially higher dissolution potential of the outermost Pt shell compared with pure Pt nanoparticles of approximately the same size. Furthermore, our DFT calculations also propose that the shell-by-shell structure shows much better oxygen reduction reaction (ORR) activity than conventional bulk or nanoparticles of pure Pt. These novel catalyst properties can be changed when the surfaces are adsorbed with oxygen atoms via selective segregation followed by the electrochemical dissolution of the alloyed Co atoms. However, these phenomena are thermodynamically not plausible if the chemical potentials of oxygen are controlled below a certain level. Therefore, we propose that the shell-by-shell structures are promising candidates for highly functional catalysts in fuel cell applications.


A sympathetic neuron autonomous role for Egr3-mediated gene regulation in dendrite morphogenesis and target tissue innervation.
Egr3 is a nerve growth factor (NGF)-induced transcriptional regulator that is essential for normal sympathetic nervous system development. Mice lacking Egr3 in the germline have sympathetic target tissue innervation abnormalities and physiologic sympathetic dysfunction similar to humans with dysautonomia. However, since Egr3 is widely expressed and has pleiotropic function, it has not been clear whether it has a role within sympathetic neurons and if so, what target genes it regulates to facilitate target tissue innervation. Here, we show that Egr3 expression within sympathetic neurons is required for their normal innervation since isolated sympathetic neurons lacking Egr3 have neurite outgrowth abnormalities when treated with NGF and mice with sympathetic neuron-restricted Egr3 ablation have target tissue innervation abnormalities similar to mice lacking Egr3 in all tissues. Microarray analysis performed on sympathetic neurons identified many target genes deregulated in the absence of Egr3, with some of the most significantly deregulated genes having roles in axonogenesis, dendritogenesis, and axon guidance. Using a novel genetic technique to visualize axons and dendrites in a subpopulation of randomly labeled sympathetic neurons, we found that Egr3 has an essential role in regulating sympathetic neuron dendrite morphology and terminal axon branching, but not in regulating sympathetic axon guidance to their targets. Together, these results indicate that Egr3 has a sympathetic neuron autonomous role in sympathetic nervous system development that involves modulating downstream target genes affecting the outgrowth and branching of sympathetic neuron dendrites and axons.


Identifying clinical trials in the medical literature with electronic databases: MEDLINE alone is not enough.
The objective of this study was to compare the performance of MEDLINE and EMBASE for the identification of articles regarding controlled clinical trials (CCTs) published in English and related to selected topics: rheumatoid arthritis (RA), osteoporosis (OP), and low back pain (LBP). MEDLINE and EMBASE were searched for literature published in 1988 and 1994. The initial selection of papers was then reviewed to confirm that the articles were about CCTs and to assess the quality of the studies. Selected journals were also hand searched to identify CCTs not retrieved by either database. Overall, 4111 different references were retrieved (2253 for RA, 978 for OP, and 880 for LBP); 3418 (83%) of the papers were in English. EMBASE retrieved 78% more references than MEDLINE (2895 versus 1625). Overall, 1217 (30%) of the papers were retrieved by both databases. Two hundred forty-three papers were about CCTs. Two-thirds of these were retrieved by both databases, and one-third by only one. An additional 16 CCTs not retrieved by either database were identified through hand searching. Taking these into account, EMBASE retrieved 16% more CCTs than MEDLINE (220 versus 188); the EMBASE search identified 85% of the CCTs compared to 73% by MEDLINE. No significant differences were observed in the mean quality scores and sample size of the CCTs missed by MEDLINE compared to those missed by EMBASE. Our findings suggest that the use of MEDLINE alone to identify CCTs is inadequate. The use of two or more databases and hand searching of selected journals are needed to perform a comprehensive search.


Efficient Application of Continuous Fractional Component Monte Carlo in the Reaction Ensemble.
A new formulation of the Reaction Ensemble Monte Carlo technique (RxMC) combined with the Continuous Fractional Component Monte Carlo method is presented. This method is denoted by serial Rx/CFC. The key ingredient is that fractional molecules of either reactants or reaction products are present and that chemical reactions always involve fractional molecules. Serial Rx/CFC has the following advantages compared to other approaches: (1) One directly obtains chemical potentials of all reactants and reaction products. Obtained chemical potentials can be used directly as an independent check to ensure that chemical equilibrium is achieved. (2) Independent biasing is applied to the fractional molecules of reactants and reaction products. Therefore, the efficiency of the algorithm is significantly increased, compared to the other approaches. (3) Changes in the maximum scaling parameter of intermolecular interactions can be chosen differently for reactants and reaction products. (4) The number of fractional molecules is reduced. As a proof of principle, our method is tested for Lennard-Jones systems at various pressures and for various chemical reactions. Excellent agreement was found both for average densities and equilibrium mixture compositions computed using serial Rx/CFC, RxMC/CFCMC previously introduced by Rosch and Maginn (Journal of Chemical Theory and Computation, 2011, 7, 269-279), and the conventional RxMC approach. The serial Rx/CFC approach is also tested for the reaction of ammonia synthesis at various temperatures and pressures. Excellent agreement was found between results obtained from serial Rx/CFC, experimental results from literature, and thermodynamic modeling using the Peng-Robinson equation of state. The efficiency of reaction trial moves is improved by a factor of 2 to 3 (depending on the system) compared to the RxMC/CFCMC formulation by Rosch and Maginn.


Dietary patterns are related to cognitive functioning in elderly enriched with individuals at increased risk for Alzheimer's disease.
To investigate cross-sectional associations between dietary patterns and cognitive functioning in elderly free of dementia. Data of 389 participants from the German DELCODE study (52% female, 69 ± 6 years, mean Mini Mental State Score 29 ± 1) were included. The sample was enriched with elderly at increased risk for Alzheimer's disease (AD) by including participants with subjective cognitive decline, mild cognitive impairment (MCI) and siblings of AD patients. Mediterranean and MIND diets were derived from 148 Food Frequency Questionnaire items, and data-driven patterns by principal component analysis (PCA) of 39 food groups. Associations between dietary patterns and five cognitive domain scores were analyzed with linear regression analyses adjusted for demographics (model 1), and additionally for energy intake, BMI, other lifestyle variables and APOe4-status (model 2). For PCA-derived dietary components, final model 3 included all other dietary components. In fully adjusted models, adherence to Mediterranean and MIND diet was associated with better memory. The 'alcoholic beverages' PCA component was positively associated with most cognitive domains. Exclusion of MCI subjects (n = 60) revealed that Mediterranean and MIND diet were also related to language functions; associations with the alcoholic beverages component were attenuated, but most remained significant. In line with data from elderly population samples, Mediterranean and MIND diet and some data-derived dietary patterns were related to memory and language function. Longitudinal data are needed to draw conclusions on the putative effect of nutrition on the rate of cognitive decline, and on the potential of dietary interventions in groups at increased risk for AD.


Transcriptomic and photosynthetic responses to grafting of the Nod1 gene in nodulated and non-nodulated soybeans.
Legume plants form symbiotic relationships with rhizobia to convert N2 into ammonia, and the nodulation status can affect plant development including photosynthesis. However, the relationship between nitrogen fixation and photosynthesis during carbon and nitrogen metabolism remains unclear. This study was undertaken to unravel regulation of nodulation and photosynthesis using a spontaneous nonnodulated soybean mutant by grafting. The results of inheritance and gene mapping showed that the nonnodulated mutant was controlled by a recessive gene overlapped with the reported rj1 locus, and might be a new rj1 allele with 1 bp deletion in the fourth exon in comparison to the sequence of normal nodulation plants. According to grafting results, soybean nodulation is obviously determined by the roots, not the seedlings. Moreover, nitrogen content along with related metabolic enzyme activity, and photosynthetic capacity were enhanced by nonnodulated scions grafted with nodulated roots. Contrary results were obtained for nodulated scions grafted with nonnodulated roots. A total of 853 differentially expressed genes (DEGs) in the leaves and 1874 in the roots were identified by transcriptome analyses of the grafting treatments. We identified 285 differential gene ontology (GO) terms and 57 differential pathway terms identified in the leaves, while 856 differential GO terms and 207 differential pathway terms in the roots. Twenty DEGs interacting at translation level were selected, and the results of transcriptome analyses were verified by q-PCR. These findings indicated that the nodulation-related Nod allelic gene increases the nitrogen content of nonnodulated plants, which affects the enzymes involved in nitrogen metabolism, leading to changes in hormone levels and further regulation of photosynthesis and carbon metabolism.


