Protective Effects of Myo-Inositol and Selenium on Cadmium-Induced Thyroid Toxicity in Mice.
Cadmium (Cd) damages the thyroid gland. We evaluated the effects of myo-inositol (MI), seleno-L-methionine (Se) or their combination on the thyroids of mice simultaneously administered with Cd chloride (CdCl2). Eighty-four male mice were divided into 12 groups (seven mice each). Six groups (controls) were treated with 0.9% NaCl (vehicle), Se (0.2 mg/kg/day), Se (0.4 mg/kg/day), MI (360 mg/kg/day), MI+Se (0.2 mg/kg) and MI+Se (0.4 mg/kg). The other six groups were treated with CdCl2 (2 mg/kg), CdCl2+MI, CdCl2+Se (0.2 mg/kg), CdCl2+Se (0.4 mg/kg), CdCl2+MI+Se (0.2 mg/kg) and CdCl2+MI+Se (0.4 mg/kg). An additional group of CdCl2-challenged animals (n= 7) was treated with resveratrol (20 mg/kg), an effective and potent antioxidant. All treatments lasted 14 days. After sacrifice, the thyroids were evaluated histologically and immunohistochemically. CdCl2 reduced the follicular area, increased the epithelial height, stroma, and cells expressing monocyte chemoattractant protein-1 (MCP-1) and C-X-C motif chemokine 10 (CXCL10). CdCl2+Se at 0.2/0.4 mg/kg insignificantly reversed the follicular and stromal structure, and significantly decreased the number of MCP-1 and CXCL10-positive cells. CdCl2+MI significantly reversed the thyroid structure and further decreased the number of MCP-1 and CXCL10-positive cells. CdCl2+MI+Se, at both doses, brought all indices to those of CdCl2-untreated mice. MI, particularly in association with Se, defends mice from Cd-induced damage. The efficacy of this combination was greater than that of resveratrol, at least when using the follicular structure as a read-out for a comparison. We suggest that the use of these nutraceuticals, more specifically the combination of MI plus SE, can protect the thyroid of Cd-exposed subjects.


Screening and use of high titered anti-HLA-DR sera in PHA-blast complement fixation and B-lymphocytotoxicity techniques.
Screening for anti-HLA-DR sera was performed by complement fixation on PHA stimulated peripheral blood lymphocytes (PHA-CF), or cultured B lymphoid cell lines. Out of 1,350 sera from multiparous women, multitransfused patients, and patients transfused during extra-corporal circulation (ECC), 219 contained anti-HLA-DR activity (16.2%). Anti-HLA-DR antibodies developed after ECC were often high titered (1:10 to 1:100). In half of these sera anti-HLA-A, B antibodies were weak or absent, making it possible to use then as anti-HLA-DR reagents without platelet absorption. Of the 219 positive sera 51 contained defined anti-DR antibodies (20 monospecific and 31 bi- or multispecific). The 13 best sera recognized DR1 and DR7 specificities with r values from 0.83 to 1. Twenty-four sera selected by CF were also studied by lymphocytotoxicity technique against peripheral blood B lymphocytes (B-LCT). Both PHA-CF and B-LCT techniques gave similar results, detecting the same specificities and showing comparable sensitivity. The advantages of CF are: easy storage of target cells at -80 degrees C or + 4 degrees C, and fast reading. For these reasons PHA-CF or CF on cultured B lymphoid cell lines can be proposed for large scale screening of anti-HLA-DR sera. The sera thus screened can be used for HLA-DR typing either by PHA-CF or B-LCT.


Nano-based strategies to overcome p-glycoprotein-mediated drug resistance.
The discussion about cancer treatment has a long history. Chemotherapy, one of the promising approaches in cancer therapy, is limited in the clinic as plenty of factors evolve and prevent appropriate therapeutic response to drugs. Multi-drug resistance (MDR), which is mostly P-glycoprotein-mediated, is described as the most well-known impediment in this contribution. It extrudes several agents out of cells, arising MDR and decreasing the bioavailability of drugs. Hence, cancer cells become insensitive to chemotherapy. Many agents have been developed to reverse MDR, but it is difficult to deliver them into cancer sites and cancer cells. The emerging nano-based drug delivery systems have been more effective to overcome P-glycoprotein-mediated MDR by increasing the intracellular delivery of these agents. Here, we represent systems including siRNA-targeted inhibition of P-gp, monoclonal antibodies, natural extracts, conventional inhibitors, hard nanoparticles and soft nanoparticles as delivery systems in addition to a novel approach applying cell penetrating peptides. Overcoming cancer drug resistance using innovative nanotechnology is being increasingly used and developed. Among resistance mechanisms, drug efflux transporter inhibitors and MDR gene expression silencing are among the those being investigated. In the near future, it seems some of these nanomedical approaches might become the mainstay of effective treatment of important human conditions like cancer.


Association of arch height with ankle muscle strength and physical performance in adult men.
Differences in arch height may have a certain impact on lower extremity muscle strength and physical performance. However, there is little evidence from investigation of the possible correlation of arch height with ankle muscle strength and physical performance measures. Sixty-seven participants took part in this study. Arch height index (AHI) was assessed and categorized using a 3-dimension foot scanner. Ankle muscle strength was measured employing a dynamometer. Physical performance measures including agility, force and proprioception were randomly tested. Compared to the medium AHI, the high AHI had lower plantarflexion and inversion peak torque. The high AHI also had lower peak torque per body weight value for plantarflexion and inversion at 120°/s (P = 0.026 and 0.006, respectively), and dorsiflexion at 30°/s (P = 0.042). No significant ankle muscle strength difference was observed between the low and medium AHI. Additionally, AHI was negatively correlated with eversion and inversion peak torque at 120°/s, and negatively associated with plantarflexion, eversion and inversion peak torque per body weight at both 30°/s and 120°/s (r ranged from -0.26 to -0.36, P values < 0.050). However, no significant relationship was found between arch height and physical performance measures. The results showed that high arches had lower ankle muscle strength while low arches exhibited greater ankle muscle strength. Arch height was negatively associated with ankle muscle strength but not related to physical performance. We suggest that the lower arch with greater ankle muscle strength may be an adaptation to weight support and shock absorption.


More Human than Human.
Within the literature surrounding nonhuman animals on the one hand and cognitively disabled humans on the other, there is much discussion of where beings that do not satisfy the criteria for personhood fit in our moral deliberations. In the future, we may face a different but related problem: that we might create (or cause the creation of) beings that not only satisfy but exceed these criteria. The question becomes whether these are minimal criteria, or hierarchical, such that those who fulfill them to greater degree should be afforded greater consideration. This article questions the validity and necessity of drawing divisions among beings that satisfy the minimum requirements for personhood; considering how future beings-intelligent androids, synthezoids, even alternate-substrate sentiences-might fit alongside the "baseline" human. I ask whether these alternate beings ought to be considered different to us, and why this may or may not matter in terms of a notion of "human community." The film Blade Runner, concerned in large part with humanity and its key synthezoid antagonist Roy Batty, forms a framing touchstone for my discussion. Batty is stronger, faster, more resilient, and more intelligent than Homo sapiens. His exploits, far beyond the capability of normal humans, are contrasted with his frailty and transient lifespan, his aesthetic appreciation of the sights he has seen, and his burgeoning empathy. Not for nothing does his creator within the mythos term him "more human than human."


Characteristics of biotrickling filter system for hydrogen sulfide removal with seasonal temperature variations: A strategy for low temperature conditions.
The impact of temperature on the biological removal of hydrogen sulfide (H2S) from air is critical to its effective application in cold regions or seasons. This study investigated the effect of seasonal temperature variations (7-30 °C) on the H2S removal performance of a biotrickling filter system, with an effective H2S elimination capacity of 98.1 g/m3/h (removal efficiency = 83.1 %) achieved at temperatures of 10-12 °C. Biofilm growth was found to be accelerated by increased secretion of extracellular polymeric substances, enhanced biofilm adhesion capacity and relatively high levels of elemental sulfur accumulation, which help to retain heat within the filter bed under cold conditions. High-throughput sequencing showed that the psychrotolerant sulfur-oxidizing bacterium (SOB) Metallibacterium was gradually enriched (54.8 %) at temperatures below 15 °C. The major pathways of sulfur metabolism under low temperature conditions were determined based on the detection of enzymes related to sulfur metabolism. Finally, a strategy to enrich Metallibacterium was proposed to promote the application of biodesulfurization under low temperature conditions.


Lyapunov Theory-Based Fusion Neural Networks for the Identification of Dynamic Nonlinear Systems.
This paper introduces a novel fusion neural architecture and the use of a novel Lyapunov theory-based algorithm, for the online approximation of the dynamics of nonlinear systems. The proposed neural system, in combination with the proposed update rule of the neural weights, achieves fast convergence of the identification process, ensuring at the same time stability of the error system in the sense of Lyapunov theory. The fusion neural system combines the features that are extracted from two-independent neural streams, a feedforward and a diagonal recurrent one, satisfying different design criteria of the identification task. Simulation results for five cases reveal the approximation strength of both proposed fusion neural architecture and proposed learning algorithm. Also, additional experiments demonstrate the effectiveness in cases of parameter variations and additive noise.


Novel immunoregulatory functions of phenotypically distinct subpopulations of CD4+ cells in the human neonate.
Although normal numbers of CD4+ T cells are present in the human neonate, cord blood CD4+ cells are deficient in their ability to provide help for antibody production. In the present studies, we have examined the cellular basis for this functional deficit by analyzing the phenotypic properties and immunoregulatory functions of the subsets of cord blood CD4+ cells defined by anti-CD45RA mAb. In contrast to CD4+ cells from adults, greater than 90% of cord blood CD4+ cells expressed the CD45RA, CD38, and Leu-8 membrane Ag. When neonatal CD4+ cells were cultured with adult B cells and PWM or anti-CD4+ mAb, no helper function was apparent. However, when the small number of CD4+CD45RA- cells in cord blood were purified and similarly analyzed, helper activity comparable to that of adult CD4+CD45RA- cells was found. This helper function was profoundly suppressed by the presence of even small numbers of cord blood (but not adult) CD4+CD45RA+ cells. Irradiation of mitomycin C treatment of neonatal CD4+CD45RA+ cells abrogated their suppressor activity, but did not induce helper capability. However, after activation with PHA and culture in IL-2, cord blood CD4+CD45RA+ cells lost their suppressor activity and acquired the ability to provide help for B cell differentiation. This functional maturation was accompanied by their conversion to the CD4+CD45RA- phenotype. Thus, whereas cord blood CD4+CD45RA+ and CD4+CD45RA- cells share certain properties with the analogous subsets in adults, our data show that the dominant immunoregulatory function of cord blood CD4+ cells is suppression mediated by CD4+CD45RA+ (and CD38+) cells. In view of these phenotypic and functional differences between neonatal and adult CD4+CD45RA+ cells, we propose that "naive" CD4+CD45RA+ cells undergo age-related maturational changes that are unrelated to their postulated activation-dependent post-thymic differentiation into CD4+CD45RA- "memory" cells capable of helper functions.


