Design, synthesis, and biological evaluation of 3, 5-disubsituted-1H-pyrazolo[3,4-b]pyridines as multiacting inhibitors against microtubule and kinases.
Combination therapy of kinases inhibitors and chemotherapeutics targeting tubulin dynamics is an important strategy to improve therapeutic efficacy and overcome the resistance to single-target drug therapies. Inspired by this, we report herein the rational design of 3,5-disubsituted-1H-pyrazolo[3,4-b]pyridines as multiacting molecules that are capable of inhibiting tubulin and kinases simultaneously. Among them, 8g showed excellent antiproliferative activities toward a panel of cancer cell lines. 8g strongly inhibited tubulin assembly and demonstrated a potent inhibition toward FLT3 and Abl1 in both enzymatic and cellular assays. 8g caused a cell cycle arrest at G2/M phase, and significantly disrupted HUVEC tube formation. In vivo efficacy studies showed that 8g significantly inhibited tumor growth on the K562 leukemia xenograft model at 10 mg/kg. Collectively our studies suggest that the excellent antiproliferative potency of 8g may be attributed to its potent inhibitory activity against both microtubule and kinases.


Enhanced kin recognition through population estimation.
Kin recognition systems enable organisms to predict genetic relatedness. In so doing, they help to maximize the fitness consequences of social actions. Recognition based on phenotypic similarity-a process known as phenotype matching-is thought to depend upon information about one's own phenotype and the phenotypes of one's partners. We provide a simple model of genetic relatedness conditioned upon phenotypic information, however, that demonstrates that individuals additionally require estimates of the distributions of phenotypes and genotypes in the population. Following the results of our model, we develop an expanded concept of phenotype matching that brings relatedness judgments closer in line with relatedness as it is currently understood and provides a heuristic mechanism by which individuals can discriminate positive from negative relatives, thereby increasing opportunities for the evolution of altruism and spite. Finally, we propose ways in which organisms might acquire population estimates and identify research that supports their use in phenotype matching.


Anti-IgE Response in Human Airways: Relative Contribution of Inflammatory Mediators.
Heman airway preparations at resting tone were relaxed with either the leukotriene synthesis inhibitor BAY x1005 (3 muM), chlorpheniramine (1 muM) or the thromboxane receptor antagonist BAY u3405 (0.1 muM). The response to anti-IgE (1:1000) was 58 +/- 8% of acetylcholine pre-contraction (2.19 +/- 0.28 g). Indomethacin (3 muM) enhanced the anti-IgE-induced contraction by 28%. The anti-IgE maximal response was not modified by either chlorpheniramine, BAY x1005 or BAY u3405. When the tissues were treated with either BAY xl005/indomethacin or BAY x1005/chlorpheniramine, the anti-IgE-induced contraction was reduced. In addition, in presence of BAY xl005/indomethacin/chlorpheniramine the response was completely blocked. These results suggest that mediatots released during anti-IgE challenge cause airway contraction which may mask the evaluation of the leukotriene component.


Electric Field-Controlled Crystallizing CaCO3 Nanostructures from Solution.
The role of electric field is investigated in determining the structure, morphology, and crystallographic characteristics of CaCO3 nanostructures crystallized from solution. It is found that the lattice structure and crystalline morphology of CaCO3 can be tailed by the electric field applied to the solution during its crystallization. The calcite structure with cubic-like morphology can be obtained generally without electric field, and the vaterite structure with the morphology of nanorod is formed under the high electric field. The vaterite nanorods can be piled up to the petaliform layers. Both the nanorod and the petaliform layer can have mesocrystal structures which are piled up by much fine units of the rods with the size of several nanometers. Beautiful rose-like nanoflowers can be self-arranged by the petaliform layers. These structures can have potential application as carrier for medicine to involve into metabolism of living cell.