Size distribution and lung-deposition of ambient particulate matter oxidative potential: A contrast between dithiothreitol and ascorbic acid assays.
Particulate matter (PM) inhaled into human lungs causes oxidative stress and adverse health effects through antioxidant depletion (oxidative potential, OP). However, there is limited knowledge regarding the association between the lung-deposited dose (LDD) of PM and OP in extrathoracic (ET), tracheobronchial (TB), and pulmonary (P) regions of human lungs. Dithiothreitol (DTT) and ascorbic acid (AA) assays were employed to measure the OP of PM size fractions to investigate OP distribution in human lungs and identify the chemical drivers. Quasi-ultrafine particles (quasi-UFP, ≤0.49 μm) exhibited high OP deposition in the TB and P regions, while coarse particles (CP, ≥3.0 μm) dominated in the ET region. A plot of extrinsic (per air volume) and intrinsic (per PM mass) OP versus LDD revealed that the OP for fine and coarse particles was greatest in the ET region, whereas the OP of quasi-UFP was greatest in alveoli. The study also demonstrated that extrinsic OP and PM doses are not strongly related. The decline in OP with increasing PM dose reveals the need for further investigation of the antagonistic effects of the chemical compositions. Overall, the results presented herein help address the gap in knowledge regarding the association between the OP and LDD of ambient particles in specific regions of human lungs.


Differences in age-independent effects of blood pressure on baroreflex sensitivity between normal and hypertensive subjects.
Inter-relationship between age, systolic blood pressure and baroreflex sensitivity index derived from the Valsalva manoeuvre was investigated in either combined or separated groups of normal and hypertensive subjects. Both in the total population as a whole and in each blood pressure subgroup, the baroreflex sensitivity index was significantly inversely related to age and to systolic blood pressure. Furthermore, age was significantly related to systolic blood pressure except in the hypertensive group. Partial correlation analysis showed that, in the total and hypertensive population, the baroreflex sensitivity index was significantly related to age and systolic blood pressure independently of each other variable. In the normal group, however, the baroreflex sensitivity index was not related to systolic blood pressure after adjusting for the effect of age, but remained significantly related to age independently of systolic blood pressure. The estimates of relative effects of the two variables on baroreflex sensitivity by multiple regression analysis were consistent with these results. Thus a prevailing concept of the inhibitory effect of blood pressure on baroreflex function may be accurate exclusively in hypertensive patients, and baroreflex function appears to be more sensitive to age-related changes in this system than to those related to blood pressure level, particularly in non-hypertensive normal subjects.


Programmable fusion of liposomes mediated by lipidated PNA.
We recently reported a DNA-programmed fusion cascade enabling the use of liposomes as nanoreactors for compartmentalized chemical reactions. This communication reports an alternative and robust strategy based on lipidated peptide nucleic acids (LiPs). LiPs enabled fusion of liposomes with remarkable 31% efficiency at 50 °C with low leakage (5%).


Beta-glucosidase isolated from soybean okara shows specificity toward glucosyl isoflavones.
A novel beta-glucosidase was isolated from soybean okara in this study. Along with the beta-glucosidase, a considerable basic 7S globulin of soybean was obtained in the initial extraction products. The protein samples pretreated with 130 mM dithiothreitol before the step of CM-Sepharose chromatography could greatly enhance the separation of the targeted beta-glucosidase from the impurities. The purified beta-glucosidase was found to be a monomer estimated to be 75 kDa by SDS-PAGE. The optimal temperature and pH for this beta-glucosidase were 45 degrees C and 4.5, respectively. The activity of this purified beta-glucosidase was completely inhibited by 1 mM Hg(2+) or 10 mM Al(3+) ion, and glucose and mannose also affected the activity. This beta-glucosidase possessed strict specificity toward glucosyl isoflavones but not malonylglucosidic conjugates of isoflavones of soybean. The N-terminal amino acid sequence of the beta-glucosidase was EYLKYKDPKA-, which highly matched that of glycosidases in maize (Zea mays) and wheat (Triticum asetivum).


Role of protein flexibility in the catalytic cycle of p-hydroxybenzoate hydroxylase elucidated by the Pro293Ser mutant.
Proline 293 of p-hydroxybenzoate hydroxylase from Pseudomonas aeruginosa is in a highly conserved region of the flavoprotein aromatic hydroxylases. It is thought to impart rigidity to the backbone, as it partially cradles the FAD in these hydroxylases. Thus, this residue has been substituted with serine by site-directed mutagenesis to investigate the importance of flexibility of the peptide segment in catalysis. Differential scanning calorimetry demonstrated that the mutation has decreased the stability of the folded mutant protein compared to the wild-type PHBH. The increased flexibility in the protein backbone enhanced the accessibility of the flavin hydroperoxide intermediate to the solvent, causing an increase in the elimination of H(2)O(2) from this labile intermediate and, consequently, a decrease in the efficiency of substrate hydroxylation. Additionally, the increased accessibility of this mutant form of the enzyme makes it more susceptible than the wild-type enzyme to being trapped in the hydroxyflavin intermediate form in the presence of high levels of p-hydroxybenzoate. The mutation also lowers the pK(a) of the phenolic oxygen of bound p-hydroxybenzoate, and eliminates the pH dependence of the rate constant for flavin reduction by NADPH. These experimental observations lead to a model that explains how the wild-type protein can sense the charge of the 4-substituent of the aromatic ligand and link this charge to a flavin conformational change that is required for reaction with NADPH: (i) The peptide oxygen of Pro 293 is repelled by the negative charge of the phenolic oxygen of p-hydroxybenzoate. (ii) This repulsion is transmitted through the peptide backbone, causing the movement of Asn 300. (iii) The change in the position of Asn 300 triggers the movement of the flavin from the largely buried "in" conformation to the exposed, reactive "out" conformation.


[Patterns in the development of cancer of the gastric stump].
The article analyzes results of the examination and surgical treatment of 24 patients with carcinoma of the gastric stump developing at different terms after resection of the stomach for gastroduodenal ulcers. Questions of pathogenesis, clinical picture and diagnosis of the disease are discussed. Special attention is called to low percentage of radical operations for gastric stump carcinoma. An important role of dispensary observation with the use of gastroscopy for patients subjected to resection of the stomach for peptic ulcers is emphasized.


Human thyroid fibroblasts exhibit a distinctive phenotype in culture: characteristic ganglioside profile and functional CD40 expression.
Fibroblasts from different regions of the human body exhibit substantial phenotypic diversity, some of which relates to the capacity for cross-talk with cells of the immune system. We examine, for the first time, thyroid fibroblast biology in culture. Thyroid explants were placed in culture, and fibroblasts were outgrown and serially passaged. These fibroblasts take on a morphology in culture resembling cells from other anatomic regions. When treated with PGE2, they assume a stellate morphology similar to that of prostanoid-treated orbital fibroblasts. The ganglioside profile exhibited by these cells is distinct from that observed previously in orbital and dermal fibroblasts. They uniformly express Thy-1, a surface glycoprotein. Messenger RNA encoding CD40, a surface receptor found on bone marrow-derived cells, and CD40 protein were expressed constitutively at low levels. Interferon-gamma (500 U/ml) treatment for 48-72 h resulted in high levels of surface HLA-DR and CD40 display. When CD40 is engaged with CD40 ligand (CD40L), nuclear factor-kappaB binding activity is up-regulated as is interleukin (IL)-6 and IL-8 expression. IL-1beta treatment up-regulates the expression of IL-1alpha, IL-1beta, and PGE2. These observations suggest that thyroid fibroblasts possess the molecular machinery necessary for cross-talk with immunocompetent cells such as lymphocytes and mast cells through the CD40/CD40L complex, as well as through classic cytokine networks, and to participate potentially in the inflammatory response of the thyroid gland.


Early warnings of COVID-19 outbreaks across Europe from social media.
We analyze data from Twitter to uncover early-warning signals of COVID-19 outbreaks in Europe in the winter season 2019-2020, before the first public announcements of local sources of infection were made. We show evidence that unexpected levels of concerns about cases of pneumonia were raised across a number of European countries. Whistleblowing came primarily from the geographical regions that eventually turned out to be the key breeding grounds for infections. These findings point to the urgency of setting up an integrated digital surveillance system in which social media can help geo-localize chains of contagion that would otherwise proliferate almost completely undetected.


A Pathological Condition Affects Motor Modules in a Bipedal Locomotion Model.
Bipedal locomotion is a basic motor activity that requires simultaneous control of multiple muscles. Physiological experiments suggest that the nervous system controls bipedal locomotion efficiently by using motor modules of synergistic muscle activations. If these modules were merged, abnormal locomotion patterns would be realized as observed in patients with neural impairments such as chronic stroke. However, sub-acute patients have been reported not to show such merged motor modules. Therefore, in this study, we examined what conditions in the nervous system merges motor modules. we built a two-dimensional bipedal locomotion model that included a musculoskeletal model with 7 segments and 18 muscles, a neural system with a hierarchical central pattern generator (CPG), and various feedback inputs from reflex organs. The CPG generated synergistic muscle activations comprising 5 motor modules to produce locomotion phases. Our model succeeded to acquire stable locomotion by using the motor modules and reflexes. Next, we examined how a pathological condition altered motor modules. Specifically, we weakened neural inputs to muscles on one leg to simulate a stroke condition. Immediately after the simulated stroke, the model did not walk. Then, internal parameters were modified to recover stable locomotion. We refitted either (a) reflex parameters or (b) CPG parameters to compensate the locomotion by adapting (a) reflexes or (b) the controller. Stable locomotion was recovered in both conditions. However the motor modules were merged only in (b). These results suggest that light or sub-acute stroke patients, who can compensate stable locomotion by just adapting reflexes, would not show merge of motor modules, whereas severe or chronic patients, who needed to adapt the controller for compensation, would show the merge, as consistent with experimental findings.