Co-culturing a novel Bacillus strain with Clostridium tyrobutyricum ATCC 25755 to produce butyric acid from sucrose.
Currently, the most promising microorganism used for the bio-production of butyric acid is Clostridium tyrobutyricum ATCC 25755T; however, it is unable to use sucrose as a sole carbon source. Consequently, a newly isolated strain, Bacillus sp. SGP1, that was found to produce a levansucrase enzyme, which hydrolyzes sucrose into fructose and glucose, was used in a co-culture with this strain, permitting C. tyrobutyricum ATCC 25755T to ferment sucrose to butyric acid. B. sp. SGP1 alone did not show any butyric acid production and the main metabolite produced was lactic acid. This allowed C. tyrobutyricum ATCC 25755T to utilize the monosaccharides resulting from the activity of levansucrase together with the lactic acid produced by B. sp. SGP1 to generate butyric acid, which was the main fermentative product within the co-culture. Furthermore, the final acetic acid concentration in the co-culture was significantly lower when compared with pure C. tyrobutyricum ATCC 25755T cultures grown on glucose. In fed-batch fermentations, the optimum conditions for the production of butyric acid were around pH 5.50 and a temperature of 37°C. Under these conditions, the final butyrate concentration was 34.2±1.8 g/L with yields of 0.35±0.03 g butyrate/g sucrose and maximum productivity of 0.3±0.04 g/L/h. Using this co-culture, sucrose can be utilized as a carbon source for butyric acid production at a relatively high yield. In addition, this co-culture offers also the benefit of a greater selectivity, with butyric acid constituting 92.8% of the acids when the fermentation was terminated.


A new tri-particle backlighter for high-energy-density plasmas (invited).
A new tri-particle mono-energetic backlighter based on laser-driven implosions of DT3He gas-filled capsules has been implemented at the OMEGA laser. This platform, an extension of the original D3He backlighter platform, generates 9.5 MeV deuterons from the T3He reaction in addition to 14.7 and 3.0 MeV protons from the deuterium and helium-3 reactants. The monoenergetic 14.7 and 3.0 MeV protons have been used with success at OMEGA and the NIF for both radiography and stopping-power studies. There are several advantages of having a third particle to diagnose plasma conditions: an extra time-of-flight-separated radiograph and an improved ability to discern between electric and magnetic fields. In cases where the 3.0 MeV protons cannot penetrate an experiment, the benefit of the additional 9.5 MeV deuterons is magnified. This capability is well-suited for NIF experiments, where large fields and plasma densities often preclude useful 3.0 MeV proton data. The advantages are demonstrated with radiographs of OMEGA plasmas with magnetic and electric fields. Tests using backlighter-scale 420 μm diameter thin glass capsules validate the platform's extended backlighting capability. The performance characteristics of this backlighter, such as source size and timing, are discussed.


Molecular screening of the neutrophil elastase gene in congenital neutropenia.
Congenital neutropenia is a rare hematopoietic disease, which occurs sporadically or as an auto-somal dominant inherited disorder. Pathogenesis of congenital neutropenia can now be attributed to mutations of the ELA2 gene encoding neutrophil elastase. A child with severe congenital neutropenia with a heterozygous mutation G1887A in exon 2 of ELA2 gene is reported.


The total cis-methylene-interrupted fatty acids in canadian margarines.
Of 20 locally available brands of margarine, four were labelled as containing polyunsaturates and three as containing corn oil. Only one product contained significantly more cis-methylene-interrupted fatty acids than did regular margarines.


Immunohistology of the antigenic pattern of a continuous cell line from a human colon tumor.
The antigenic surface pattern of a continuous cell line (HT29) derived from a human primary carcinoma of the colon was studied by the immunofluorescence technique. Monovalent and polyvalent immune sera were used. The cells of this long-term culture kept the ability to synthesize the three principal colon tumor antigens: carcinoembryonic and nonspecific cross-reacting antigens, and the membrane-associated tissular autoantigen. On the HT29 cells, which still carry the original blood group of the tumor donor, no receptors for human Ig's were detected.


Hippocampal CA3-dentate gyrus volume uniquely linked to improvement in associative memory from childhood to adulthood.
Associative memory develops into adulthood and critically depends on the hippocampus. The hippocampus is a complex structure composed of subfields that are functionally-distinct, and anterior-posterior divisions along the length of the hippocampal horizontal axis that may also differ by cognitive correlates. Although each of these aspects has been considered independently, here we evaluate their relative contributions as correlates of age-related improvement in memory. Volumes of hippocampal subfields (subiculum, CA1-2, CA3-dentate gyrus) and anterior-posterior divisions (hippocampal head, body, tail) were manually segmented from high-resolution images in a sample of healthy participants (age 8-25 years). Adults had smaller CA3-dentate gyrus volume as compared to children, which accounted for 67% of the indirect effect of age predicting better associative memory via hippocampal volumes. Whereas hippocampal body volume demonstrated non-linear age differences, larger hippocampal body volume was weakly related to better associative memory only when accounting for the mutual correlation with subfields measured within that region. Thus, typical development of associative memory was largely explained by age-related differences in CA3-dentate gyrus.


Thaumarchaeotal signature gene distribution in sediments of the northern South China Sea: an indicator of the metabolic intersection of the marine carbon, nitrogen, and phosphorus cycles?
Thaumarchaeota are abundant and active in marine waters, where they contribute to aerobic ammonia oxidation and light-independent carbon fixation. The ecological function of thaumarchaeota in marine sediments, however, has rarely been investigated, even though marine sediments constitute the majority of the Earth's surface. Thaumarchaeota in the upper layer of sediments may contribute significantly to the reservoir of nitrogen oxides in ocean waters and thus to productivity, including the assimilation of carbon. We tested this hypothesis in the northern South China Sea (nSCS), a section of a large oligotrophic marginal sea with limited influx of nutrients, including nitrogen, by investigating the diversity, abundance, community structure, and spatial distribution of thaumarchaeotal signatures in surface sediments. Quantitative real-time PCR using primers designed to detect 16S rRNA and amoA genes in sediment community DNA revealed a significantly higher abundance of pertinent thaumarchaeotal than betaproteobacterial genes. This finding correlates with high levels of hcd genes, a signature of thaumarchaeotal autotrophic carbon fixation. Thaumarchaeol, a signature lipid biomarker for thaumarchaeota, constituted the majority of archaeal lipids in marine sediments. Sediment temperature and organic P and silt contents were identified as key environmental factors shaping the community structure and distribution of the monitored thaumarchaeotal amoA genes. When the pore water PO4(3-) concentration was controlled for via partial-correlation analysis, thaumarchaeotal amoA gene abundance significantly correlated with the sediment pore water NO2(-) concentration, suggesting that the amoA-bearing thaumarchaeota contribute to nitrite production. Statistical analyses also suggest that thaumarchaeotal metabolism could serve as a pivotal intersection of the carbon, nitrogen, and phosphorus cycles in marine sediments.


Frailty is strongly associated with self-reported symptom burden among patients with cirrhosis.
Although patients with cirrhosis often experience debilitating symptoms, few are referred for palliative care. Frailty is increasingly incorporated in liver transplantation evaluation and has been associated with symptom burden in other populations. We hypothesized that frail patients with cirrhosis are highly symptomatic and thus are likely to benefit from palliative care. Patients with cirrhosis undergoing outpatient liver transplantation evaluation completed the Liver Frailty Index (grip strength, chair stands and balance) and a composite of validated measures including the Edmonton Symptom Assessment Scale, distress and quality of life (QOL) measures. Of 233 patients (median age 61 years, 43% women), 22% were robust, 59% prefrail and 19% frail. Overall, 38% of patients reported ≥1 severe symptoms based on preestablished Edmonton Symptom Assessment Scale criteria. Higher frailty categories were associated with increased prevalence of pain, dyspnea, fatigue, nausea, poor appetite, drowsiness, depression and poor well-being (test for trend, all P < 0.05). Frail patients were also more likely to report psychological distress and poor QOL (all P < 0.01). In univariate analysis, each 0.5 increase in liver frailty index was associated with 44% increased odds of experiencing ≥1 severe symptoms [95% confidence interval (CI), 1.2-1.7, P < 0.001], which persisted (odds ratio, 1.3, 95% CI, 1.0-1.6, P = 0.004) even after adjusting for Model for End Stage Liver Disease-Sodium, ascites, hepatic encephalopathy and age. In patients with cirrhosis, frailty is strongly associated with physical/psychological symptoms, including pain and depression and poor QOL. Frail patients with cirrhosis may benefit from palliative care co-management to address symptoms and improve QOL.


Impact of the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) study and its post hoc analyses on clinical practice in the United States: A survey of Haemophilia and Thrombosis Research Society members.
A recent randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET), confirmed that exposure to recombinant FVIII (rFVIII) products doubled the risk of inhibitor development compared to plasma-derived FVIII (pdFVIII) in previously untreated (or minimally treated) patients (PUPs) with severe haemophilia A. SIPPET post hoc analyses showed that early exposure to rFVIII was more immunogenic and that rFVIII could harm low-risk PUPs with non-null mutations. Clinical implications of SIPPET findings for the haemophilia community were unclear. Study the impact of the SIPPET study and its post hoc analyses on clinical practice for PUPs with severe haemophilia A in the United States. Members of the North American Hemophilia and Thrombosis Research Society (HTRS) completed two online questionnaires related to SIPPET publications and PUP management (study period: 12/2016-8/2018). Over 50% participated the study. Sixty per cent expressed methodological concerns about the SIPPET study, yet 55% shared the study with new families. During the study period, rFVIII selection fell from 43/61 (70%) to 15/54 (28%) while use of pdFVIII and shared decision-making increased from 5/61 (8%) to 9/54 (17%) and from 4/61 (7%) to 10/54 (19%), respectively. Based on post hoc analyses, 44/54 (82%) would change their clinical practice with 31/44 (70%) using pdFVIII for PUPs. Barriers to translation of SIPPET analyses included study design concerns, non-inclusion of novel therapies, inability to perform genetic testing at diagnosis and risk of plasma-derived infections. Despite the methodological concerns about the SIPPET study, this Grade I evidence appears to have influenced the clinical practice of haemophilia providers in the United States.