Haemoglobin diagnostic cut-offs for anaemia in Indian women of reproductive age.
The persistent high prevalence of anaemia among Indian women of reproductive age (WRA) despite aggressive long-term iron supplementation could be related to over-diagnosis from an inappropriately high haemoglobin (Hb) diagnostic cut-off. To develop an appropriate cut-off for Indian WRA, we hypothesized that during iron-folic acid (IFA) supplementation to a mixed (anaemic/non-anaemic) WRA population, the positive slope of the Hb-plasma ferritin (PF) response in anaemic women would inflect into a plateau (zero-response) as a non-anaemic status is reached. The 2.5th percentile of the Hb distribution at this inflection point will be the diagnostic Hb cut-off for iron-responsive anaemia. A hierarchical mixed effects model, with a polynomial mean and variance model to account for intraclass correlation due to repeated measures, was used to estimate the response curve of Hb to PF, or body iron stores, in anaemic and non-anaemic WRA (without inflammation), who were receiving a 90-day IFA supplementation. The Hb response curve at low PF values showed a steep increase, which inflected into a plateau at a PF of 10.1 µg/L and attained a steady state at a PF of 20.6 µg/L. The Hb distribution at the inflection was a normal probability distribution, with a mean of 12.3 g/dL. The 2.5th percentile value of this distribution, or the putative diagnostic Hb cut-off for anaemia, was 10.8 g/dL (~11 g/dL). The derived Hb cut-off is lower than the current adult values of 12 g/dL and could partly explain the persistently high prevalence of anaemia.


Increased hydrophobic surface exposure in the cataract-related G18V variant of human γS-crystallin.
The objective of this study was to determine whether the cataract-related G18V variant of human γS-crystallin has increased exposure of hydrophobic residues that could explain its aggregation propensity and/or recognition by αB-crystallin. We used an ANS fluorescence assay and NMR chemical shift perturbation to experimentally probe exposed hydrophobic surfaces. These results were compared to flexible docking simulations of ANS molecules to the proteins, starting with the solution-state NMR structures of γS-WT and γS-G18V. γS-G18V exhibits increased ANS fluorescence, suggesting increased exposed hydrophobic surface area. The specific residues involved in ANS binding were mapped by NMR chemical shift perturbation assays, revealing ANS binding sites in γS-G18V that are not present in γS-WT. Molecular docking predicts three binding sites that are specific to γS-G18V corresponding to the exposure of a hydrophobic cavity located at the interdomain interface, as well as two hydrophobic patches near a disordered loop containing solvent-exposed cysteines, all but one of which is buried in γS-WT. Although both proteins display non-specific binding, more residues are involved in ANS binding to γS-G18V, and the affected residues are localized in the N-terminal domain and the nearby interdomain interface, proximal to the mutation site. Characterization of changes in exposed hydrophobic surface area between wild-type and variant proteins can help elucidate the mechanisms of aggregation propensity and chaperone recognition, presented here in the context of cataract formation. Experimental data and simulations provide complementary views of the interactions between proteins and the small molecule probes commonly used to study aggregation. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.


Chemiluminescence biosensor system for lactic acid using natural animal tissue as recognition element.
A new method based on natural animal tissue porcine kidney as recognition element for chemiluminescence sensing of lactic acid is proposed in this paper. The principle for lactic acid sensing is that lactic acid is oxidized by oxygen under the catalysis of alpha-hydroxy acid oxidase in the tissue column to produce hydrogen peroxide, which can react with luminol in the presence of potassium ferricyanide to generate a CL signal. The experimental results show that the CL emission intensity was linear with lactic acid concentration in the range of 1-1000 micromol/L and the detection limit (3sigma) for lactic acid was 0.2 micromol/L. The biosensor could be used continuously for 6h with no significant changes in the response. More than 240 measurements were carried out during this time. A complete analysis, including sampling and washing, could be performed in 1.5 min with a relative standard deviation of 1.12% for 100 micromol/L lactic acid. The reproducibility among tissue columns was satisfactory (RSD among columns is less than 5%). The biosensor has been applied successfully to the analysis of lactic acid in plasma and milk samples.