Females suffer a reduction in the viability of stored sperm following an immune challenge.
Despite the ubiquitous nature of sperm storage in invertebrates, relatively little is known about its costs, or the impact that immune activation can have on a female's ability to maintain viable sperm stores. We explored the effects of an immune challenge on sperm storage under food-limited and ad libitum conditions in the field cricket, Teleogryllus oceanicus, by injecting mated adult females with either a LD5 dose of live bacteria or a nonpathogenic immune elicitor [lipopolysaccharide (LPS)] and then scoring the viability of their stored sperm. Females that were infected with bacteria showed a reduction in the viability of stored sperm 48 h after infection; interestingly, this pattern was not evident when females were injected with LPS. Reduction in sperm viability post-infection may reflect a reproductive trade-off between immune function and sperm store maintenance, as only females injected with bacteria showed an elevated antibacterial immune (lytic) response. Alternatively, bacteria may act directly on sperm quality. Dietary manipulations showed that lytic activity in females is condition dependent, irrespective of their immune challenge treatment. Diet affected the ability of females to maintain the viability of stored sperm, suggesting that sperm storage is condition dependent. That bacterial infection associated with a reduction in stored sperm quality has potentially important implications for the outcomes of sperm competition in T. oceanicus and in other species in which females store sperm between matings.


Prevalence of musculoskeletal symptoms among Canadian firefighters.
Musculoskeletal symptoms (MSSs) remain the most frequently reported type of injuries sustained during fire-ground operations in firefighters. However, there is a paucity of reports concerning the prevalence estimates of MSSs among female firefighters and different fire services across Canada. To assess the point prevalence of self-reported MSSs, stratified by age and sex in a cohort of active duty firefighters from across Canada, and to determine whether age, sex or length of service can be used to predict the likelihood of the number of MSSs sustained. We recruited 390 firefighters (272 males, 118 females). To identify the prevalence of self-reported rates of MSSs, firefighters were asked to complete a standardized 11-item questionnaire that asked, "Please indicate whether you have experienced pain in any body region within the last week", with response options that included "Yes", "No", and "Head", "Neck", "Shoulder", "Arm/Elbow/Hand", "Back", "Stomach/Abdomen", "Upper Thigh", "Knee", "Lower Leg", "Foot", "Other, please specify". Among the 390 full-time firefighters, 212 (54%) indicated to have experienced some type of MSSs within the last week. The most prevalent region-specific MSSs included, 123 (32%) in the back region, 92 (24%) in the shoulder region, 74 (19%) in the neck region and 70 (18%) in the knee region. In addition, women indicated a 1.6 times greater likelihood of sustaining ≥2 MSSs when controlling for individual differences in age and years of service. The point prevalence of MSSs in a cohort of full-time firefighters was 54% (55% males; 53% females). Women experienced a 1.4-1.6 times greater likelihood of sustaining MSSs when controlling for individual differences in age and years of service.


Mediterranean fever gene mutations in Greek patients with Behcet's disease.
It is known that clinical similarities between Behcet's disease and Familial Mediterranean Fever have led to the hypothesis of a common pathogenesis. Familial Mediterranean Fever is caused by MEFV gene mutations coding for pyrin. Therefore, we examined whether these pyrin mutations are also associated with Behcet's disease. Molecular testing for pyrin mutations was performed in 96 unrelated Greek patients with an established diagnosis of Behcets disease. The results were compared with an analysis for pyrin mutations in 140 unrelated healthy Greek controls. We found no pyrin mutations among the Behcet cases tested; this result is comparable with the control group. Pyrin gene mutations in Greek patients with Behcet's disease are not more common than those in the general population. This finding is not in agreement with the findings in other populations. It is suggested that screening for pyrin mutations not be included in the evaluation of Greeks suspected to have Behcet's disease.


SPION-enhanced magnetic resonance imaging of Alzheimer's disease plaques in AβPP/PS-1 transgenic mouse brain.
In our program to develop non-invasive magnetic resonance imaging (MRI) methods for the diagnosis of Alzheimer's disease (AD), we have synthesized antibody-conjugated, superparamagnetic iron oxide nanoparticles (SPIONs) for use as an in vivo agent for MRI detection of amyloid-β plaques in AD. Here we report studies in AβPP/PS1 transgenic mice, which demonstrate the ability of novel anti-AβPP conjugated SPIONs to penetrate the blood-brain barrier to act as a contrast agent for MR imaging of plaques. The conspicuity of the plaques increased from an average Z-score of 5.1 ± 0.5 to 8.3 ± 0.2 when the plaque contrast to noise ratio was compared in control AD mice with AD mice treated with SPIONs. The number of MRI-visible plaques per brain increased from 347 ± 45 in the control AD mice, to 668 ± 86 in the SPION treated mice. These results indicated that our SPION enhanced amyloid-β detection method delivers an efficacious, non-invasive MRI detection method in transgenic mice.


Prediction of self-assembly of adenosine analogues in solution: a computational approach validated by isothermal titration calorimetry.
The recent discovery of the role of adenosine-analogues as neuroprotectants and cognitive enhancers has sparked interest in these molecules as new therapeutic drugs. Understanding the behavior of these molecules in solution and predicting their ability to self-assemble will accelerate new discoveries. We propose a computational approach based on density functional theory, a polarizable continuum solvation description of the aqueous environment, and an efficient search procedure to probe the potential energy surface, to determine the structure and thermodynamic stability of molecular clusters of adenosine analogues in solution, using caffeine as a model. The method was validated as a tool for the prediction of the impact of small structural variations on self-assembly using paraxanthine. The computational results were supported by isothermal titration calorimetry experiments. The thermodynamic parameters enabled the quantification of the actual percentage of dimer present in solution as a function of concentration. The data suggest that both caffeine and paraxanthine are present at concentrations comparable to the ones found in biological samples.


Abnormal macrophage response to microbial stimulus in a 43-year-old man with a severe form of atherosclerosis: a case report.
New evidence indicates infections are emerging as risk factors for atherosclerosis although their specific role in the development and progression of atherosclerosis is still unclear. A 43-year-old Caucasian man who had been treated for four years for multiple sclerosis progressively manifested systemic hypertension, polycythemia, peripheral arterial occlusion with intermittent claudication, and persistent headaches. In 2006, an instrumental analysis (magnetic resonance imaging) of our patient revealed widespread fibrocalcific atherosclerotic lesions which accounted for all his current symptoms, including those related to microbial stimulus. Two particular aspects were of interest, namely a lack of conventional cardiovascular risk factors and a negative family history for cardiovascular events. His chemical blood tests all yielded negative findings although a low positive hepatitis C virus-ribonucleic acid titer was detected. The titer had progressively increased and worsening atherosclerosis threatened the life of our patient. Interferon therapy was not appropriate for our patient due to the severe adverse effects observed shortly after its administration. The reaction of individual cells to infections may provide an explanation as to why individuals with a similar microbial burden, corrected for the presence of other risk factors, display a different susceptibility to developing or worsening atherosclerosis. The identification of susceptible individuals and the treatment even of silent infections may provide an additional tool against atherosclerosis and its clinical complications. The evaluation of cell susceptibility before and after the correction of risk factors may contribute to the assessment of the efficacy of drug therapy.


Changes in the predominant human Lactobacillus flora during in vitro fertilisation.
Signature matching of nucleotide sequences in the V1 and V3 regions 16S rRNA genes using pyrosequencing technology is a powerful tool for typing vaginal Lactobacilli to the species level and has been used for investigating the vaginal microbial niche. This study has characterized the normal cultivable vaginal Lactobacillus flora at varying estradiol levels in plasma; the study comprised 17 patients undergoing ovarian stimulation for In Vitro Fertilization (IVF) treatment. The vaginal status of each participant was initially assessed as normal according to Amsel and Nugent criteria. L. crispatus, L. gasseri and/or L. jensenii were present in 10 of the patients throughout the study period, and little variation among these three species was encountered in individual patients. The flora of three women was dominated by L. delbrüeckii, L. rhamnosus or L. vaginalis. One woman exhibited a dominance of L. iners. The flora of the remaining three women were initially dominated by L. rhamnosus or L. reuteri, but as their estrogen levels rose, their flora composition altered, to become dominated by one of the three species most common in a normal, healthy vagina. Signature matching of nucleotide sequences in the V1 and V3 regions of 16S rRNA genes is a discriminative tool for the study of vaginal Lactobacilli and can be used to track the Lactobacillus flora under a variety of physiological conditions.