Butyrate-induced cytoarchitectural reorganization of Mallory body-containing rat hepatic tumor cells.
Diethylnitrosamine (CAS: 55-18-5)-transformed 72/22 rat hepatic tumor cells undergo marked cytoarchitectural changes during exposure to sodium butyrate in vitro. Butyrate treatment of this cell line resulted in an increased cell size, volume, and protein content and in structural reorganization within both the intermediate filament and microfilament networks resulting in the generation of a more normal appearing hepatocytic phenotype. Induced changes in the microfilament system involved the accumulation of F-actin at the cellular margins in the form of a peripheral band and in the development of an extensive, predominantly centralized network of thickened cytoplasmic filament bundles. Such butyrate-induced changes in hepatic tumor cellular morphology and microfilament organization were reflected in a 26-51% increase in the amount of cytoskeletal-associated actin in 72/22 cells, as determined by flow cytofluorimetry of permeabilized intact cells or by scanning densitometry of the electrophoretically separated, detergent-resistant cytoskeletal protein fraction, respectively. It is unlikely that this increase in cellular microfilament content was due to a direct effect of butyrate on actin polymerization per se since butyrate (in final concentrations equal to that used in culture) did not alter either actin monomer-polymer transitions or the nucleation reaction in a defined in vitro polymerization assay. The available data suggest that butyrate may regulate the synthesis or modulate the actin-binding capacity of microfilament-associating proteins in cultured cells. Butyrate-induced "normalization" of 72/22 cytoarchitecture was previously shown to be reflected in a reduction or loss in the expression of specific growth traits characteristic of the transformed phenotype. The experimental reversal of defined cytoarchitectural abnormalities and transformed growth characteristics of 72/22 cells by butyrate provided an in vitro model to elucidate both particular cytoskeletal events associated with epithelial cell transformation and the mechanism of action of apparent differentiation-inducing agents, such as sodium butyrate, on responsive tumor cells.


Serological analysis of the deoxyribonucleic acid polymerase of avian oncornaviruses. I. Preparation and characterization of monospecific antiserum with purified deoxyribonucleic acid polymerase.
Monospecific antiserum was prepared against purified deoxyribonucleic acid (DNA) polymerase from avian myeloblastosis virus (AMV). Immunodiffusion assay with purified DNA polymerase revealed that the anti-DNA polymerase serum formed one precipitation band, whereas no reaction with any of the seven major structural proteins of AMV was observed. The antiserum also demonstrated enzyme-neutralizing antibody activity that was associated with the immunoglobulin G fraction. There was no difference in the neutralization of DNA polymerase activity directed by ribonucleic acid (RNA), DNA, or RNA-DNA hybrid templates.


Mammalian target of rapamycin inhibitors, temsirolimus and torin 1, attenuate stemness-associated properties and expression of mesenchymal markers promoted by phorbol-myristate-acetate and oncostatin-M in glioblastoma cells.
The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway is crucial for tumor survival, proliferation, and progression, making it an attractive target for therapeutic intervention. In glioblastoma, activated mammalian target of rapamycin promotes invasive phenotype and correlates with poor patient survival. A wide range of mammalian target of rapamycin inhibitors are currently being evaluated for cytotoxicity and anti-proliferative activity in various tumor types but are not explored sufficiently for controlling tumor invasion and recurrence. We recently reported that mammalian target of rapamycin inhibitors-rapamycin, temsirolimus, torin 1, and PP242-suppressed invasion and migration promoted by tumor necrosis factor-alpha and phorbol-myristate-acetate in glioblastoma cells. As aggressive invasion and migration of tumors are associated with mesenchymal and stem-like cell properties, this study aimed to examine the effect of mammalian target of rapamycin inhibitors on these features in glioblastoma cells. We demonstrate that temsirolimus and torin 1 effectively reduced the constitutive as well as phorbol-myristate-acetate/oncostatin-M-induced expression of mesenchymal markers (fibronectin, vimentin, and YKL40) and neural stem cell markers (Sox2, Oct4, nestin, and mushashi1). The inhibitors significantly abrogated the neurosphere-forming capacity induced by phorbol-myristate-acetate and oncostatin-M. Furthermore, we demonstrate that the drugs dephosphorylated signal transducer and activator transcription factor 3, a major regulator of mesenchymal and neural stem cell markers implicating the role of signal transducer and activator transcription factor 3 in the inhibitory action of these drugs. The findings demonstrate the potential of mammalian target of rapamycin inhibitors as "stemness-inhibiting drugs" and a promising therapeutic approach to target glioma stem cells.


Using ambulatory A&E care to cut admissions.
Evidence shows many conditions can be effectively managed out of hospital, with greater patient satisfaction and fewer hospital admissions. South Tyneside Foundation Trust ran a pilot project in which an ambulatory emergency care (AEC) department saw patients admitted to hospital via their GP, producing the benefits stated above.


Reconsolidation impairment of reward memory by stimulating stress response.
Research in memory reconsolidation has raised hope for new treatment options of persistent psychiatric disorders like substance dependence and post-traumatic stress disorder (PTSD). While animal research showed successful memory modification by interfering with reconsolidation, human research requires less invasive techniques. In our pilot study, we aimed to reduce appetitive memory reconsolidation of a newly acquired reward memory by exerting a stressor. Thirty healthy participants were randomly assigned to two groups performing a monetary reward paradigm at a personal computer. Day 1 was considered to allow for memory acquisition; on day 2, the experimental group was exposed to a frightening stimulus in the reconsolidation window; and day 3 again served to determine reward memory effects. Measures of reward memory were reaction times to reward announcing stimuli (ie, showing instrumental behavior), actual reward gained, and electrodermal response as a measure for reward anticipation. We found significantly smaller reaction time improvements to reward stimuli over time in the experimental group, as well as reduced achievements in monetary reward. Electrodermal response to reward announcing stimuli was lower in the experimental group after intervention, whereas it was higher in the untreated group. Thus, we argue in favor of the reconsolidation hypothesis, assuming our intervention had successfully interfered with the reconsolidation process. This points towards future treatment options that interfere with an addiction memory.


Mechanical properties of bare and protein-coated giant unilamellar phospholipid vesicles. A comparative study of micropipet aspiration and atomic force microscopy.
In this study, protein-coated giant phospholipid vesicles were used to model cell plasma membranes coated by surface protein layers that increase membrane stiffness under mechanical or osmotic stress. These changed mechanical properties like bending stiffness, membrane area compressibility modulus, and effective Young's modulus were determined by micropipet aspiration, while bending stiffness, effective Young's modulus, and effective spring constant of vesicles were analyzed by AFM. The experimental setups, the applied models, and the results using both methods were compared here. As demonstrated before, we found that bare vesicles were best probed by micropipet aspiration due to its high sensitivity. The mechanical properties of vesicles with protein surface layers were, however, better determined by AFM because it enables very local deformations of the membrane with barely any structural damage to the protein layer. Mechanical properties of different species of coating proteins, here streptavidin and avidin, could be clearly distinguished using this technique.


Local interactions and their group-level consequences in flocking jackdaws.
As one of nature's most striking examples of collective behaviour, bird flocks have attracted extensive research. However, we still lack an understanding of the attractive and repulsive forces that govern interactions between individuals within flocks and how these forces influence neighbours' relative positions and ultimately determine the shape of flocks. We address these issues by analysing the three-dimensional movements of wild jackdaws ( Corvus monedula) in flocks containing 2-338 individuals. We quantify the social interaction forces in large, airborne flocks and find that these forces are highly anisotropic. The long-range attraction in the direction perpendicular to the movement direction is stronger than that along it, and the short-range repulsion is generated mainly by turning rather than changing speed. We explain this phenomenon by considering wingbeat frequency and the change in kinetic and gravitational potential energy during flight, and find that changing the direction of movement is less energetically costly than adjusting speed for birds. Furthermore, our data show that collision avoidance by turning can alter local neighbour distributions and ultimately change the group shape. Our results illustrate the macroscopic consequences of anisotropic interaction forces in bird flocks, and help to draw links between group structure, local interactions and the biophysics of animal locomotion.


Great Expectations: HIV Risk Behaviors and Misperceptions of Low HIV Risk among Incarcerated Men.
Incarcerated populations have relatively high HIV prevalence but little has been reported about their aggregate HIV risk behaviors or perceptions of risk. A random selection of HIV-negative men (n = 855) entering a US state prison system were surveyed to assess five risk behaviors and his self-perceived HIV risk. Using multivariate logistic regression, we identified factors associated with having elevated actual but low perceived risk (EALPR). Of the 826 men with complete data, 88% were at elevated risk. While 64% of the sample had risk perceptions concordant with their actual risk, 14% had EALPR (with the remainder at low actual but high perceived risk). EALPR rates were lower in those with a pre-incarceration HIV test but higher for those with a negative prison entry HIV test. HIV testing counseling should assess for discordance between actual and perceived risk and communicate the continued risk of HIV despite a negative result.


Clinical neuroscience approaches in psychiatry.
Recent advances in the clinical neurosciences have begun to expand and change our understanding of how the brain functions. As further neuroscientific principles are delineated we may gain insights into the underlying pathophysiology of some psychiatric disorders and through this new understanding we may be able to define new therapeutic interventions. Two illustrative examples of neuroscientific research are discussed and reviewed both in terms of the promises and dangers inherent in these new approaches to the mind.


Voyaging into the third dimension: A perspective on virtual methods and their application to studies of juvenile sex estimation and the ontogeny of sexual dimorphism.
In contrast to the well-established and highly accurate morphological methods available for sexing adult skeletons, juvenile sex estimation is widely recognised as a difficult task that faces a series of challenges. The acquisition of 3D data, and construction of 3D models from volume or surface scans, has become increasingly common in forensic sciences, and these data offer considerable opportunity for the development and refinement of methods in sex estimation. The suitability and potential of virtual methods for juvenile sex estimation are evaluated with the aims of identifying (1) the benefits and challenges associated with virtual data and quantitative analysis of 3D models, and (2) pathways that may lead to practical improvements for sexing juveniles. The issues associated with sex estimation in juveniles are discussed and approached in the context of a framework that unifies classification results for a given trait, which provide information on its capacity to discriminate between the sexes, with the underlying patterns of dimorphism over ontogeny. Virtual collections of 3D models are suggested as integral to this framework because they enable the magnitude and mode of sexual dimorphism to be comprehensively quantified for a chosen trait or set of traits. Those data can be used to inform decisions about how to apply a method for sex estimation to maximize its success. Virtual collections, through extending the scope of analyses and impacting the way in which questions on sexual dimorphism in juveniles may be answered, are undoubtedly set to play a central role in future research.