A need for clinical trial: re-purposing the Monoamine Oxidase Inhibitors (MAO-I) for rheumatoid arthritis (RA).
There is a group of enzymes called monoamine oxidase(s) (MAOs) that help with the oxidation of amines found in both our diet and our bodies. Currently, monoamine oxidase inhibitors (MAO-Is) are utilized to manage conditions like depression, Parkinson's disease, and other psychiatric disorders. Rheumatoid arthritis (RA) is an auto-immune disease that has been linked to negative changes in mental health, such as depression. When depression co-occurs with RA, it can further worsen the outcome of the disease. Inhibiting monoamine oxidases could potentially treat RA by improving its pathological markers. Using existing pre-clinical and clinical data on safety and toxicity makes drug re-purposing advantageous. Hence, the pre-clinical validation of MAO-I's effectiveness in managing RA requires urgent regulatory intervention to commence clinical trials. Back in 1983, a clinical case report put forward the idea of repurposing MAO-I for RA treatment. Although MAO-I had been used for depression, it was observed to have a significant reduction in joint pain and stiffness. However, no significant clinical research has been conducted on this matter since then. In this commentary article, we provide a summary of the pre-clinical data that is currently available. The main focus of our discussion is on the significance of clinical trials for MAO-I, repurposing it for RA, and using it for the simultaneous management of depression and RA.


Uncarboxylated osteocalcin promotes osteogenic differentiation of mouse bone marrow-derived mesenchymal stem cells by activating the Erk-Smad/β-catenin signalling pathways.
Uncarboxylated osteocalcin (unOc) is an osteoblast-derived hormone with multiple regulatory functions. Osteocalcin knockdown delays the maturation of mineral species and downregulates the expression of osteogenic-specific genes in human mesenchymal stromal cells. However, the underlying mechanisms remain unclear. Here, we investigated the effects of unOc on the osteogenic differentiation of mouse bone marrow-derived mesenchymal stem cells (BMSCs) and discovered that unOc promoted osteogenic differentiation of BMSCs, which was characterized by increases in alkaline phosphatase (ALP) activity, type I collagen (COLI) production, calcified nodule formation, and expression of osteogenic-specific genes including the osterix, runt-related transcription factor 2 (Runx2), ALP, and COLI genes. Further experiments indicated that unOc promoted the osteogenic differentiation of BMSCs via activation of the Erk-Smad/β-catenin signalling pathways. SIGNIFICANCE OF THE STUDY: Osteoporosis is associated with the osteogenic differentiation of BMSCs. In recent years, the role of unOc function as an endocrine hormone has received much attention. In this study, we reported for the first time that unOc promoted the osteogenic differentiation of mouse BMSCs through Erk-Smad/β-catenin signalling pathway. Our results highlight the importance of unOc as a hormone in promoting the osteogenic differentiation of BMSCs, indicating that this hormone may be beneficial in treatments for osteoporosis and fracture healing.


Performance and application of new inorganic retarding sealing material suitable for multi-scale fractures.
Gas extraction is an important way to solve coal mine gas in China. At present, the development of new and more efficient gas sealing materials is an urgent problem in China's coal mining industry. In order to improve the gas extraction efficiency and promote the development and utilization of coalbed methane, we developed a new inorganic slow setting material which used bentonite as main material. We added two kinds of organic modified materials and two kinds of inorganic modified materials to optimize the sealing performance, and analyzed the viscosity, sealing and particle size changes after modification. The rheological properties and diffusion properties of sealing materials was studied. Meanwhile, field experiments were carried out to verify that it has more efficient sealing performance than traditional cement materials and could improves the efficiency of gas drainage and reduces mine gas disaster accidents.


Thromboelastography Identifies Cyclic Haemostatic Variations in Healthy Women Using Oral Contraceptives.
Using thromboelastography (TEG) and standard laboratory haemostatic tests we examined the influence of the menstrual cycle and monophasic oral contraceptive (OC) use on haemostasis in healthy women. Tests were performed on citrated whole-blood and plasma (respectively) collected from 33 healthy non-pregnant women (18 non-OC users and 15 OC users) during menses, the follicular phase and the luteal phase of non-OC users, and the placebo, early-medicated phase, and late-medicated phase of OC users. Results for various coagulation parameters determined by TEG and standard laboratory haemostatic tests were compared within and between groups. TEG detected significantly increased coagulability in OC users during the late-medicated phase when compared to the placebo and early-medicated phases, whereas standard laboratory haemostatic tests failed to reveal significant differences in haemostasis within the OC steroid medication cycle. Neither TEG nor standard laboratory haemostatic tests detected significant differences in haemostasis within the menstrual cycle in non-OC users. When compared to non-OC users, TEG revealed that OC users had significantly increased coagulability only during the late-medicated phase; whereas standard laboratory haemostatic tests detected significant differences between all individual phases of the steroid medication cycle of OC users and the combined phases of the menstrual cycle in non-OC users. In conclusion, TEG provides additional insight into haemostatic function not identifiable using standard laboratory haemostatic tests.