Effectiveness of Distal Sodium Channel Block in Managing Lumbosacral Radicular Syndrome: A Pilot Study.
To find the effectiveness of distal sodium channel blocks in managing lumbosacral radicular syndrome. Open-labelled, non-randomised, single-group, prospective, pilot study. Place and Duration of the Study: Pain Clinic of Armed Forces Institute of Rehabilitation Medicine (AFIRM) Rawalpindi, Pakistan, from January to June 2022. Patients having low back pain radiating to L5/S1/both dermatomes with severity of numerical rating scale (NRS) score of more than 4/10 were included. Straight leg raise (SLR) and NRS score were noted down at baseline and at 30 minutes, 24 hours, 1 week, and 4 weeks post-distal sodium channel block (DSCB). DSCB was performed at beta 1, 2, 3, and 5 portals using 2 ml of 2% injection plain lignocaine + 1 ml (40 mg) injection triamcinolone + 7 ml distilled water. Statistical analysis was done using Statistical Package for Social Sciences (SPSS) 21. Out of 50 patients, 24 (48%) were females and 26 (52%) were males. No serious procedural complications were noted. Post-DSCB, follow-up was done for 4 weeks. A significant fall in NRS and an increase in SLR score were observed at every visit. Results were statistically significant (p<0.001) when mean NRS and SLR scores at every follow-up were compared for pre- and post-DSCBs. DSCB reduced pain and improved SLR in patients even at 4 weeks of follow-up. Advantages included immediate pain relief, easy to perform as outdoor procedure, cost-effective and a time buying alternative procedure allowing for the analgesic effect of medicine to kick in. Radiculopathy, Low-back pain, Epidural spinal injection, Sciatica, Pain management, Distal sodium channel blocks.


Cellular ion interactions in two endemic tropical rainforest species of a novel metallophytic tree genus.
Gossia, a small genus of physiologically novel rainforest trees restricted to the Western Pacific and belonging to a key neotropical Southern Hemisphere family, the Myrtaceae, is characterized by high foliar manganese (Mn) concentrations. This field study provides a quantitative in planta snapshot detailing cellular localization of foliar Mn and other mineral nutrients in sympatric Gossia grayi N. Snow & Guymer and Gossia shepherdii N. Snow & Guymer endemic to far northeastern Australia, and previously not examined. Elements localized in the cells of fresh hydrated leaf tissues were quantified via in vivo cryo-scanning electron microscopy energy dispersive spectroscopy, a non-invasive method that effectively immobilizes cell contents. Leaf anatomical differences were found between species, along with foliar Mn spatial distribution patterns. Localized cellular Mn concentrations exceeding 600 mmol kg-1 were detected in G. shepherdii, whose Mn accumulation across different mesophyll cell types was heterogeneous compared with G. grayi. In both species there was little evidence to support previous findings on other Gossia species of carboxylate association with excess Mn. The analytical X-ray data strongly implicated chloride as a counter-ion to Mn in the two species examined here. The key findings align with the hypothesis that Mn disposal in the mesophyll is a generic trait in Gossia. This research has forged an emerging view of Gossia as being characterized by unusual cellular metal and mineral accumulation patterns that vary at the species level. It contributes to current limited knowledge about generic plant metallophyty, highlighting that assimilating a broader perspective of the phenomenon demands evaluation of individual taxa through field studies.


[A 57-year-old woman with progressive disturbance of gait and mental deterioration].
We report a 57-year-old woman with progressive gait disturbance and mental deterioration. She was well until March 1995, when she was 54 years of the age. At that time she noted a gradual onset of tremor and difficulty using her hand. Similar symptoms appeared in her right hands, and she visited another hospital, where 300 mg of levodopa and 7.5 mg of bromocriptine were prescribed. These medication did not help her symptoms. In the summer of 1996, she became to fall down easily. In September of the same year, she started to repeat the same words many times. She was unable to stop it. She was hospitalized to our service on January 25, 1997. On admission, she was alert but demented moderately; her Hasegawa dementia scale was 15/30. She showed palilallia, logoclonia, and echolalia. She showed constructional apraxia and questionable left-right disorientation. She had marked vertical gaze palsy with preserved oculocephalic response. She had masked face and small voice. Her gait was wide based with small steps. No muscle atrophy or weakness was noted. She showed only mild rigidity in the neck, but no rigidity was noted in the limb. No tremor was noted. She was bradykinetic. Deep tendon reflexes were symmetric and within normal limits. Laboratory findings on admission was unremarkable. MRI showed atrophy of the brain stem as well as cerebral cortical areas, particularly in the fronto-temporal region. Her hospital course was complicated with paralytic ileus and septicemia. She developed hypotension and pronounced dead on July 28, 1998. She was discussed in the neurological CPC. The chief discussant arrived at a conclusion that the patient had progressive supranuclear palsy and died of septic shock. All the participants wondered between PSP and CBD, but majority agreed with this diagnosis of the chief discussant. Only one thought that she might have had corticobasal degeneration rather than PSP, because of dementia, cortical atrophy in MRI, and lack of limb rigidity. Postmortem examination revealed cortical and brain stem atrophy. In the premotor cortex, marked astrocytosis and ballooned neurons were seen. Furthermore, astrocytic plaques were seen; this is considered to be pathognomonic for CBD. The substantia nigra showed marked neuronal loss and gliosis, but no neurofibrillary tangles or Lewy bodies were seen. Gliosis was also seen in the globus pallidus and in the medial thalamus. The pathologic diagnosis was corticobasal degeneration. This patient was very interesting case, in that the clinical manifestations appeared to be consistent with PSP, yet pathologic diagnosis was CBD. Lack of limb rigidity may be atypical for advanced PSP. In addition, palilalia appears to be more associated with CBD.


SAD2 in Arabidopsis functions in trichome initiation through mediating GL3 function and regulating GL1, TTG1 and GL2 expression.
Most genes identified that control Arabidopsis trichome initiation and formation are transcription factors or regulatory components in transcriptional networks and include GLABROUS1 (GL1), GLABRA2 (GL2), GLABRA3 (GL3) and TRANSPARENT TESTA GLABRA1 (TTG1). Herein, we report that an importin beta-like protein, SENSITIVE TO ABA AND DROUGHT2 (SAD2), is required for trichome initiation. Mutations in SAD2 disrupted trichome initiation resulting in reduced trichome number, but had no effect on trichome development or root hair number and development. Expression levels of GL1, MYB23, GL2 and TTG1 were reduced in shoots of sad2 mutants while expression levels of GL3 and ENHANCER OF GLABRA3 (EGL3) were enhanced. Overexpression of GL3 increased trichome numbers in wild type but not in sad2 mutants, indicating that the function of the GL3 protein is altered in the sad2 mutants. In contrast, overexpression of GFP-GL1 decreased trichome number in both wild type and sad2. Double mutant analysis of gl1 sad2 and gl3 sad2 indicated that SAD2 functions genetically, at least in part, in the same pathway with these two genes. Co-immunoprecipitation indicated that the sad2 mutation does not disrupt formation of the TTG1-GL3-GL1 complex. Analysis of GFP fusions of GL1, GL2, GL3 and TTG1 suggested that these proteins are most likely not direct cargo of SAD2. Our data suggest that SAD2 is involved in trichome initiation by regulating these nuclear genes.


Comparison of three-dimensional echocardiographic findings to those of magnetic resonance imaging for determination of left ventricular mass in patients with ischemic and non-ischemic cardiomyopathy.
The standard echocardiographic evaluation of left ventricular (LV) mass, particularly in ischemic cardiomyopathy (IC) is challenging because it is based on geometric assumptions. The aim of this study was to assess the accuracy of LV mass calculation using echocardiographic modalities compared with cardiac magnetic resonance (CMR) in IC and in nonischemic cardiomyopathy (non-IC). Echocardiography was performed in 104 patients (mean age 55 ± 15 years) referred for CMR: 63 with IC and 41 with non-IC. CMR, M-mode echocardiography, 2-dimensional echocardiography, and 3-dimensional echocardiography (3DE) were analyzed using standard commercial tools to obtain LV mass. LV mass on 3DE showed a higher correlation with CMR than 2-dimensional echocardiography (r = 0.87 vs r = 0.70, p <0.001). M-mode echocardiography overestimated LV mass (bias +30%) and 2-dimensional echocardiography underestimated LV mass (bias -11%), whereas measurements on 3DE showed only minimal bias (-2%). LV mass on 3DE in non-IC showed a significantly higher correlation with CMR than in IC (r = 0.92 vs r = 0.84, z = 2.3, p <0.05). In non-IC, the mean difference was -2 g (-1% of the mean), with 95% limits of agreement of ±33 g (±19% of the mean). In IC, the mean difference was -7 g (-4% of the mean), with limits of agreement of ±56 g (±31% of the mean). There was a correlation between the absolute LV mass differences (3DE derived and CMR derived) and scar percentage (infarcted mass/total LV mass) using delayed-hyperenhancement images (r = 0.40, p <0.05). The net reclassification index with 3DE was +16% for concentric LV hypertrophy. In conclusion, the most accurate and reliable echocardiographic measurement of LV mass is 3DE, but underestimation and variability remain challenges in IC.