A model for identifying and ranking need for trauma service in nonmetropolitan regions based on injury risk and access to services.
Timely access to definitive trauma care has been shown to improve survival rates after severe injury. Unfortunately, despite development of sophisticated trauma systems, prompt, definitive trauma care remains unavailable to over 50 million North Americans, particularly in rural areas. Measures to quantify social and geographic isolation may provide important insights for the development of health policy aimed at reducing the burden of injury and improving access to trauma care in presently under serviced populations. Indices of social deprivation based on census data, and spatial analyses of access to trauma centers based on street network files were combined into a single index, the Population Isolation Vulnerability Amplifier (PIVA) to characterize vulnerability to trauma in socioeconomically and geographically diverse rural and urban communities across British Columbia. Regions with a sufficient core population that are more than one hour travel time from existing services were ranked based on their level of socioeconomic vulnerability. Ten regions throughout the province were identified as most in need of trauma services based on population, isolation and vulnerability. Likewise, 10 communities were classified as some of the least isolated areas and were simultaneously classified as least vulnerable populations in province. The model was verified using trauma services utilization data from the British Columbia Trauma Registry. These data indicate that including vulnerability in the model provided superior results to running the model based only on population and road travel time. Using the PIVA model we have shown that across Census Urban Areas there are wide variations in population dependence on and distances to accredited tertiary/district trauma centers throughout British Columbia. Many of the factors that influence access to definitive trauma care can be combined into a single quantifiable model that researchers in the health sector can use to predict where to place new services. The model can also be used to locate optimal locations for any basket of health services.


Tetramethoxydibenzoquinolizinium salts. Preparation and antileukemic activity of some positional and structural isomers of coralyne.
Some positional and structural isomers of coralyne were prepared and evaluated in the P388 lymphocytic leukemia system for their inhibitory activity. The levels of antileukemic activity of coralyne, neocoralyne, isocoralyne, and stracoralyne were comparable, thus implying that two sets of the N-O-O triangular pharmacophore in a condensed isoquinoline molecule are preferable and the angle between these two sets has little influence on antileukemic activity. The importance of the environment around the C5-C6 region of the dibenzo[a,g]quinolizine ring to antileukemic activity was demonstrated by the activity differences between coralyne and allocoralyne.


Effectiveness of a Sugar-Yeast Monitor and a Chemical Lure for Detecting Bed Bugs.
Effective bed bug (Cimex lectularius L.) monitors have been actively sought in the past few years to help detect bed bugs and measure the effectiveness of treatments. Most of the available active monitors are either expensive or ineffective. We designed a simple and affordable active bed bug monitor that uses sugar-yeast fermentation and an experimental chemical lure to detect bed bugs. The sugar-yeast mixture released carbon dioxide at a similar rate (average 405.1 ml/min) as dry ice (average 397.0 ml/min) during the first 8 h after activation. In naturally infested apartments, the sugar-yeast monitor containing an experimental chemical lure (nonanal, L-lactic acid, 1-octen-3-ol, and spearmint oil) was equally effective as the dry ice monitor containing the same lure in trapping bed bugs. Placing one sugar-yeast monitor per apartment for 1-d was equally effective as 11-d placement of 6-18 Climbup insect interceptors (a commonly used bed bug monitor) under furniture legs for trapping bed bugs. When carbon dioxide was present, pair-wise comparisons showed the experimental lure increased trap catch by 7.2 times. This sugar-yeast monitor with a chemical lure is an affordable and effective tool for monitoring bed bugs. This monitor is especially useful for monitoring bed bugs where a human host is not present.


C-F Bond Activation of P(C6F5)3 by Ruthenium Dihydride Complexes: Isolation and Reactivity of the "Missing" Ru(PPh3)3H(halide) Complex, Ru(PPh3)3HF.
The major product of the reaction between Ru(IMe4)2(PPh3)2H2 (1; IMe4 = 1,3,4,5-tetramethylimidazol-2-ylidene) and P(C6F5)3 (PCF) is the five-coordinate complex Ru(IMe4)2(PF2{C6F5})(C6F5)H (2), which is formed via a complex series of C-F/P-C bond cleavage and P-F bond formation steps. In contrast, hydrodefluorination of all six ortho C-F bonds in PCF occurs with Ru(PPh3)4H2 to afford Ru(PPh3)3HF (3). NaBArF4 abstracted the fluoride ligand in 3 to give [Ru({η6-C6H5}PPh2)(PPh3)2H][BArF4], while B2pin2 reacted with 3 in C6D6 to yield a mixture of [Ru({η6-C6D6)(PPh3)2H]+ and Ru(PPh3)4H2. The treatment of 3 with HBpin (5 equiv) and HSiR3 (R = Et, Ph; 2 equiv) afforded Ru(PPh3)3(σ-HBpin)H2 and Ru(PPh3)3(SiR3)3H3, respectively. No stable substitution products were generated when 3 was reacted with Me3SiX (X = CF3, C6F5).


Depression in diabetes mellitus-A comprehensive systematic review of literature from an Indian perspective.
Diabetes and depression are rapidly growing chronic health conditions that have significant negative impact upon the physical, psychological, social and occupational functioning, quality of life and often leads to socio-economic burden. Presence of both these comorbid diseases results in various short term and long term complications and increases the mortality as compared to those with depression or diabetes alone. Systematic review of the epidemiological data, risk factors and relationship between depression and glycaemic control among the Indian studies. We searched Pubmed, Pubmed Central, Google Scholar and Directory of Open Access Journal (DOAJ) databases to identify relevant Indian studies. Substantial variation in the prevalence of depression in people with diabetes was found across the 41 selected studies; according to this review the range is 2% to 84% (T1DM - 2-7%; T2DM - 8%-84%). Correlates of depression in diabetic patients are advancing age, female gender, low literacy rate, burden of being from a lower socioeconomic status, rural domicile, marriage and duration of diabetes of >2years, diabetes related complications and poor glycaemic control. Sedentary life without adequate physical activities, lack of self-care are often the factors that precipitates depression in a T2DM patient and vice versa. According to this review, among Indian population there is a significant association between depression and diabetes.


The Impact of Entry Restrictions on the Spread of Severe Acute Respiratory Syndrome Coronavirus Variants Between 2021 and 2022.
To contain the surge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the South Korean government has implemented non-pharmacological interventions as well as border restrictions. The efficacy of entry restrictions should be evaluated to facilitate their preparation for new variants of SARS-CoV-2. This study explored the impact of border policy changes on overseas entrants and local cases of SARS-CoV-2 variants. Data from the Korea Disease Control and Prevention Agency randomly collected between April 11, 2021 and August 20, 2022 were evaluated using the Granger causality model. The results showed that the outbreak gap of delta variants between international and domestic cases was 10 weeks, while that of omicron variants was approximately 2 weeks, meaning that the quarantine policy helped contain delta variants rather than more transmissible variants. It is recommended that countries implement quarantine policies based on particular purposes accounting for the specific features of different variants to avoid potential negative impacts on the economy.


An Overview of Noninvasive Brain Stimulation: Basic Principles and Clinical Applications.
The brain has the innate ability to undergo neuronal plasticity, which refers to changes in its structure and functions in response to continued changes in the environment. Although these concepts are well established in animal slice preparation models, their application to a large number of human subjects could only be achieved using noninvasive brain stimulation (NIBS) techniques. In this review, we discuss the mechanisms of plasticity induction using NIBS techniques including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), random noise stimulation (RNS), transcranial ultrasound stimulation (TUS), vagus nerve stimulation (VNS), and galvanic vestibular stimulation (GVS). We briefly introduce these techniques, explain the stimulation parameters and potential clinical implications. Although their mechanisms are different, all these NIBS techniques can be used to induce plasticity at the systems level, to examine the neurophysiology of brain circuits and have potential therapeutic use in psychiatric and neurological disorders. TMS is the most established technique for the treatment of brain disorders, and repetitive TMS is an approved treatment for medication-resistant depression. Although the data on the clinical utility of the other modes of stimulation are more limited, the electrical stimulation techniques (tDCS, tACS, RNS, VNS, GVS) have the advantage of lower cost, portability, applicability at home, and can readily be combined with training or rehabilitation. Further research is needed to expand the clinical utility of NIBS and test the combination of different modes of NIBS to optimize neuromodulation induced clinical benefits.


Relationships between certain metabolic diseases and selected serum biochemical parameters in seropositive dairy cows against Neospora caninum infection in different stages of lactation
Neospora caninum is an important cause of abortion in dairy cattle. The general health of affected cows has not been investigated before. Therefore, the main objective of this study was to identify possible relationships between certain metabolic diseases and selected serum biochemical parameters in seropositive dairy cows against N. caninum antibodies in different stages of lactation. The study was carried out using 72 N. caninum seropositive cows and 61 seronegative dairy cows (control). Serum from all cows was tested to determine their N. caninum status (seropositive vs seronegative) using commercially available indirect enzyme-linked immunosorbent assay test kit (iELISA). In addition, serum biochemical parameters including beta-hydroxybutyrate (BHB), glucose, creatinine, blood urea nitrogen, total protein, albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH) and gamma-glutamyltranspeptidase (GGT) were determined using routine laboratory methods. The stage of lactation was obtained at the time of sampling from farm records. Student independent t-test showed that there was a significant difference in the serum concentrations of BHB, AST, ALT, and LDH between seropositive and seronegative cows. There was no significant association between seropositivity and the stage of lactation. However, multivariable logistic regression analysis showed that there was a strong association between seropositivity and BHB concentrations. Results of this study indicate a possible relationship between N. caninum seropositivity and certain metabolic diseases such as ketosis and fatty liver syndrome in dairy cows.


[Grain protein content in wheat: genetics of the character and some predictions for its improvement in common wheat].
The results of studies on genetic control of the grain protein content character in common wheat and the attempts of its improvement using traditional breeding approaches and methods of experimental mutagenesis and introgressive hybridization are presented. The evolution of the views on the genetic structure of the character is considered. Possible explanations are given to the fact that the attempts to significantly improve the character in question in common wheat cultivars have failed in spite of long-term genetic and selection studies. Possible lines of further investigation of genetic control of grain protein content and its increase in common wheat are discussed.