[Cognitive/affective processes, social interaction and social structure].
Research on brain and structural analysis are overlapping but developed most often in independent ways. Here we consider biological mechanisms and environmental pressures for survival as simultaneously creating a gradual intersection of these various registers and changes in collaborative social interaction and communicative skills. We consider the ways humans have learned to characterize their brain life often depend on unexamined "representational redescriptions" that facilitate the depiction of practices.


The risk of hospitalization for psychotic disorders following hospitalization for COVID-19: a French nationwide longitudinal study.
COVID-19, like other infectious diseases, may be a risk factor for psychotic disorders. We aimed to compare the proportions of hospitalizations for psychotic disorders in the 12 months following discharge from hospital for either COVID-19 or for another reason in the adult general population in France during the first wave of the pandemic. We conducted a retrospective longitudinal nationwide study using the national French administrative healthcare database. Psychotic disorders were first studied as a whole, and then chronic and acute disorders separately. The role of several adjustment factors, including sociodemographics, a history of psychotic disorder, the duration of the initial hospitalization, and the level of care received during that hospitalization, were also analyzed. Between 1 January 2020 and 30 June 2020, a total of 14,622 patients were hospitalized for psychotic disorders in the 12 months following discharge from hospital for either COVID-19 or another reason. Initial hospitalization for COVID-19 (vs. another reason) was associated with a lower rate of subsequent hospitalization for psychotic disorders (0.31% vs. 0.51%, odds ratio (OR) = 0.60, 95% confidence interval (CI) [0.53-0.67]). This was true for both chronic and acute disorders, even after adjusting for the various study variables. Importantly, a history of psychotic disorder was a major determinant of hospitalization for psychotic disorders (adjusted OR = 126.56, 95% CI [121.85-131.46]). Our results suggest that, in comparison to individuals initially hospitalized for another reason, individuals initially hospitalized for COVID-19 present a lower risk of hospitalization for first episodes of psychotic symptoms/disorders or for psychotic relapse in the 12 months following discharge. This finding contradicts the hypothesis that there is a higher risk of psychotic disorders after a severe COVID-19.


Evaluation of PI polyamide conjugates with eight-base pair recognition and improvement of the aqueous solubility by PEGylation.
To investigate the effect of elongating base-pair (bp) recognition sequences, we synthesized N-methylpyrrole-N-methylimidazole (PI) polyamide conjugates with eight-bp recognition (3-5). The DNA alkylating activities of conjugates 3-5 were evaluated by high-resolution denaturing polyacrylamide gel electrophoresis with a 208-bp DNA fragment. Conjugates 3-5 showed high alkylating activities at nanomolar concentrations. We then addressed the following issue about PI conjugates. Generally, PI polyamide conjugates hardly dissolve in aqueous solution. To improve the aqueous solubility, by the introduction of hydrophilic groups, we synthesized PI polyamide conjugates that were modified with a seco-CBI moiety (6-11). Conjugates 9-11 that were modified by methoxypolyethylene glycol (PEG) 750 acquired moderate solubility and stability in aqueous solution. In addition, conjugates 10 and 11 had high cytotoxicity against A549 and DU145.