Predictive value of pre-infusion tumor growth rate for the occurrence and severity of CRS and ICANS in lymphoma under CAR T-cell therapy.
Chimeric antigen receptor T-cell therapy (CART) can be administered outpatient yet requires management of potential side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The pre-infusion tumor burden is associated with CRS, yet there is no data on the relevance of pre-infusion tumor growth rate (TGR). Our objective was to investigate TGR for the occurrence and severity of CRS and ICANS. Consecutive patients with available pre-baseline and baseline (BL) imaging before CART were included. TGR was determined as both absolute (abs) and percentage change (%) of Lugano criteria-based tumor burden in relation to days between exams. CRS and ICANS were graded according to ASTCT consensus criteria. Clinical metadata was collected including the international prognostic index (IPI), patient age, ECOG performance status, and LDH. Sixty-two patients were included (median age: 62 years, 40% female). The median pre-BL TGR [abs] and pre-BL TGR [%] was 7.5 mm2/d and 30.9%/d. Pre-BL TGR [abs] and pre-BL TGR [%] displayed a very weak positive correlation with the grade of CRS (r[abs] = 0.14 and r[%] = 0.13) and no correlation with ICANS (r[abs] = - 0.06 and r[%] = - 0.07). There was a weak positive correlation between grade of CRS and grade of ICANS (r = 0.35; p = 0.005) whereas there was no significant correlation of CRS or ICANS to any other of the examined parameters. The pre-infusion TGR before CART was weakly associated with the occurrence of CRS, but not the severity, whereas there were no significant differences in the prediction of ICANS. There was no added information when compared to pre-infusion tumor burden alone. Outpatient planning and toxicity management should not be influenced by the pre-infusion TGR.


Inhibition of induced and spontaneous platelet aggregation by destabilase from medicinal leech.
Destabilase, endo-epsilon-(gamma-Glu)-Lys isopeptidase from the medicinal leech, inhibits arterial thrombus formation in rats. Inhibition of platelet aggregation was supposed to be one of the main mechanisms of this phenomenon. To elucidate this question highly purified destabilase preparations were used. Aggregation was monitored both by a turbidometric method and by a method based on real-time estimation of mean aggregate size. Spontaneous aggregation of human platelets was completely blocked by destabilase. At 5 microM ADP maximal inhibition was 63%. Aggregation induced by PAF (100 nM) and collagen (0.1 mg/ml) was inhibited in the presence of destabilase by 50 and 65%, respectively. This enzyme does not activate adenylate cyclase but inhibits it. We suggest that destabilase interacts with high-affinity binding sites on the platelet plasma membrane, thus providing an anti-aggregating effect. This idea coincides with the data that destabilase primary structure has high homology with some adhesive proteins.


Variation in the Assessment of Immune-Related Adverse Event Occurrence, Grade, and Timing in Patients Receiving Immune Checkpoint Inhibitors.
Toxic effects of conventional chemotherapy and molecularly targeted cancer therapies are generally well defined and occur at predictable points. By contrast, owing to their heterogeneous manifestations, unpredictable timing, and clinical overlap with other conditions, immune-related adverse events (irAE) may be more difficult to diagnose and characterize. To determine concordance of algorithm-driven medical record review by medical oncologists for the characterization of 8 irAE in patients treated with immune checkpoint inhibitors. Cross-sectional study of patients treated with immune checkpoint inhibitors at a National Cancer Institute-designated comprehensive cancer center from November 30, 2015, to March 7, 2018. A sample size of 52 patients provided 80% power to distinguish substantial agreement (κ = 0.85) from poor agreement (κ = 0.5) based on the Cohen κ. Interrater agreement of 2 observers in the occurrence and grade of irAE. Of 52 patients (32 [61.5%] male; mean [SD] age, 69 [9] years) analyzed, 42 (80.8%) had non-small cell lung cancer and all received anti-programmed cell death 1 or anti-programmed cell death ligand 1 antibodies, with 3 patients (5.8%) receiving combinations with anti-cytotoxic T-lymphocyte antigen 4 antibodies. A median (interquartile range) of 82 (47-180) documents were reviewed per case. There was limited or poor interrater agreement on irAE occurrence (Cohen κ, 0.37-0.64), with the exception of hypothyroidism (κ = 0.8). Weighted κ similarly showed limited or poor agreement for irAE grade (κ = 0.31-0.75). Differences in assessed time of onset ranged from 5 to 188 days. As a control for data availability and access, observers had a high degree of agreement for the exact start date (98%) and end date (96%) of immunotherapy administration, suggesting that information interpretation rather than identification largely accounted for assessment differences. In multivariable analysis, therapy duration (adjusted odds ratio, 4.80; 95% CI, 1.34-17.17; P = .02) and Charlson Comorbidity Index (adjusted odds ratio, 4.09; 95% CI, 1.10-15.18; P = .03) were significantly associated with discordant irAE assessment. These findings underscore critical challenges in assessing the occurrence, type, timing, and severity of irAE. Apart from hypothyroidism (a condition that has a discrete diagnostic laboratory test and few other likely etiologies during immunotherapy treatment), interobserver agreement was poor. Given the importance of accurate and timely assessment of toxic effects for clinical trials and real-world disease management, efforts to improve irAE diagnosis and characterization are needed.


Energy restriction reduces the number of advanced aberrant crypt foci and attenuates the expression of colonic transforming growth factor beta and cyclooxygenase isoforms in Zucker obese (fa/fa) rats.
Several epidemiological studies have supported the concept that high energy intake, obesity, and/or hyperinsulinemia are risk factors for colon cancer. Previously, it was shown that Zucker obese rats are more sensitive to chemically induced colon cancer than their lean counterparts. The present study investigated whether moderate (20-25%) dietary energy restriction (ER) would attenuate colon carcinogenesis in the Zucker obese rat model. Six-week-old Zucker obese (fa/fa) rats and lean (Fa/Fa) rats received s.c. injections of azoxymethane at a dose of 10 mg/kg body weight once weekly for 2 weeks. A week later, obese rats (n = 16) were assigned to an ER diet (Ob-ER group), based on a low-fat AIN-93G semisynthetic diet. The remaining obese and lean rats (n = 16 rats/group) were fed the low-fat diet ad libitum (Ob group and Ln group, respectively). All rats were euthanized after 8 weeks, and their colons were assessed for aberrant crypt foci (ACF; n = 8/group) or for the expression of transforming growth factor (TGF)-beta and cyclooxygenase (COX) isoforms at the protein and mRNA transcript levels (n = 8/group). Ob rats had a higher number of advanced ACF (crypt multiplicity >or=7) than Ln rats. Dietary ER significantly reduced the appearance of advanced ACF in Ob-ER rats without significantly affecting the blood insulin level or body weights. TGF-beta and COX isoforms were differentially expressed in the colonic mucosae of Ob and Ln rats. Dietary ER significantly reduced TGF-beta1/beta2 and COX-1/2 protein expression in obese rats. This study is the first to demonstrate that moderate ER attenuated TGF-beta and COX protein expression and the carcinogenic process in Zucker obese rats. These findings provide insights leading to the proposal that the mechanism(s) underlying the early events of colon carcinogenesis in Zucker obese rats may extend beyond the role of excessive body weight and hyperinsulinemia per se.


Hepatorenal Tyrosinaemia: Impact of a Simplified Diet on Metabolic Control and Clinical Outcome.
Background: Tyrosinaemia type 1 is a rare inherited metabolic disease caused by an enzyme defect in the tyrosine degradation pathway. It is treated using nitisinone and a low-protein diet. In a workshop in 2013, a group of nutritional specialists from Germany, Switzerland and Austria agreed to advocate a simplified low-protein diet and to allow more natural protein intake in patients with tyrosinaemia type 1. This retrospective study evaluates the recommendations made at different treatment centers and their impact on clinical symptoms and metabolic control. Methods: For this multicenter study, questionnaires were sent to nine participating treatment centers to collect data on the general therapeutic approach and data of 47 individual patients treated by those centers. Results: Dietary simplification allocating food to 3 categories led to increased tyrosine and phenylalanine blood concentrations without weighing food. Phenylalanine levels were significantly higher in comparison to a strict dietary regimen whereas tyrosine levels in plasma did not change. Non-inferiority was shown for the simplification and liberalization of the diet. Compliance with dietary recommendations was higher using the simplified diet in comparison to the stricter approach. Age correlates negatively with compliance. Conclusions: Simplification of the diet with increased natural protein intake based on three categories of food may be implemented in the diet of patients with tyrosinaemia type 1 without significantly altering metabolic control. Patient compliance is strongly influencing tyrosine blood concentrations. A subsequent prospective study with a larger sample size is necessary to get a better insight into the effect of dietary recommendations on metabolic control.