Activatable near-infrared fluorescent probe for in vivo imaging of fibroblast activation protein-alpha.
Fibroblast activation protein-alpha (FAPα) is a cell surface glycoprotein which is selectively expressed by tumor-associated fibroblasts in malignant tumors but rarely on normal tissues. FAPα has also been reported to promote tumor growth and invasion and therefore has been of increasing interest as a promising target for designing tumor-targeted drugs and imaging agents. Although medicinal study on FAPα inhibitors has led to the discovery of many FAPα-targeting inhibitors including a drug candidate in a phase II clinical trial, the development of imaging probes to monitor the expression and activity of FAPα in vivo has largely lagged behind. Herein, we report an activatable near-infrared (NIR) fluorescent probe (ANP(FAP)) for in vivo optical imaging of FAPα. The ANP(FAP) consists of a NIR dye (Cy5.5) and a quencher dye (QSY21) which are linked together by a short peptide sequence (KGPGPNQC) specific for FAPα cleavage. Because of the efficient fluorescence resonance energy transfer (FRET) between Cy5.5 and QSY21 in ANP(FAP), high contrast on the NIR fluorescence signal can be achieved after the cleavage of the peptide sequence by FAPα both in vitro and in vivo. In vitro assay on ANP(FAP) indicated the specificity of the probe to FAPα. The in vivo optical imaging using ANP(FAP) showed fast tumor uptake as well as high tumor to background contrast on U87MG tumor models with FAPα expression, while much lower signal and tumor contrast were observed in the C6 tumor without FAPα expression, demonstrating the in vivo targeting specificity of the ANP(FAP). Ex vivo imaging also demonstrated ANP(FAP) had high tumor uptake at 4 h post injection. Collectively, these results indicated that ANP(FAP) could serve as a useful NIR optical probe for early detection of FAPα expressing tumors.


The prevalence of celiac disease in blood donors in Iceland.
Prospective epidemiological studies based on serological methods have shown that celiac disease is more common than previously thought. The aim of this study was to evaluate the prevalence of celiac disease among apparently healthy blood donors in Iceland. Plasma samples were obtained from 813 apparently healthy blood donors at the FSA Hospital Blood Bank in Akureyri, Iceland, between December 2004 and January 2007 and screened for human tissue transglutaminase IgA antibodies. Positive samples were retested and, if the test was again positive, the subject was referred to a gastroenterologist for clinical examination and a duodenoscopy with mucosal biopsies. Six subjects tested positive for tissue transglutaminase. The prevalence of biopsy-confirmed celiac disease, according to modified Marsh classification, among apparently healthy blood donors in Iceland was found to be 1:136 (0.74%, 95% confidence interval 1/667-1/75, 0.15-1.33%). Prevalence of celiac disease in Iceland is similar to what has been reported in many other countries.


Changes in the mucosa of the stomach and duodenum during immunosuppressive therapy after renal transplantation.
Upper gastrointestinal endoscopic examination of 40 patients on immunosuppressive therapy after successful kidney transplantation revealed a duodenal ulcer in four cases and duodenal erosions in six. Between four and six biopsies were collected from the antral and the fundal mucosa in each case and from the duodenal mucosa in 29. Antral superficial gastritis was found in 13 cases and fundal superficial gastritis in three. In the fundus, heterotopic calcifications were seen in eight cases and cytomegalovirus inclusion bodies in two. Parietal cells were increased in number and reached the pyloric zone in 34 cases, whilst they spread within the duodenal mucosa in 12. Multinucleate parietal cells were of common occurrence and in some cases showed mitotic figures. Duodenitis was found in 16 cases and in duodenal mucosal cells cytomegalovirus inclusion bodies were seen in nine cases. Biopsy evidence of hyperplasia of Brunner's glands was encountered in 26 cases. Of 20 patients tested for gastric acid secretion, hypersecretion occurred in 14 and normal secretion in six. Endoscopic and histological changes relate to the secretory pattern. Cytomegalovirus inclusion bodies relate to immunosuppressive therapy. An inverse temporal relationship exists between heterotopic calcification and the duration of renal transplant. Steroids seem to be responsible for gastroduodenal changes in transplanted patients.


Genotypic Variation of Purple Rice in Response to Shading in Yield, Anthocyanin Content, and Gene Expression.
Purple rice (Oryza sativa L.) contains anthocyanin, which acts as an antioxidant and functional food for humans. The levels of anthocyanin growth and production in rice are mainly controlled by the availability of light. However, shade can affect anthocyanin biosynthesis genes. Therefore, the objective of this study was to determine the yield and anthocyanin content among four purple rice varieties, which provide the difference in colors of purple and green leaves. This study also evaluated gene expression affected by shading treatment to understand the relation of grain anthocyanin and expression level. This research was conducted using a split plot design using four levels of shading (levels of shading from anthesis to maturity) with three replications, no shading, 30% shading, 50% shading, and 70% shading, as the main plots and purple rice varieties as subplots, KJ CMU-107, K2, K4, and KDK10, from anthesis to maturity. Shading significantly decreased yield and yield components, but increased grain anthocyanin content. Nonetheless, the response of yield and grain anthocyanin content to shading did not show a significant different between purple and green leaf varieties. In addition, the level of OsDFR gene expression was different depending on the shading level in four rice varieties. The OsDFR gene presented the highest expression at shading levels of 30% for K4 and 50% for KDK10, while the expression of the OsDFR gene was not detected in the purple rice varieties with green leaves (KJ CMU-107 and K2). The response of grain anthocyanin and gene expression of OsDFR to light treatment did not show significantly differences between the purple and green leaf varieties, suggesting that the appearance of anthocyanin in leaves might be not related to anthocyanin synthesis in the grain. Taken together, the results suggest that some purple rice varieties were more suitable for planting under low light intensity based on a lower level of grain yield loss, strong shade tolerance, and high anthocyanin content in leaf and grain pericarp. However, it is necessary to explore the effects of light intensity on genes and intermediates in the anthocyanin synthesis pathway for further study.


Retinoic acid signaling is dispensable for somatic development and function in the mammalian ovary.
Retinoic acid (RA) is a potent inducer of cell differentiation and plays an essential role in sex-specific germ cell development in the mammalian gonad. RA is essential for male gametogenesis and hence fertility. However, RA can also disrupt sexual cell fate in somatic cells of the testis, promoting transdifferentiation of male Sertoli cells to female granulosa-like cells when the male sexual regulator Dmrt1 is absent. The feminizing ability of RA in the Dmrt1 mutant somatic testis suggests that RA might normally play a role in somatic cell differentiation or cell fate maintenance in the ovary. To test for this possibility we disrupted RA signaling in somatic cells of the early fetal ovary using three genetic strategies and one pharmaceutical approach. We found that deleting all three RA receptors (RARs) in the XX somatic gonad at the time of sex determination did not significantly affect ovarian differentiation, follicle development, or female fertility. Transcriptome analysis of adult triple mutant ovaries revealed remarkably little effect on gene expression in the absence of somatic RAR function. Likewise, deletion of three RA synthesis enzymes (Aldh1a1-3) at the time of sex determination did not masculinize the ovary. A dominant-negative RAR transgene altered granulosa cell proliferation, likely due to interference with a non-RA signaling pathway, but did not prevent granulosa cell specification and oogenesis or abolish fertility. Finally, culture of fetal XX gonads with an RAR antagonist blocked germ cell meiotic initiation but did not disrupt sex-biased gene expression. We conclude that RA signaling, although crucial in the ovary for meiotic initiation, is not required for granulosa cell specification, differentiation, or reproductive function.


Lung tissue viscoelasticity: a mathematical framework and its molecular basis.
Recent studies indicated that lung tissue stress relaxation is well represented by a simple empirical equation involving a power law, t-beta (where t is time). Likewise, tissue impedance is well described by a model having a frequency-independent (constant) phase with impedance proportional to omega-alpha (where omega is angular frequency and alpha is a constant). These models provide superior descriptions over conventional spring-dashpot systems. Here we offer a mathematical framework and explore its mechanistic basis for using the power law relaxation function and constant-phase impedance. We show that replacing ordinary time derivatives with fractional time derivatives in the constitutive equation of conventional spring-dashpot systems naturally leads to power law relaxation function, the Fourier transform of which is the constant-phase impedance with alpha = 1 - beta. We further establish that fractional derivatives have a mechanistic basis with respect to the viscoelasticity of certain polymer systems. This mechanistic basis arises from molecular theories that take into account the complexity and statistical nature of the system at the molecular level. Moreover, because tissues are composed of long flexible biopolymers, we argue that these molecular theories may also apply for soft tissues. In our approach a key parameter is the exponent beta, which is shown to be directly related to dynamic processes at the tissue fiber and matrix level. By exploring statistical properties of various polymer systems, we offer a molecular basis for several salient features of the dynamic passive mechanical properties of soft tissues.


Double Free Flap Transfer using a Vascularized Free Fibular Flap and a Rectus Abdominalis Musculocutaneous Flap for an Extensive Oromandibular Defect: Prevention of Sinking or Drooping of the Flap With an Anterior Rectus Sheath.
The double free flap procedure is a preferred treatment for extensive composite defects of the oromandibular area. In this procedure, the choice and use of the flaps are both important. Flaps with adequate soft tissue are required to fill the extensive dead space for huge oromandibular defects. Such flaps, however, tend to sink and droop with time because of gravity, resulting in poor functional and aesthetic results. Here, the authors describe a procedure that avoids flap sinking and drooping, using a vascularized fibular osteocutaneous flap, which is well established for mandibular bone defects, and a rectus abdominalis musculocutaneous flap, which has a lot of soft tissue and a firm anterior rectus sheath. This method was used in 2 patients with extensive composite defects of the oromandibular area. In a patient with resection of the mobile tongue and oral floor, the anterior rectus sheath was fixed to the fibula and mandible to give a mylohyoid muscle-like structure, to prevent sinking of the reconstructed oral floor and tongue. Good swallowing function was maintained. In a patient with defects transversally from the submandibular region to the cheek, the sheath was fixed to the zygomatic arch to prevent cheek drooping. An acceptable aesthetic result was obtained.


Variational determination of ground and excited-state two-electron reduced density matrices in the doubly occupied configuration space: A dispersion operator approach.
This work implements a variational determination of the elements of two-electron reduced density matrices corresponding to the ground and excited states of N-electron interacting systems based on the dispersion operator technique. The procedure extends the previously reported proposal [Nakata et al., J. Chem. Phys. 125, 244109 (2006)] to two-particle interaction Hamiltonians and N-representability conditions for the two-, three-, and four-particle reduced density matrices in the doubly occupied configuration interaction space. The treatment has been applied to describe electronic spectra using two benchmark exactly solvable pairing models: reduced Bardeen-Cooper-Schrieffer and Richardson-Gaudin-Kitaev Hamiltonians. The dispersion operator combined with N-representability conditions up to the four-particle reduced density matrices provides excellent results.