Changes in transcription of cytokinin metabolism and signalling genes in grape (Vitis vinifera L.) berries are associated with the ripening-related increase in isopentenyladenine.
Cytokinins are known to play an important role in fruit set and early fruit growth, but their involvement in later stages of fruit development is less well understood. Recent reports of greatly increased cytokinin concentrations in the flesh of ripening kiwifruit (Actinidia deliciosa (A. Chev.) C.F. Liang & A.R. Ferguson) and grapes (Vitis vinifera L.) have suggested that these hormones are implicated in the control of ripening-related processes. A similar pattern of isopentenyladenine (iP) accumulation was observed in the ripening fruit of several grapevine cultivars, strawberry (Fragaria ananassa Duch.) and tomato (Solanum lycopersicum Mill.), suggesting a common, ripening-related role for this cytokinin. Significant differences in maximal iP concentrations between grapevine cultivars and between fruit species might reflect varying degrees of relevance or functional adaptations of this hormone in the ripening process. Grapevine orthologues of five Arabidopsis (Arabidopsis thaliana L.) gene families involved in cytokinin metabolism and signalling were identified and analysed for their expression in developing grape berries and a range of other grapevine tissues. Members of each gene family were characterised by distinct expression profiles during berry development and in different grapevine organs, suggesting a complex regulation of cellular cytokinin activities throughout the plant. The post-veraison-specific expression of a set of biosynthesis, activation, perception and signalling genes together with a lack of expression of degradation-related genes during the ripening phase were indicative of a local control of berry iP concentrations leading to the observed accumulation of iP in ripening grapes. The transcriptional analysis of grapevine genes involved in cytokinin production, degradation and response has provided a possible explanation for the ripening-associated accumulation of iP in grapes and other fruit. The pre- and post-veraison-specific expression of different members from each of five gene families suggests a highly complex and finely-tuned regulation of cytokinin concentrations and response to different cytokinin species at particular stages of fruit development. The same complexity and specialisation is also reflected in the distinct expression profiles of cytokinin-related genes in other grapevine organs.


Edge-Decorated Polycyclic Aromatic Hydrocarbons by an Oxidative Coupling Approach.
Oxidative phenol coupling reduces reliance on halo/metalated substrates used in conventional redox neutral couplings. A new strategy for constructing polycyclic aromatic hydrocarbons (PAHs) that incorporates oxidative phenol coupling is outlined in a three-stage approach: oxidative fragment coupling, linking of the two resultant units, and oxidative cyclization. The protocol allows rapid assembly of both planar and helical systems with a high degree of edge functionalization. The incorporation of 12 alkoxy groups on systems with 12 rings gave rise to lower optical gaps compared to systems with a lesser degree of edge functionalization.


Prognosis and Circumferential Margin in Patients with Resected Hilar Cholangiocarcinoma.
Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear. Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006-2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern. Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33-80). The median follow-up was 21.7 months (range 0.3-92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P < 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P > 0.05). Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.


Intra-laboratory evaluation of Microbial Assay for Risk Assessment (MARA) for potential application in the implementation of the Water Framework Directive (WFD).
The Microbial Assay for Risk Assessment (MARA) is an innovative system based on an array of 11 different microbial species freeze-dried in a 96-well micro-titre plate format. Developed for testing the toxicity of chemicals, mixtures and environmental samples, the assay employs species of a taxonomically diverse range. In addition to ten prokaryotic species, a eukaryote (yeast) is included in the range. The MARA's innate scope of a multi-dimensional test allows determination of toxicity based on a unique assay fingerprint or index, numerically expressed as the mean Microbial Toxic Concentration (MTC). The most significant potential of the test is in the additional inference that can be conveyed to the toxicity evaluation because of the presence of each of the constituent species. In view of the fact that conventional aquatic bioassays, like fish or cladoceran tests, are expensive and impractical, the MARA could provide a cost-effective solution for routine ecotoxicological testing. The performance of the MARA was evaluated to ascertain its capability and potential scope. Sensitivity to toxicants and different environmental samples was assessed. Evaluation included comparison with other tests: namely Microtox, invertebrate (Daphnia magna and Thamnocephalus platyurus) microbiotests, and respiration-inhibition and nitrification-inhibition tests. The most sensitive invertebrate test was found to be the T. platyurus microbiotest for three of the four metals tested. The LC(50) values for this test for Cd(ii), Cr(vi) and As(iii) were 0.2, 0.018 and 0.3 mg l(-1), respectively; and the corresponding most sensitive MARA species MTC values were 4.4, 2.8 and 17 mg l(-1), respectively.