Literature review and clinical presentation of cervical spondylitis due to salmonella enteritidis in immunocompetent.
A 48-year-old woman was presented to our clinic with some fever and neck pains for about one month. Based on the symptoms and results of image, an empirical diagnosis of tuberculous cervical spondylitis was made. The pain was not significantly decreased after anti-tuberculosis therapy. And, 3 weeks later, she was re-admitted to our hospital for the unbearable pain. An exploration of the C4/5 by the anterior medial approach was recommended to evaluate the germ and debridement. Bacteriological tests showed that the pathogen was Salmonella Enteritidis. The pain was relieved significantly after operation and sensitive antibiotic treatments. Infections with Salmonella Typhi or Salmonella Paratyphi have been well-documented, while there are few reports of cervical spondylitis caused by Salmonella Enteritidis. We reported a case of a healthy woman with whom pyogenic cervical spondylitis of Salmonella Enteritidis was corroborated and treated and reviewed according to previous reports about spondylitis caused by Salmonella Enteritidis in the literature.


A petunia MADS box gene involved in the transition from vegetative to reproductive development.
We have identified a novel petunia MADS box gene, PETUNIA FLOWERING GENE (PFG), which is involved in the transition from vegetative to reproductive development. PFG is expressed in the entire plant except stamens, roots and seedlings. Highest expression levels of PFG are found in vegetative and inflorescence meristems. Inhibition of PFG expression in transgenic plants, using a cosuppression strategy, resulted in a unique nonflowering phenotype. Homozygous pfg cosuppression plants are blocked in the formation of inflorescences and maintain vegetative growth. In these mutants, the expression of both PFG and the MADS box gene FLORAL BINDING PROTEIN26 (FBP26), the putative petunia homolog of SQUAMOSA from Antirrhinum, are down-regulated. In hemizygous pfg cosuppression plants initially a few flowers are formed, after which the meristem reverts to the vegetative phase. This reverted phenotype suggests that PFG, besides being required for floral transition, is also required to maintain the reproductive identity after this transition. The position of PFG in the hierarchy of genes controlling floral meristem development was investigated using a double mutant of the floral meristem identity mutant aberrant leaf and flower (alf) and the pfg cosuppression mutant. This analysis revealed that the pfg cosuppression phenotype is epistatic to the alf mutant phenotype, indicating that PFG acts early in the transition to flowering. These results suggest that the petunia MADS box gene, PFG, functions as an inflorescence meristem identity gene required for the transition of the vegetative shoot apex to the reproductive phase and the maintenance of reproductive identity.


Gastric and intestinal phenotypic expressions of human signet ring cell carcinomas revealed by their biochemistry, mucin histochemistry, and ultrastructure.
Gastric and intestinal phenotypic expression in 37 surgically obtained primary signet ring cell carcinomas, five of their metastases to lymph nodes, and three signet ring cell carcinomas transplanted into nude mice were determined by biochemical, mucin, histochemical, and ultrastructural studies. Crude extracts of cancer tissues were used for measurements of pepsinogen isozymes, sucrase, aminopeptidase (microsomal), and alkaline phosphatase. Histochemical staining of mucin by paradoxical concanavalin A, the galactose oxidase-Schiff sequence and sialidase-galactose oxidase-Schiff, and the periodate-borohydride technique/potassium hydroxide/periodic acid-Schiff procedure was performed. The procedures allowed clear definition of pyloric gland, surface mucous, small and large intestinal goblet, and intestinal absorptive cell types. Of 40 specimens examined, 19 consisted entirely of gastric-type cells, and three entirely of intestinal-type cells. The others consisted of mixtures of gastric and intestinal-type cells. The observed high incidence of intestinal-type cells in signet ring cell carcinomas suggested that intestinal-type cells develop independently from intestinal metaplasia within signet ring cell carcinomas (diffuse-type gastric cancers), which probably originate from nonmetaplastic gastric mucosa.


Handicap-related problems in mothers of children with physical impairments.
An inventory was developed for the measurement of handicap-related problems experienced by mothers of children with chronic physical conditions and an initial evaluation of its psychometric properties was completed in a sample of 119 mothers of children with physical or sensory impairments. Principal component analysis of the Handicap-related Problems for Parents Inventory (HPPI) yielded three subscales, which accounted for 54% of the total variance. The HPPI demonstrated excellent internal consistency for each scale and total score. It also generally had good test-retest reliability over 6-, 12-, and 18-month periods. There was minimal covariation between HPPI scores and demographic status. Concurrent validity was demonstrated by significant correlations between appropriate HPPI scales and measures of daily stress and the child's physical condition or disability status. Support for its construct validity was obtained when expected convergent and discriminant relationships were confirmed between HPPI scales and measures of maternal adaptation, maternal social support, and child behavior problems. Among other results, HPPI scores predicted maternal adaptation 18 months later. The potential uses of the HPPI in research and intervention with mothers of children with chronic physical conditions were discussed.


Brain potentials associated with conscious aftereffects induced by unseen stimuli in a blindsight subject.
The study is of brain activity in a blindsight subject (D.B.), who reports conscious visual afterimages of stimuli of which he is unaware when they are presented. This contrast offered a unique opportunity to study event-related potential recordings of conscious versus unconscious visual phenomena generated by the very same stimulus in the identical locus of the visual field. The behavioral results confirmed the reliability of the difference in the subject's report for inducing stimuli versus their aftereffects. The rationale of the event-related potential analysis was to subtract "on" signals from "off" signals, the latter associated with the onset of conscious events and the former for events that remained unconscious. Because there are inherent differences in on and off potentials, the subtractive resultants for the blind hemifield were compared with the same subtractions for the good hemifield when the subject was aware both of the stimuli and their afterimages. A differential pattern in subtractive resultants emerged with a strong anterior left frontal focus for the blind field and a posterior focus for the intact field. The results are compared with other studies suggesting an anterior focus for conscious visual events.


Nitric oxide (NO) detection by DAF fluorescence and chemiluminescence: a comparison using abiotic and biotic NO sources.
Because of controversies in the literature on nitric oxide (NO) production by plants, NO detection by the frequently used diaminofluorescein (DAF-2 and DAF-2DA) and by chemiluminescence were compared using the following systems of increasing complexity: (i) dissolved NO gas; (ii) the NO donor sodium nitroprusside (SNP); (iii) purified nitrate reductase (NR); and (iv) tobacco cell suspensions. Low (physiological) concentrations (< or =1 nM) of dissolved NO could be precisely quantified by chemiluminescence, but caused no DAF-2 fluorescence. In contrast to NO gas, SNP, NR, or cell suspensions produced both good DAF fluorescence and chemiluminescence signals which were completely (chemiluminescence) or partly (DAF fluorescence) prevented by NO scavengers. Signal strength ratios between the two methods were variable depending on the NO source, and eventually reflect variable NO oxidation. DAF fluorescence in cell suspension cultures was also increased by an as yet unidentified compound(s) released from cells into the medium. These compounds gave no chemiluminescence signal and were not produced by NR-free mutants. Their production was stimulated by anoxia, by inhibitors of mitochondrial electron transport, and by the fungal elicitor cryptogein. Thus, changes in DAF fluorescence are not necessarily indicative for NO production, but may also reflect NO oxidation and/or production of other DAF-reactive compounds.


The Effect of Using Marathon Shoes or Track Spikes on Neuromuscular Fatigue caused by a Long-distance Track Training Session.
This study aims to compare the effect of the Nike ZoomX Dragonfly track spikes and the Nike ZoomX VaporflyNext% 2 marathon shoes on the fatigue manifestations present over and after a long-distance track training session. Thirteen highly trained athletes completed two training sessions (i. e., 9- and 3-minute time trials with complete recovery) with the aforementioned footwear models. The pace, ground contact time, and stride length were measured over the time trials, and maximal countermovement jumps were performed previously and after the training session. The results revealed that, although there was no significant interaction in the pace distribution (p≥0.072), athletes tend to be only able to increase the pace at the last lap with the marathon shoes (5.4 meters [-3.7 to 14.5 meters]) meanwhile with the track spikes it further decreased (-3.1 meters [-9.8 to 3.6 meters]). A reduced ground contact time over the session (p=0.025) and a tendency toward increasing stride length (p=0.09) in the last time trial were observed. The significant interaction on the countermovement jump height (p=0.023; Track spikes: -5.60%; Marathon shoes: 0.61%) also indicates that footwear influences the resulted allostatic load.


Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy.
To evaluate the safety and efficacy of single and multiple doses of a chimeric anti-TNF-alpha monoclonal antibody (infliximab) in patients with rheumatoid arthritis (RA) who had active disease despite therapy with methotrexate (MTX). Twenty-eight patients with active RA despite receiving therapy with 10 mg/week of MTX were randomized to receive a single, blinded infusion of either placebo or 5, 10, or 20 mg/kg infliximab. Twenty-three patients who completed the blinded study entered an open, multiple dose extension study in which they received up to 3 additional infusions of 10 mg/kg infliximab at Weeks 12, 20, and 28. Safety, efficacy, and pharmacokinetics were evaluated during the blinded and open trial. There were no serious infusion related reactions. In the blinded phase, 17 (81.0%) of 21 patients receiving infliximab achieved an American College of Rheumatology (ACR) 20% response at some point during the 12 weeks of followup compared to one (14.3%) of 7 patients receiving placebo (p = 0.003). Clinical improvement was evident by the first week and was sustained through Week 12. For the 19 patients who received infliximab during the blinded part of the trial and continued into the open label trial, 53% maintained an ACR 20% response with multiple infusions of 10 mg/kg infliximab through Week 40. Three patients withdrew from the trial during the open continuation phase because of adverse events: cellulitis, infusion related dizziness and headache, and vasculitic rash. Infliximab in doses of 5 to 20 mg/kg had a mean terminal half-life ranging from 9 to 12 days and was detectable in sera from most patients 8 to 12 weeks after dosing. Infliximab is generally well tolerated during 40 weeks of therapy. A single infusion of 5 to 20 mg/kg infliximab significantly decreases the signs and symptoms of RA compared to placebo in patients with active disease receiving MTX. Multiple doses of infliximab produce sustained clinical benefit for up to 40 weeks.


The relation between maternal ADHD symptoms & improvement in child behavior following brief behavioral parent training is mediated by change in negative parenting.
This study examined the extent to which maternal attention-deficit/hyperactivity disorder (ADHD) symptoms predict improvement in child behavior following brief behavioral parent training. Change in parenting was examined as a potential mediator of the negative relationship between maternal ADHD symptoms and improvement in child behavior. Seventy mothers of 6-10 year old children with ADHD underwent a comprehensive assessment of adult ADHD prior to participating in an abbreviated parent training program. Before and after treatment, parenting was assessed via maternal reports and observations and child disruptive behavior was measured via maternal report. Controlling for pre-treatment levels, maternal ADHD symptomatology predicted post-treatment child disruptive behavior problems. The relation between maternal ADHD symptomatology and improvement in child behavior was mediated by change in observed maternal negative parenting. This study replicated findings linking maternal ADHD symptoms with attenuated child improvement following parent training, and is the first to demonstrate that negative parenting at least partially explains this relationship. Innovative approaches combining evidence-based treatment for adult ADHD with parent training may therefore be necessary for families in which both the mother and child have ADHD. Larger-scale studies using a full evidence-based parent training program are needed to replicate these findings.


Text Message Intervention (TEACH) Improves Quality of Life and Patient Activation in Celiac Disease: A Randomized Clinical Trial.
To determine the impact of the Text Message Educational Automated Compliance Help (TEACH) text message intervention as a pragmatic approach for patient engagement among adolescents with celiac disease (CD) as measured by gluten-free diet (GFD) adherence, patient activation, and quality of life (QOL). Randomized controlled trial with patient recruitment at a pediatric, university-based hospital and through social media; 61 participants ages 12-24 years with CD diagnosed at least 1 year were enrolled. The TEACH intervention cohort received 45 unique text messages over a 3-month study period while the control group received standard of care treatment. Primary outcome measures included objective markers of GFD adherence included serum tissue transglutaminase IgA and deamidated gliadin peptide IgA levels. Secondary patient-reported outcomes collected via online survey included the Celiac Dietary Adherence Test, National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS) Global Short Form measure of QOL, Celiac Symptom Index, and Patient Activation Measure. All measures were assessed at enrollment and after the 3-month study period. Statistical analysis performed using the 2-tailed paired Student t test. Among the TEACH intervention group, there was significant improvement comparing enrollment scores with 3-month follow-up scores in patient activation (Patient Activation Measure score 63.1 vs 72.5, P?=?.01) and QOL (NIH PROMIS Global Mental Health 50.8 vs 53.3, P?=?.01 and NIH PROMIS Global Physical Health 50.8 vs 57.7, P?=?.03). There was no statistically significant difference in patient-reported or objectively measured GFD adherence. TEACH is an effective intervention among patients with CD to improve patient activation and QOL, even among a cohort with GFD adherence at baseline. ClinicalTrials.gov: NCT02458898.


Health problems in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Following the introduction of life-saving glucocorticoid replacement 60 years ago, congenital adrenal hyperplasia (CAH) has evolved from being perceived as a paediatric disorder to being recognized as a lifelong, chronic condition affecting patients of all age groups. Increasing evidence suggests that patients with CAH have an increased risk to develop health problems during adult life, with signs and symptoms of forerunner conditions of adult disease already emerging during the time of paediatric care. Transition of paediatric CAH patients to medical care in the adult setting is an important step to ensure optimal lifelong treatment, aiming to achieve good health and normal life expectancy and quality of life. Thus, primary and secondary prevention of health problems has to become a task of increasing importance for those involved in the care of CAH patients throughout their life.


Model of a training program in robotic surgery and its initial results.
to describe the implementation of a training program in robotic surgery and to point the General Surgery procedures that can be performed with advantages using the robotic platform. we conducted a retrospective analysis of data collected prospectively from the robotic surgery group in General and Colo-Retal Surgery at the Samaritan Hospital (Rio de Janeiro, Brazil), from October 2012 to December 2015. We describe the training stages and particularities. two hundred and ninety three robotic operations were performed in general surgery: 108 procedures for morbid obesity, 59 colorectal surgeries, 55 procedures in the esophago-gastric transition area, 16 cholecystectomies, 27 abdominal wall hernioplasties, 13 inguinal hernioplasties, two gastrectomies with D2 lymphadenectomy, one vagotomy, two diaphragmatic hernioplasties, four liver surgeries, two adrenalectomies, two splenectomies, one pancreatectomy and one bilio-digestive anastomosis. The complication rate was 2.4%, with no major complications. the robotic surgery program of the Samaritan Hospital was safely implemented and with initial results better than the ones described in the current literature. There seems to be benefits in using the robotic platform in super-obese patients, re-operations of obesity surgery and hiatus hernias, giant and paraesophageal hiatus hernias, ventral hernias with multiple defects and rectal resections.


Periventricular leucomalacia and neurodevelopmental outcome in preterm infants.
During an 18 month period, 120 preterm infants of 34 weeks' gestation or less were prospectively examined for periventricular leucomalacia (PVL) by cerebral ultrasound. Neurological and developmental assessment was carried out at 18 months of age corrected for prematurity in 82 surviving neonates. The developmental outcome (Griffiths development quotient) was above 80 and similar in infants with normal scans (n = 41), isolated periventricular-intraventricular haemorrhage (n = 13), and post-haemorrhagic hydrocephalus (n = 4), and no major handicap was diagnosed in these groups. By contrast, the prognosis was variable and poorer in infants with PVL (n = 24) and depended on the extent and site of the lesion. Infants with frontal PVL (n = 13) developed normally. Major sequelae (n = 8) were closely related to frontal-parietal PVL and frontal-parietal-occipital PVL and could be ascribed to the presence of cysts as well as to a persistent hyperechogenic ultrasonographic PVL appearance. A relation between size and site of the lesion and type and severity of the handicap was established.


An in vivo antilymphatic screen in zebrafish identifies novel inhibitors of mammalian lymphangiogenesis and lymphatic-mediated metastasis.
The growth of new lymphatic vessels (lymphangiogenesis) in tumors is an integral step in the metastatic spread of tumor cells, first to the sentinel lymph nodes that surround the tumor and then elsewhere in the body. Currently, no selective agents designed to prevent lymphatic vessel growth have been approved for clinical use, and there is an important potential clinical niche for antilymphangiogenic agents. Using a zebrafish phenotype-based chemical screen, we have identified drug compounds, previously approved for human use, that have antilymphatic activity. These include kaempferol, a natural product found in plants; leflunomide, an inhibitor of pyrimidine biosynthesis; and cinnarizine and flunarizine, members of the type IV class of calcium channel antagonists. Antilymphatic activity was confirmed in a murine in vivo lymphangiogenesis Matrigel plug assay, in which kaempferol, leflunomide, and flunarizine prevented lymphatic growth. We show that kaempferol is a novel inhibitor of VEGFR2/3 kinase activity and is able to reduce the density of tumor-associated lymphatic vessels as well as the incidence of lymph node metastases in a metastatic breast cancer xenograft model. However, in this model, kaempferol administration was also associated with tumor deposits in the pancreas and diaphragm, and flunarizine was found to be tumorigenic. Although this screen revealed that zebrafish is a viable platform for the identification and development of mammalian antilymphatic compounds, it also highlights the need for focused secondary screens to ensure appropriate efficacy of hits in a tumor context.