T cell-targeted immunotherapy in murine collagen-induced arthritis.
Counteracting the effect of autoimmunity can be achieved by elimination or inactivation of autoreactive T cells. We have focused on two approaches targeting on autoaggressive T cells in the model of collagen-induced arthritis (CIA) in mice. First, type II collagen (CII) primed DBA/1 mice were treated with various monoclonal antibodies (mAb) specific for the beta chains of the T cell receptor (TCR) using a protocol resulting in a long-term elimination of the target T cells. Indeed, CIA could be suppressed by injection of anti-V beta 8.1, 2 mAb and down-regulated by that of anti-V beta 2 and/or anti-V beta 5, presumably by deleting pathogenic T cell clones. In contrast, treatment with either anti-V beta 6 or anti-V beta 11 mAb did not alter CIA. Second, we generated CII-specific T cell hybrid clones that recognize the antigenic peptides in association with Kq and IA(q) molecules respectively for CD8+ and CD4+ cells. Vaccination with the irradiated hybrid clones, 3 weeks prior to immunization, was effective in preventing the development of arthritis. Furthermore, this suppression was antigen and disease specific. Most importantly, one CD8+ clone could reverse the ongoing disease. These new therapeutic approaches derived from animal models may offer a hope of more selective interventions for the treatment of human autoimmune diseases.


Direct and homogeneous immunoassay for IgG analyses.
A concept involving the use of antibody conjugated with reporter molecules for direct sensing of subtle changes in the local electrostatic environment of an antigen-antibody complex due to the antigen binding is presented. The proposed direct sensing mechanism is studied using the protein A-immunoglobulin G (IgG) complex as the model system. The change in the local electrostatic potential and pH around the protein A-IgG complex is observed by measuring the fluorescence intensity of fluorescein molecules conjugated with protein A before and after the introduction of IgG. Factors affecting the efficiency of our direct sensing mechanism including the conjugation ratio of fluorescein per protein A molecule, Solution conditions, and the amount of protein A-fluorescein conjugate used in the experiment are investigated. The IgG(2A) concentrations in the cell supernatants are analyzed by using our direct sensing method and then compared with the results obtained from enzyme-linked immunosorbent assay (ELISA). The comparisons between our homogeneous assay and heterogeneous ELISA in the analysis time, analysis procedures, cost, and sensitivity are reported and discussed.


Reviving Lonidamine and 6-Diazo-5-oxo-L-norleucine to Be Used in Combination for Metabolic Cancer Therapy.
Abnormal metabolism is another cancer hallmark. The two most characterized altered metabolic pathways are high rates of glycolysis and glutaminolysis, which are natural targets for cancer therapy. Currently, a number of newer compounds to block glycolysis and glutaminolysis are being developed; nevertheless, lonidamine and 6-diazo-5-oxo-L-norleucine (DON) are two old drugs well characterized as inhibitors of glycolysis and glutaminolysis, respectively, whose clinical development was abandoned years ago when the importance of cancer metabolism was not fully appreciated and clinical trial methodology was less developed. In this review, a PubMed search using the words lonidamine and 6-diazo-5-oxo-L-norleucine (DON) was undertaken to analyse existing information on the preclinical and clinical studies of these drugs for cancer treatment. Data show that they exhibit antitumor effects; besides there is also the suggestion that they are synergistic. We conclude that lonidamine and DON are safe and potentially effective drugs that need to be reevaluated in combination as metabolic therapy of cancer.


Advances in Anaesthetic Monitoring for the 1990s.
Given the anaesthesiologists 'credo 'vigilance' it should come as no surprise that monitoring is accorded high priority in anaesthetic practice. Although the critical basics of monitoring have changed little since the earliest days of the specialty, namely visual observation (i.e. skin colour, rate and depth of respiration, position and location of patient and endotracheal tube etc.) and physical contact with the patient (i.e. finger on the pulse for heart rate and estimation of blood pressure, temperature, peripheral perfusion etc.) there is no question that technological advances have greatly enhanced these basic observations. The 1980s were especially pivotal. In this decade major advances have been made in respiratory and cardiovascular monitoring. Many of these advances have been credited with facilitating a major reduction in perioperative anaesthetic morbidity and mortality. For instance, with the routine use of pulse oximetry and capnography, the chance of an unrecognized esophageal intubation of sufficient duration to result in anoxic brain damage have been almost eliminated.


Weight trends in United States living kidney donors: Analysis of the UNOS database.
To analyze the national trends associated with body mass index (BMI) and living kidney donation. Forty-seven thousand seven hundred and five adult living kidney donors as reported to the Organ Procurement and Transplantation Network from 1999 to 2011 were analyzed using their pre-donation BMI. Predictor variables of interest included age, gender, ethnicity, relationship, education status, and transplant region. Sixteen thousand nine hundred and seventy-one of the living kidney donors were normal weight (35.6%); 19337 were overweight (40.5%); 9007 were mildly obese (18.9%); 1992 were moderate to morbidly obese (4.2%). Overweight and mildly obese kidney donors have increased through time by 12% and 20% every 5 years, respectively (P < 0.05). Donors 35-49 years of age, hispanic males or females and black females, those with high school diploma or general Education Degree, and biologically related or partner/spouses were more likely to be obese. Over the past 13 years, the majority of living kidney donors have spanned the overweight to obese categories. Paralleling the national rise is an increase in overweight and mildly obese kidney donors. A fair number of moderate to morbidly obese living kidney donors are still allowed to donate.


Approaching threatening stimuli cause an expansion of defensive peripersonal space.
When sudden environmental stimuli signaling threat occur in the portion of space surrounding the body (defensive peripersonal space), defensive responses are enhanced. Recently Bisio et al. (Bisio A, Garbarini F, Biggio M, Fossataro C, Ruggeri P, Bove M. J Neurosci 37: 2415-2424, 2017) showed that a marker of defensive peripersonal space, the defensive hand-blink reflex, is modulated by the motion of the eliciting threatening stimulus. These results can be parsimoniously explained by the continuous monitoring of environmental threats, resulting in an expansion of defensive peripersonal space when threatening stimuli approach.


The enzyme immunosorbent assay (ELISA) for serologic diagnosis of toxoplasmosis in pregnancy.
The enzyme-linked immunosorbent assay (ELISA) is simple, quick, and inexpensive, characteristics that make it particularly suitable for large screening programs. We compared the results obtained by ELISA with those obtained by immunofluorescent antibody test (IFAT), indirect hemoagglutination test (IHAT), and Sabin Feldman Dye test in a group of 105 pregnant women in the course of a screening for toxoplasmosis. Prevalence of IgG antibody titers were not significantly different. ELISA results were particularly close to those of the reference tests (IFAT and Dye test).


Contentious host-microbiota relationship in inflammatory bowel disease--can foes become friends again?
Inflammatory bowel diseases (IBDs) are chronic debilitating disorders of unknown etiology, consisting of two main conditions, ulcerative colitis and Crohn's disease. Major advances have recently taken place in human genetic studies of IBD and over 160 risk loci for these two diseases have been uncovered. These genetic data highlight a key role for genes that code for immunological and epithelial barrier functions. Environmental factors also make substantial contributions to the pathogenesis of IBD and account for the growing incidence of the diseases around the world. Intestinal microbiota creates resistance to infection, provides nutrients, and educates the immune system and in many ways has a significant impact on human health. Aberrant microbiota composition and decreased diversity (dysbiotic microbiota) are key etiopathological events in IBD. Dysbiotic microbiota can lead to loss of normal, regulatory immune effects in the gut mucosa. This may play a central role in the development and perpetuation of chronic inflammation. Further, the expression of specific innate immune receptors that recognize microbes is altered in the IBD epithelium. Therefore, the combination of host side epithelial barrier functions and the presence of dysbiotic microbiota in the gut together promote inflammation. New therapeutic options targeting microbiota are currently considered for IBD and they may, in the future, provide means to reverse the pathogenic host-microbiota relationship into a symbiotic one. In this review, the focus is on the intestinal microbiota and host-microbe interactions in IBD.


Prevalence of Helicobacter pylori pathogenicity-associated cagA and vacA genotypes among Pakistani dyspeptic patients.
The cytotoxin-associated gene A (cagA), and the vacuolating cytotoxin gene A (vacA) products are considered the most important pathogenic determinants of Helicobacter pylori, a gram-negative bacterium causing gastrointestinal disorders such as duodenal ulcers, gastritis and mucosa-associated lymphoid tissue disease. A higher prevalence of H. pylori has been reported in various regions in the Pakistani population; however, no data are available about the virulence-associated genetic determinants. The objective of this study was to determine the prevalence of virulence-associated genes, cagA, vacA and particularly vacA allelic variants among dyspeptic patients from Pakistan. Gastric biopsy samples were obtained from 78 adult patients presenting dyspepsia symptoms. DNA was isolated and analyzed for the presence of H. pylori and its genotypes by PCR. Genus-specific PCR involving 16S rRNA gene revealed that 66 of the 78 patients were positive for H. pylori, an overall prevalence of 84.6% for this particular study. The most common vacA genotype was s1b/m2 (54.5%) followed by s1a/m1 (19.7%). cagA was positive in 24.2% of the cases and strongly associated with s1a/m1, vacA. The prevalence of virulent cagA, and vacA allelic form s1a/m1 was lower than that reported from neighboring countries.


Anthropometric characteristics and risk of uterine leiomyoma.
The etiology of uterine leiomyoma (or fibroids) is poorly understood. Sex steroid hormones and growth factors have been hypothesized to play a role in their development, and anthropometric characteristics may influence uterine leiomyoma risk. We analyzed prospectively-collected data from the Nurses' Health Study II, a cohort of 116,609 female registered nurses age 25 to 42 years at baseline. Incidence of uterine leiomyoma and anthropometric characteristics were assessed every 2 years. We calculated hazard ratios and 95% confidence intervals adjusted for known and suspected risk factors for uterine leiomyoma. Uterine leiomyomas were associated with current body mass index, change in weight since age 18, and waist-to-hip ratio. However, there was little evidence of their association with body mass index at age 18, childhood or adolescent body size, or adult height. Body mass and weight gain in adulthood may increase the risk of uterine leiomyoma, but body mass in early life does not.