Magnetic resonance imaging of mouse Ehrlich carcinoma growth inhibition by thiacarpine, an analogue of cytotoxic marine alkaloid polycarpine.
The anticancer effect of thiacarpine, a synthetic analogue of the known cytotoxic alkaloid polycarpine isolated from the Pacific ascidian Polycarpa aurata, was investigated in vivo in experiments using mouse solid Ehrlich carcinoma tumor as the target. A high-resolution magnetic resonance imaging (MRI) technique using a MR tomograph "PharmaScan" US70/16 (Bruker, Ettlingen, Germany) was used for visualization and quantification of tumor size. Fluorescence microscopy and image analysis were applied to determine Ehrlich carcinoma cell chromatin condensing (apoptosis) and necrosis in Ehrlich carcinoma cells at the action of thiacarpine in in vitro experiments. The scan and size calculations of the tumor and some mouse organs were carried out during the experiments. Thiacarpine in a total dose of 100 mg/kg was found to exhibit the delay in growth of the mouse tumor. The antineoplastic effect of this compound was accompanied by an increase in the lifetime of experimental mice in comparison with the control group of animals. Our data show that the ability of thiacarpine to induce apoptosis in carcinoma cells may contribute to thiacarpine anticancer effects against mice solid Ehrlich carcinoma in vivo detected by MRI.


Defective expression of HLA class I antigens: a case of the bare lymphocyte without immunodeficiency.
A case of the bare lymphocyte without apparent immunodeficiency was observed in a 33-year-old woman who had no history of severe infections but suffered from sino-bronchial disease. No HLA-A and -B antigens (class I antigens) were detected at the cell surface of lymphocytes, granulocytes, and platelets, but they were expressed, although at a reduced level, on the cultured B lymphoid cell line. T lymphocytes were normal in number and in the relative proportion of T4/T8 and responded to mitogens but not to PPD and candida. HLA-DR antigens (class II antigens) were present on B lymphocytes and showed intermediate MLR-stimulatory capacity, which made it possible to deduce the patient's HLA genotype. She was found to be homozygous at consanguinity for HLA-A, -B, and -DR antigens. The numbers of B lymphocytes, immunoglobulins, and complements were all in the normal range; there was, however, a low level of IgM. Two-dimensional gel analysis of class I antigens revealed the presence of normally expressed beta-2 microglobulins (B2M) and an apparently single set of class I heavy chains, allowing us to consider two alternative cellular mechanisms in this defect; the presence of one abnormal class I structural gene and the regulatory mechanism that acted in cis were suggested.


Developmental study of a lamellar body fraction isolated from human amniotic fluid.
Several properties of a pellet fraction obtained on centrifuging amniotic fluid at 10,000 X g for 20 min were investigated. From these analyses, we defined a developmental profile which appears to describe the maturational process of the fetal lung surfactant system. At 14 to 18 wk gestation, the pellet fraction consisted of membrane-bound vesicles without internal lamellae. The phospholipid composition did not resemble that of surfactant, the major phospholipid being sphingomyelin. This stage, designated as presurfactant, persisted until 30 to 32 wk gestation. After this time, the phospholipid concentration of the pellet fraction increased continuously throughout development, and gradual but continuous changes in phospholipid composition were observed. Lecithin and phosphatidylinositol increased between 30 and 35 wk gestation. Interruption of pregnancies at this stage, termed onset of surfactant synthesis, resulted in 100% incidence of respiratory distress syndrome. From 36 wk gestation to postterm, the pellet fraction contained structures with the characteristic morphology of the lamellar inclusion bodies. The presence of single membrane components in these preparations did not contribute to the phospholipid composition. Early formed lamellar bodies lacked phosphatidylglycerol and had a high content of phosphatidylinositol. Once phosphatidylglycerol appeared in the lamellar body fraction, it continued to increase, accompanied by a decrease in phosphatidylinositol with little change in lecithin. A phosphatidylglycerol value of greater than 1% of the total phospholipids appeared to represent the stage of maturity at which there was no risk of respiratory distress syndrome.