Milvexian for the Prevention of Venous Thromboembolism.
Factor XIa inhibitors for the prevention and treatment of venous and arterial thromboembolism may be more effective and result in less bleeding than conventional anticoagulants. Additional data are needed regarding the efficacy and safety of milvexian, an oral factor XIa inhibitor. In this parallel-group, phase 2 trial, we randomly assigned 1242 patients undergoing knee arthroplasty to receive one of seven postoperative regimens of milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 mg, or 200 mg once daily) or enoxaparin (40 mg once daily). The primary efficacy outcome was venous thromboembolism (which was a composite of asymptomatic deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death from any cause). The principal safety outcome was bleeding. Among the patients receiving milvexian twice daily, venous thromboembolism developed in 27 of 129 (21%) taking 25 mg, in 14 of 124 (11%) taking 50 mg, in 12 of 134 (9%) taking 100 mg, and in 10 of 131 (8%) taking 200 mg. Among those receiving milvexian once daily, venous thromboembolism developed in 7 of 28 (25%) taking 25 mg, in 30 of 127 (24%) taking 50 mg, and in 8 of 123 (7%) taking 200 mg, as compared with 54 of 252 patients (21%) taking enoxaparin. The dose-response relationship with twice-daily milvexian was significant (one-sided P<0.001), and the 12% incidence of venous thromboembolism with twice-daily milvexian was significantly lower than the prespecified benchmark of 30% (one-sided P<0.001). Bleeding of any severity occurred in 38 of 923 patients (4%) taking milvexian and in 12 of 296 patients (4%) taking enoxaparin; major or clinically relevant nonmajor bleeding occurred in 1% and 2%, respectively; and serious adverse events were reported in 2% and 4%, respectively. Postoperative factor XIa inhibition with oral milvexian in patients undergoing knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Bristol Myers Squibb and Janssen Research and Development; AXIOMATIC-TKR ClinicalTrials.gov number, NCT03891524.).


Pilot study of the Sensory Over-Responsivity Scales: assessment and inventory.
This article describes 3 stages of construction of the Sensory Over-Responsivity (SensOR) Scales: instrument development, reliability and validity analyses, and cross-validation on a new sample. The SensOR Scales include the SensOR Assessment, an examiner-administered performance evaluation, and the SensOR Inventory, a caregiver self-rating scale. Both scales measure sensory overresponsivity in 7 sensory domains. Data were collected from 2 samples consisting of participants who were typically developing (ns = 60 and 44, respectively) and participants with sensory overresponsivity (ns = 65 and 48, respectively), ages 3 to 55. In developing the research edition, items on the pilot version were reviewed for their internal consistency reliability, discriminant validity, and construct validity. Data from both samples on the research edition revealed high internal consistency reliability for domains and the total test and significant discrimination between the overresponsive and the typically responsive groups (p < .05). The preliminary psychometric integrity of the scales, along with continued research efforts, is an important contribution to evidence-based practice.


Infections in the first year after renal transplant.
Infections are frequent complications of kidney transplants. We aimed at determining the frequency and type of infections that occur in renal transplant recipients during the early (0-1 month), intermediate (1-6 months) and late (6-12 months) post-transplant period and analyzing the risk factors for infection. To this aim, we conducted a retrospective cohort study on 1-year post-transplant follow-up in two third-level university hospitals in Cordoba city. All consecutive recipients of renal transplants performed between 2009 and 2015 were included, except those with multiple solid organ transplantation and pediatric patients. We included 375 recipients, of which 235 (62.7%) had at least one episode of infection during follow-up. There were 504 episodes of infection, of which 131 (26%) occurred in the early, 272 (53.9%) in the intermediate, and 101 (20.1%) in the late post-transplant period. The most frequent infections in all periods were caused by bacteria (mainly urinary tract infections), and the most frequent viral infection was caused by Cytomegalovirus (mainly in the second and third period). In the multivariate analysis, infection risk factors were: age > 60 years (adjusted odds ratio [aOR] = 1.92; 95% CI = 1.05-3.49), organ transplantation from deceased donor (aOR = 8.19; 95% CI = 2.32-28.9), use of pigtail catheter for urinary tract drainage (aOR = 4.06; 95% CI = 1.27-12.9), and number of days in hospital after transplant (aOR = 1.05; 95% CI = 1.01-1.11). In conclusion, infections in renal transplant recipients represent a very frequent health problem in our hospitals. Understanding the local epidemiology of infection and the potential risk factors for infection acquires utmost importance.


Quantum chemical data generation as fill-in for reliability enhancement of machine-learning reaction and retrosynthesis planning.
Data-driven synthesis planning has seen remarkable successes in recent years by virtue of modern approaches of artificial intelligence that efficiently exploit vast databases with experimental data on chemical reactions. However, this success story is intimately connected to the availability of existing experimental data. It may well occur in retrosynthetic and synthesis design tasks that predictions in individual steps of a reaction cascade are affected by large uncertainties. In such cases, it will, in general, not be easily possible to provide missing data from autonomously conducted experiments on demand. However, first-principles calculations can, in principle, provide missing data to enhance the confidence of an individual prediction or for model retraining. Here, we demonstrate the feasibility of such an ansatz and examine resource requirements for conducting autonomous first-principles calculations on demand.


Prediction of contrast-induced nephropathy in patients with serum creatinine levels in the upper normal range by cystatin C: a prospective study in 374 patients.
Preexisting renal impairment is a risk factor for contrast-induced nephropathy (CIN). In patients with creatinine in the upper normal level, cystatin C might be a more sensitive predictor of CIN than creatinine. Therefore, in this study, we investigated the usefulness of cystatin C to predict CIN. In 400 consecutive patients with creatinine baseline levels between 0.8 and 1.3 mg/dL undergoing coronary angiography (n = 200) or CT (n = 200), baseline values of cystatin C, creatinine, blood urea nitrogen (BUN) and risk factors of CIN were determined. Creatinine was also assessed 24 and 48 hours after contrast administration. Creatinine significantly (p < 0.001) increased after 24 hours and 48 hours compared with baseline (1.06 ± 0.28 and 1.07 ± 0.28 vs 0.99 ± 0.18 mg/dL). Fifty-three of 373 evaluable patients (14.2%) had an increase in creatinine of ≥ 25% or ≥ 0.5 mg/dL within 48 hours. CIN according to this definition was significantly more frequent after intraarterial contrast administration (38/190, 20%) compared with IV contrast administration (15/183, 8.2%; p = 0.001). CIN was predicted by baseline cystatin C (area under the receiver operating characteristic [ROC] curve [AUC], 0.715; p < 0.001), whereas creatinine, creatinine clearance, and BUN were not predictive. The best predictive capabilities were provided by cystatin C/creatinine-ratio (AUC, 0.826; p < 0.001). Multivariate regression analysis showed that intraarterial contrast administration (p = 0.002) and higher baseline cystatin C (p < 0.001) combined with low creatinine (p = 0.044) were independently associated with higher increases in creatinine within 48 hours after contrast administration. CIN in patients with creatinine within the upper normal range is significantly more frequent after intraarterial than after IV contrast administration. In these patients, renal impairment after contrast administration is independently predicted by cystatin C and cystatin C/creatinine-ratio, whereas BUN and creatinine were not predictive.


Intraguild interactions between Euseius stipulatus and the candidate biocontrol agents of Tetranychus urticae in Spanish clementine orchards: Phytoseiulus persimilis and Neoseiulus californicus.
Spanish clementine orchards are frequently infested by the two-spotted spider mte Tetranychus urticae. Natural control of T. urticae is insufficient despite the presence of Neoseiulus californicus and Phytoseiulus persimilis. The phytoseiid community is dominated by the generalist Euseius stipulatus which is poorly adapted to exploit T. urticae. Having the intention to promote biological control of T. urticae by augmentative releases we were interested whether P. persimilis and N. californicus are negatively affected by intraguild (IG) interactions with E. stipulatus. Two experiments were conducted. Firstly, we assessed female aggressiveness (quantified as combination of attack probability and latency) in IG predation on larvae. Secondly, we measured mortality, escaping rate and developmental time of immature IG prey in presence and absence of an adult IG predator female. Euseius stipulatus appeared the strongest IG opponent but microhabitat structure modulated the IG interactions and the advantage of E. stipulatus was partially offset when spider mite webbing was present. Implications of these IG interactions for natural and biological control of T. urticae in clementine orchards are discussed.


Neurobiological background for the development of new drugs in schizophrenia.
Psychopharmacology of schizophrenia has remained static for many years because the mechanisms explored have been basically monoaminergics, primarily focused toward the modification of dopaminergic function and, later on, serotonergic. In fact, most of the antipsychotics introduced in clinical practice in the last years have been antagonists or selective agonists of these receptors (D(2)/5-HT(2)). The exploration of other receptor pathways, and in particular those additionally involved in the action of the paradigmatic "atypical" antipsychotic clozapine (ie, cholinergic and noradrenergic), has not been very significant. Besides, research in the antipsychotics field has developed also by exploring pathways that are beyond the spectrum of clozapine. Among the most promising mechanisms are those based on the glutamatergic hypothesis of schizophrenia (agonists at the glycine-binding modulatory site of the N-methyl-D-aspartate receptor, glycine transporter inhibitors, modulators of the AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid] receptor and selective agonists of the metabotropic receptor Glu(2)). Other less classic pathways are also under study and have led to some agents that are found in very early stages of development such as those acting on sigma receptors, cholecystokinin antagonists, neurotensin agonists, neurokinin receptor antagonists, GABAergic (+-aminobutyric acid [GABA]) enhancers, and cannabinoid(gamma-aminobutiric) receptor modulators.