Comparison of recognition and grating acuities in very-low-birth-weight children with and without retinal residua of retinopathy of prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group.
To compare recognition (letter) and resolution (grating) acuity in eyes with and without retinopathy of prematurity (ROP) residua. Letter acuity measured with the crowded HOTV chart or pocket cards (Good-Lite), and grating acuity measured with the Teller Acuity Card (TAC) procedure, were compared at the 3 1/2- and 4 1/2-year follow-up exams in the CRYO-ROP study. Testers were unaware of the retinal status of individual eyes. Measurable scores for both letter and grating acuity were obtained from 1694 eyes at 3 1/2 years and 2101 eyes at 4 1/2 years. Correlation analysis showed that the relation between crowded HOTV and grating acuity scores was best described by a quadratic function, with r2 values of 0.57 at 3 1/2 years and 0.68 at 4 1/2 years. Difference scores were calculated for each eye by subtracting the log of the HOTV score (converted to cyc/deg based on the convention that 20/20 = 30 cyc/deg) from the log TAC score. Normal eyes showed HOTV acuity that was higher than TAC acuity by an average of 0.37 octave (SD = 0.46, n = 1150) at 3 1/2 years and 0.27 octave (SD = 0.43, n = 1337) at 4 1/2 years. HOTV and grating acuity scores were similar to each other in eyes with retinal residua of ROP. Overall, eyes with acuity better than 20/150 to 20/300 tended to show better HOTV than grating acuity, whereas those with acuity below 20/150 to 20/300 generally showed better grating than HOTV acuity. There is a significant correlation between crowded HOTV letter acuity and TAC grating acuity in young children for normal eyes and eyes with ROP residua. In both groups of eyes, eyes with lower acuity show better grating than letter acuity, whereas eyes with better acuity show slightly higher letter than grating acuity.


Understanding how viruses can cause malignant disease.
This article discusses the contribution made by viral infections to the global burden of cancer. The greatest impact of virally-induced cancers is felt in the developing world--in those countries that experience greatest difficulty in meeting the costs of vaccination programmes. Support by wealthier nations for vaccination programmes, organised through the World Health Organization, could have an enormous impact on the global burden of disease and specifically on cancer incidence.


Ninety percent of the adverse outcomes occur in 10% of patients: can we identify the populations at high risk of developing peritoneal metastases after curative surgery for colorectal cancer?
Peritoneal metastases (PM) occur in 3.4-6.3% after curative surgery for non-metastatic colorectal cancer. Systematic "2nd look" surgery helps overcoming the diagnostic problem but can be only proposed to selected patients. The aim of this study was to update the knowledge on risk factors of developing PM after curative surgery for colorectal cancer. A systematic review of the literature published between 2011 and 2016 was made, searching for all clinical studies reporting the incidence of recurrent PM after curative surgery for colorectal cancer and factors associated with the primary tumour that were likely to influence this recurrence rate. Seven new clinical studies were considered informative for risk factors and added to the 16 reviewed in 2013. Even if the level of evidence was low, data suggested rates of recurrent PM at 1 year between 54% and 71% after completely resected synchronous PM, between 62% and 71% after resection of isolated synchronous ovarian metastases, of 27% after surgery for a perforated primary tumour, of 16% after surgery for a pT4 tumour, and between 11% and 36% after surgery for a mucinous histological subtype. No new risk factor was identified. Evidence regarding the incidence of recurrent PM after curative surgery for colorectal cancer is poor. Situations at higher risk of recurrent PM are synchronous PM, synchronous isolated ovarian metastases, perforated primary tumour with serosa invasion and mucinous histological subtype.


Rise in power of Yb:YCOB for green light generation by self-frequency doubling.
Spectroscopic properties and self-frequency-doubling laser performance are presented for Yb:YCa4O(BO3)3 (Yb:YCOB) crystals oriented for type I second-harmonic generation in the ZX plane. In a plane-concave cavity 10 cm long, up to 330 mW of green light (544.5 nm) is obtained for 14.7 W of laser diode incident pump power. Broad emission bands and weak anisotropy in the 1060-1100 nm range between the two eigenstates of polarization may explain the instability of the self-frequency-doubled output power.


Asynchronous progression through the lytic cascade and variations in intracellular viral loads revealed by high-throughput single-cell analysis of Kaposi's sarcoma-associated herpesvirus infection.
Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus-8) is frequently tumorigenic in immunocompromised patients. The average intracellular viral copy number within infected cells, however, varies markedly by tumor type. Since the KSHV-encoded latency-associated nuclear antigen (LANA) tethers viral episomes to host heterochromatin and displays a punctate pattern by fluorescence microscopy, we investigated whether accurate quantification of individual LANA dots is predictive of intracellular viral genome load. Using a novel technology that integrates single-cell imaging with flow cytometry, we found that both the number and the summed immunofluorescence of individual LANA dots are directly proportional to the amount of intracellular viral DNA. Moreover, combining viral (immediate early lytic replication and transcription activator [RTA] and late lytic K8.1) and cellular (syndecan-1) staining with image-based flow cytometry, we were also able to rapidly and simultaneously distinguish among cells supporting latent, immediate early lytic, early lytic, late lytic, and a potential fourth "delayed late" category of lytic replication. Applying image-based flow cytometry to KSHV culture models, we found that de novo infection results in highly varied levels of intracellular viral load and that lytic induction of latently infected cells likewise leads to a heterogeneous population at various stages of reactivation. These findings additionally underscore the potential advantages of studying KSHV biology with high-throughput analysis of individual cells.


Evaluation of psoriasis severity and inflammatory responses under concomitant treatment with methotrexate plus micronutrients for psoriasis vulgaris: a randomized double blind trial.
We evaluated the effectiveness of concomitant treatment with methotrexate (MTX) plus micronutrients in comparison with monotherapy with MTX only in psoriasis patients. Plasma levels of interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) were also measured and their association with clinical severity was evaluated. Thirty psoriasis patients 20 to 50 years old with a PASI score > 10 were divided randomly into two groups. Both groups were given oral methotrexate (0.2-0.3 mg/kg/week) for 12 weeks. In addition, Group B received one tablet of micronutrient supplement daily. Disease severity was calculated using the psoriasis area and severity index (PASI) score before and after 12 weeks. Levels of IL-1β and TNF-α were measured using enzyme-linked immunosorbent assay (ELISA). We found that 13 (86.6%) patients in Group B and 8 (53.3%) patients in Group A attained a mild PASI score (≤ 10% body involvement). IL-1β and TNF-α levels were significantly decreased in favor of Group B (p < 0.05). There was a significant correlation between changes in both IL-1β and TNF-α levels and PASI score after the study (p < 0.05). The results obtained were positive, and therefore double-blind randomized trials with a larger sample size are highly suggested to confirm or reject these results.


Mesoscopic transport in chemically doped carbon nanotubes.
Electronic quantum transport is investigated in boron- and nitrogen-doped carbon nanotubes using tight-binding methods correlated to ab initio calculations. The present technique accurately accounts for both effects of dopants, namely, charge transfer and elastic scattering. Generic transport properties such as conduction mechanisms, mean-free paths, and conductance scalings are derived for various concentration of randomly distributed boron and nitrogen dopants. Our calculations allow direct comparison with experiments and demonstrate that a small amount of dopants (<0.5%) can drastically modify the electronic transport properties of the tube, which is certainly a key effect feature for envisioning nanoelectronics.


A comparative evaluation of the speed of kill and duration of efficacy against weekly infestations with fleas on cats treated with fipronil-(S)-methoprene or metaflumizone.
Spot-on formulations of metaflumizone and a combination of fipronil-(S)-methoprene were evaluated in adult cats to determine the duration of 24- and 48-hour efficacy and short-term speed of kill against adult cat fleas, Ctenocephalides felis felis. Speed of kill efficacies (at 12, 18, 24, and 48 hours) were assessed against existing (day -1) infestations and against infestations at day 7, and efficacy was assessed 24 and 48 hours after weekly flea infestations through day 42. Cats treated with fipronil-(S)-methoprene had significantly (P<.01) fewer fleas than those treated with metaflumizone at 12 and 18 hours after treatment (day 0) and on the day 7 infestations. Fipronil-(S)-methoprene-treated cats also had significantly (P<.05) fewer fleas than metaflumizone-treated cats for all 24-hour counts from initial treatment on day 0 through infestation day 42 and for the 48-hour counts on day 28 through day 42.


Clinico-pathological features and surgical management of primary epithelial hepatic malignancies.
Between January 1983 and January 1990, 89 patients with primary epithelial hepatic malignancy were admitted to the Department of Surgery, University of Heidelberg, for surgical treatment. Histopathologically, tumours were hepatocellular carcinoma (HCC) 75, fimbrolamellar carcinoma (FLC) 1 and cholangiocellular carcinoma (CCC) 13. Concomitant liver cirrhosis was found in 61%. Among the cirrhotic patients, hepatitis-B infection was found in 65% and post-alcoholic cirrhosis in 30%. Pre-operative alpha-fetoprotein serum levels were elevated in 66% of the patients with HCC and none of the patients with CCC or FLC. The resectability rate was 35.9% (32/83). Twenty-six patients underwent curative resection; six were resected palliatively. In 44 patients exploratory laparotomy and biopsy only were performed. Thirteen patients remained without any surgical procedure. The hospital mortality rate after resection was 21.8%. Short-term prognosis depended predominantly on concomitant cirrhosis associated with peri-operative blood loss and extent of hepatic resection. Long-term survival rates after curative resection were 78%, 55% and 21% for 1, 3, and 5 years, respectively. Prognostic factors of long-term survival were investigated by the Kaplan-Meier method.


The fractal structure of communities of practice: Implications for business organization.
Communities of practice (COP) are informal (sometimes formal) groupings of professionals with shared interests that form to facilitate the exchange of expertise and shared learning or to function as professional support networks. We analyse a dataset on the size of COPs and show that their distribution has a fractal structure similar to that found in huntergatherer social organisation and the structure of human personal social networks. Small communities up to about 40 in size can be managed democratically, but all larger communities require a leadership team structure. We show that frequency of interaction declines as size increases, as is the case in personal social networks. This suggests that professional work-oriented organisations may be subject to the same kinds of constraint imposed on human social organisation by the social brain. We discuss the implications for business management structure.