Changes in Von Willebrand factor profile predicts clinical outcomes in patients on mechanical circulatory support.
The associations between mechanical circulatory support (MCS), acquired von Willebrand syndrome (AvWS), and clinical outcome are incompletely understood. In 128 heart failure patients with pulsatile MCS implants (65 total artificial heart or biventricular assist device implants, 63 left ventricular assist device [LVAD] implants) and 76 patients with continuous flow LVAD implants, we analyzed the von Willebrand factor (vWF) profile before (≤24 h) and 17.5 (standard deviation: 5.1) days after device implant. We determined vWF concentrations, vWF activity, and vWF collagen binding capacity and calculated ratios of vWF activity/binding capacity with vWF concentration. The relation of the vWF profile with clinical outcomes such as stroke, gastrointestinal bleeding, and survival was also evaluated. Events were assessed up to 1 year of device implant. All entities of vWF were already significantly elevated preoperatively and remained high after MCS implantation. The ratios of vWF activity/concentration (vWF:RCo/Ag) and collagen binding capacity/concentration (vWF:CBA/Ag) were significantly reduced preoperatively and remained low postoperatively, indicating AvWS. The preoperative alterations in the vWF profile were already present in patients without intra-aortic balloon pump and/or extracorporeal circulatory membrane oxygenation implants. The vWF profile was unrelated to postoperative stroke. However, a higher postoperative ratio of vWF:CBA/Ag was independently associated with increased gastrointestinal bleeding. In addition, a postoperative increase in vWF concentrations and activity were independent predictors of increased 1-year mortality. Our data indicate that AvWS is present in heart failure patients before device implantation, and is independently associated with clinical outcomes, especially with 1-year mortality.


Hydrogen peroxide inhibits the immune response to lipopolysaccharide by attenuating signaling through c-Jun N-terminal kinase and p38 associated with protein kinase C.
This study examined the immunomodulatory effects of hydrogen peroxide (H(2)O(2)) in B6C3F1 mouse splenic lymphocytes. H(2)O(2) produced a marked and dose-related inhibition of both lipopolysaccharide (LPS)-induced B-cell proliferation and concanavalin A (Con A)-induced T-cell proliferation. Unexpectedly, little effect was observed with H(2)O(2) on the antibody-forming cell (AFC) response to the polyclonal B-cell activator, LPS. It was also observed that H(2)O(2) did not have any detectable effect on forskolin-stimulated adenylate cyclase, indicating that cyclic AMP (cAMP) is not a mediator of H(2)O(2)-induced suppression of the immune response. Rather, LPS-induced activation of protein kinase C (PKC) was completely inhibited when cells were pretreated with H(2)O(2) for 18 h, although PKC activity was increased approximately twofold following treatment with H(2)O(2) for 10 min. In addition, H(2)O(2) pretreatment blocked the phosphorylation of two stress-activated mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK) and p38 by LPS in a concentration-dependent fashion. Therefore, these data suggest that H(2)O(2) suppresses immune response through the desensitization of PKC, which subsequently results in inhibition of JNK and p38.


Effective therapeutic regimens in two South Asian countries with high resistance to major Helicobacter pylori antibiotics.
Nepal and Bangladesh have a high prevalence of Helicobacter pylori with high resistance rates to clarithromycin, metronidazole, and levofloxacin. Here, we evaluated the susceptibility and genetic mutations of 5 alternative antibiotics against isolates from both countries to obtain an effective treatment regimen for H. pylori eradication. We used the agar dilution method to determine the minimal inhibitory concentration of 5 alternative antibiotics against 42 strains from Nepal and 56 from Bangladesh and performed whole genome mutation analysis. No resistance to furazolidone or rifabutin and a high susceptibility of sitafloxacin (95.2% in Nepal and 98.2% in Bangladesh) were observed. In contrast, resistance to rifaximin (52.4% in Nepal and 64.3% in Bangladesh) was high. Moreover, resistance to garenoxacin was higher in Bangladesh (51.6%) than in Nepal (28.6%, P = 0.041), most likely due to its correlation with levofloxacin resistance (P = 0.03). Garenoxacin and rifaximin were significantly correlated in Bangladesh (P = 0.014) and occurred together with all sitafloxacin-resistant strains. Mutations of gyrA could play a significant role in garenoxacin resistance, and double mutations of A87 and D91 were associated with sitafloxacin resistance. Analysis of the rpoB gene demonstrated well-known mutations, such as V657I, and several novel mutations, including I2619V, V2592 L, T2537A, and F2538 L. Rifabutin can be cautiously implemented as therapy for H. pylori infection due to its interaction with the tuberculosis endemic in Bangladesh. The high susceptibility of furazolidone and sitafloxacin suggests their possible future application in Nepal and Bangladesh.