Circulating forms and biological activity of intact and truncated insulin-like growth factor I in adult and neonatal rats.
A variant of IGF-I with a truncated aminoterminal region has been isolated and shown to display increased biological activity in vitro, but weak affinity of binding to the IGF binding proteins compared with intact IGF-I. In the present study, the circulating molecular forms and biological activity of intact and truncated IGF-I were compared after in vivo administration. Adult and 10-day-old rats were given 125I-truncated or 125I-intact IGF-I iv. In both adult and 10-day-old rats 125I-truncated IGF-I showed weaker affinity of binding to the IGF binding proteins and greater degradation than 125I-intact IGF-I. Serum half-life was 2 h for 125I-truncated IGF-I and 3 h for 125I-intact IGF-I in adult rats. The half-life in 10-day-old rats was 20.5 min for 125I-truncated IGF-I and 27 min for 125I-intact IGF-I. The uptake of 125I-truncated IGF-I into the kidney, liver and brain of 10-day-old rats was significantly higher than for 125I-intact IGF-I 15 min after iv administration. The insulin-like effects of the IGF-I peptides were examined in vitro and in vivo. Truncated IGF-I stimulated [3-3H]glucose incorporation into free fatty acids in adipocytes in vitro to a greater extent than did intact IGF-I. In vivo administration of both intact and truncated IGF-I to adult rats significantly decreased serum glucose levels and significantly increased the incorporation of [U-14C]glucose into glycogen.(ABSTRACT TRUNCATED AT 250 WORDS)


[Characteristics of migration of adipose tissue derived mesenchymal stromal cells after co-cultivation with activated monocytes in vitro].
Mesenchymal stromal cells (MSC) are considered to be promising tool of regenerative medicine. Migration of MSC toward damaged inflammatory site is essential for physiological tissue reparation. Therefore we studied modifications of migratory features of adipose tissue derived MSC (AT-MSC) after co-cultivation with activated monocytes derived from THP-1 cell line. As a result, we have observed an increased migration rate of AT-MSC in vitro in the absence of chemoattractant gradient as well as toward the gradient of PDGF BB (platelet-derived growth factor BB), which is well known chemoattractant for the cells of mesenchymal origin. Furthermore, the rate of directional AT-MSC migration through fibronectin was also increased. We have established that signaling from PDGFRβ which is activated through binding of integrin receptors with extracellular matrix may be possible way to stimulate cellular migration under simulated inflammatory conditions.


Wait-list mortality of young patients with Biliary atresia: Competing risk analysis of a eurotransplant registry-based cohort.
Liver transplantation (LT) is the standard treatment for biliary atresia (BA) patients with end-stage liver disease. The prognosis after LT has steadily improved, but overall prognosis of BA patients is also determined by mortality before LT. We aimed to quantify mortality in young BA patients on the Eurotransplant waiting list and to determine the effect of disease severity and age at time of listing on pretransplant mortality. We used a cohort study design, which incorporated data from the Eurotransplant registry. Participants were 711 BA patients who were below 5 years of age from 5 countries and listed for LT between 2001 and 2014. We applied a competing risk analysis to evaluate simultaneously the outcomes death, LT, and still waiting for a suitable organ. We used Cox proportional hazards regression to assess 2-year mortality. In a subcohort of 416 children, we performed multivariate analyses between 2-year mortality and disease severity or age, each at listing. Disease severity at listing was quantified by the Model for End-Stage Liver Disease (MELD) score, which assesses bilirubin, creatinine, albumin, and international normalized ratio as continuous variables. Two-year wait-list mortality was 7.9%. Age below 6 months and MELD score above 20 points, each at listing, were strongly and independently associated with 2-year mortality (each P < 0.001). A total of 21% of infants who fulfilled both criteria did not survive the first 6 months on the waiting list. In conclusion, our findings quantify mortality among young BA patients on the waiting list and the relative importance of risk factors (age and severity of disease at listing). Our results provide both an evidence base to rationally address high mortality in subgroups and a methodology to assess effects of implemented changes, for example, in allocation rules. Liver Transplantation 24 810-819 2018 AASLD.


[HPLC-MS/MS method for determination of sodium cromoglycate concentration in human plasma and its pharmacokinetics].
The study established an HPLC-MS/MS method for determining the concentrations of sodium cromoglycate in human plasma and evaluated the pharmacokinetics of nasal drops and nasal spray. A C18 column was used to separate sodium cromoglycate in plasma with a mobile phase of a mixture of ammonium-methanol (involves 50% acetonitrile) (15:85) at a flow rate of 0.4 mL x min(-1). Electronic spray ionization (ESI) and multiple-reaction monitoring (MRM) were used for the determination of sodium cromoglycate in human plasma. The linear range of the standard curve of sodium cromoglycate was from 0.3 to 20 ng x mL(-1), and the minimum concentration of detection was 0.3 ng x mL(-1). The extraction recovery was more than 94.1%, intra-day and inter-day RSD were less than 14.3%. After a single dose of sodium cromoglycate, the main pharmacokinetic parameters of nasal spray and nasal drops were as follows, T(1/2)(1.82 +/- 0.54) h, (1.59 +/- 0.52) h; Tmax (0.47 +/- 0.12) h, (0.44 +/- 0.15) h; Cmax, (9.79 +/- 4.66) ng x mL(-1), (10.88 +/- 4.05) ng x mL(-1); AUC(0-5 h)(11.52 +/- 3.46) ng x mL(-1) x h x h, (12.63 +/- 4.23) ng x mL(-1) x h, Fr(93.6 +/- 13.8)%. The method is sensitive, rapid and accurate. It is suitable for therapeutic drug monitoring and human pharmacokinetic study of sodium cromoglycate.


Egg Albumen as a Fast and Strong Medical Adhesive Glue.
Sutures penetrate tissues to close wounds. This process leads to inflammatory responses, prolongs healing time, and increases operation complexity. It becomes even worse when sutures are applied to stress-sensitive and fragile tissues. By bonding tissues via forming covalent bonds, some medical adhesives are not convenient to be used by surgeons and have side effects to the tissues. Here egg albumen adhesive (EAA) is reported with ultrahigh adhesive strength to bond various types of materials and can be easily used without any chemical and physical modifications. Compared with several commercial medical glues, EAA exhibits stronger adhesive property on porcine skin, glass, polydimethylsiloxane. The EAA also shows exceptional underwater adhesive strength. Finally, wound closure using EAA on poly(caprolactone) nanofibrous sheet and general sutures is investigated and compared in a rat wound model. EAA also does not show strong long-term inflammatory response, suggesting that EAA has potential as a medical glue, considering its abundant source, simple fabrication process, inherent nontoxicity, and low cost.


Novel HIVEP2 Variants in Patients with Intellectual Disability.
Intellectual disability (ID) occurs in approximately 1% of the population. Over the last years, broad sequencing approaches such as whole exome sequencing (WES) substantially contributed to the definition of the molecular defects underlying nonsyndromic ID. Pathogenic variants in HIVEP2, which encodes the human immunodeficiency virus type I enhancer binding protein 2, have recently been reported as a cause of ID, developmental delay, behavioral disorders, and dysmorphic features. HIVEP2 serves as a transcriptional factor regulating NF-ĸB and diverse genes that are essential in neural development. To date, only 8 patients with pathogenic de novo nonsense or frameshift variants and 1 patient with a pathogenic missense variant in HIVEP2 have been reported. By WES, we identified 2 novel truncating HIVEP2 variants, c.6609_6616delTGAGGGTC (p.Glu2204*) and c.6667C>T (p.Arg2223*), in 2 young adults presenting with developmental delay and mild ID without any dysmorphic features, systemic malformations, or behavioral issues.


Sn(II)-carbon bond reactivity: radical generation and consumption via reactions of a stannylene with alkynes.
Thermal Sn-C cleavage in the diarylstannylene Sn(AriPr4)2 (AriPr4 = C6H3-2,6-(C6H3-2,6-iPr2)2) was used to generate ˙Sn(AriPr4) and ˙AriPr4 radicals for alkyne arylstannylation. The radical pair and RCCR' (R = H, R' = Ph; R = Ph, R' = Ph; R = H, R' = C4H9; R = H, R' = SiMe3) in refluxing benzene generate the aryl vinyl stannylene complexes, AriPr4Sn{C(C6H5)-C(H)(AriPr4)} (1), AriPr4Sn{C(C6H5)-C(H)(C6H5)} (2) and AriPr4Sn{C(C4H9)-C(H)(AriPr4)} (3) respectively. For HCCSiMe3, the known distannene {Sn(CCSiMe3)AriPr4}2 (4) was also generated from this new method.


Oxidase Activity of the Barnacle Adhesive Interface Involves Peroxide-Dependent Catechol Oxidase and Lysyl Oxidase Enzymes.
Oxidases are found to play a growing role in providing functional chemistry to marine adhesives for the permanent attachment of macrofouling organisms. Here, we demonstrate active peroxidase and lysyl oxidase enzymes in the adhesive layer of adult Amphibalanus amphitrite barnacles through live staining, proteomic analysis, and competitive enzyme assays on isolated cement. A novel full-length peroxinectin (AaPxt-1) secreted by barnacles is largely responsible for oxidizing phenolic chemistries; AaPxt-1 is driven by native hydrogen peroxide in the adhesive and oxidizes phenolic substrates typically preferred by phenoloxidases (POX) such as laccase and tyrosinase. A major cement protein component AaCP43 is found to contain ketone/aldehyde modifications via 2,4-dinitrophenylhydrazine (DNPH) derivatization, also called Brady's reagent, of cement proteins and immunoblotting with an anti-DNPH antibody. Our work outlines the landscape of molt-related oxidative pathways exposed to barnacle cement proteins, where ketone- and aldehyde-forming oxidases use peroxide intermediates to modify major cement components such as AaCP43.


[Generation and functions of dreams].
Over the last decade an ever-increasing number of articles have been published on dreams, which reflects the interest that several fields of neuroscience have in the topic. In this work we review the main scientific theories that have contributed to the body of knowledge on how they are produced and what function they serve. The article discusses the evolution of their scientific study, following a neurophysiological and neurocognitive approach. The first of these two methods seeks to determine the neurobiological mechanisms that generate them and the brain structures involved, while the second considers dreams to be a kind of cognition interacting with that of wake-fulness. Several different hypotheses about the function of dreams are examined, and more particularly those in which they are attributed with a role in the consolidation of memory and the regulation of emotional states. Although the exact mechanism underlying the generation of dreams has not been determined, neurobiological data highlight the importance of the pontine nuclei of the brainstem, several memory systems, the limbic system and the brain reward system and a number of neocortical areas. Neurocognitive data underline the relation between the cognitive and emotional processing that occurs during wakefulness and during sleep, as well as the influence of the surroundings on the content of dreams. With regard to their function, one point to be stressed is their adaptive value, since they contribute to the reprocessing of the information acquired in wakefulness and the control of the emotions. This suggests that dreams participate in the development of the cognitive capabilities.