Arthroscopic Suprapectoral and Open Subpectoral Biceps Tenodesis: Radiographic Characteristics.
To provide a detailed account of the location of the long head of the biceps (LHB) tenodesis tunnels using an all-arthroscopic suprapectoral technique in a prospective group of patients. These patients were then compared with a retrospective group of open subpectoral tenodesis patients of similar characteristics. Postoperative radiographs from a prospective group of all-arthroscopic suprapectoral LHB tenodeses were compared with a retrospective group of open subpectoral tenodeses. Digital anteroposterior images were used to measure distances from clinically pertinent radiographic landmarks to tenodesis tunnel sites. Forty patients (20 all-arthroscopic, 20 open) met the inclusion criteria. The inferior border of the bicipital groove was located a mean distance of 33.7 ± 6.9 mm from the top of the humeral head. The mean distance measured in the open group was approximately 28 mm (P < .001) distal compared with the arthroscopic group. The humeral diameter was 7.5 ± 5.4 mm narrower at the subpectoral tenodesis site (P < .001). All 20 patients in the open subpectoral group had tenodesis tunnels placed distal to the bicipital groove compared with 17 of 20 patients (85%) in the all-arthroscopic group. There were 2 cases of lateral wall cortical reaming during subpectoral tenodesis but no periprosthetic humeral fractures. There were 2 cases of bicortical reaming during the all-arthroscopic tenodesis with no known complications. The location of biceps tenodesis significantly differs between all-arthroscopic suprapectoral and open subpectoral techniques, and the open subpectoral method achieves fixation in a significantly narrower region of the humerus. Level III, retrospective comparative study.


FtsK and SpoIIIE, coordinators of chromosome segregation and envelope remodeling in bacteria.
The translocation of DNA during bacterial cytokinesis is mediated by the SpoIIIE/FtsK family of proteins. These proteins ensure efficient chromosome segregation into sister cells by ATP-driven translocation of DNA and they control chromosome dimer resolution. How FtsK/SpoIIIE mediate chromosome translocation during cytokinesis in Gram-positive and Gram-negative organisms has been the subject of debate. Studies on FtsK in Escherichia coli, and recent work on SpoIIIE in Bacillus subtilis, have identified interactions between each translocase and the division machinery, supporting the idea that SpoIIIE and FtsK coordinate the final steps of cytokinesis with completion of chromosome segregation. Here we summarize and discuss the view that SpoIIIE and FtsK play similar roles in coordinating cytokinesis with chromosome segregation, during growth and differentiation.


LEF-1 recognition of platinated GG sequences within double-stranded DNA. Influence of flanking bases.
The lymphoid enhancer-binding factor 1 (LEF-1) recognizes a double-stranded 9 base-pairs (bp) long motif in DNA which is significantly bent upon binding. This bend is centered at two destacked adenines whose geometry closely resembles that of two adjacent guanines crosslinked by the antitumor drug cisplatin. It has been proposed that cisplatin-GG crosslinks could hijack high mobility group (HMG) box containing transcription factors such as LEF-1. In order to examine such a possibility, we used electrophoretic mobility shift assays to determine the affinity of the HMG box of LEF-1 for a series of 25 oligonucleotides containing a central GG sequence, free or site-specifically modified by cisplatin. The binding affinity of the GG-platinated oligonucleotides was 3-6-fold higher than that determined for the corresponding unplatinated oligonucleotides, however, the binding to all cisplatin-modified oligonucleotides was at least 1 order of magnitude weaker than that to the 25 bp oligonucleotide containing the recognition 9 bp motif. The binding affinity was dependent on the nature of bases flanking the cisplatin-crosslinked G(*)G(*) dinucleotide, the AG(*)G(*)T sequence displaying the strongest affinity and CG(*)G(*)T showing the strongest binding enhancement upon platination. In contrast, modification of the AGGT sequence with the third-generation platinum antitumor drug oxaliplatin did not enhance the affinity significantly. These results suggest that the cisplatin-caused bending of DNA does produce a target for LEF-1 binding, however, the cisplatinated DNA does not appear to be a strong competitor for the LEF-1 recognition sequence.


The GTPase domain of Galphao contributes to the functional interaction of Galphao with the promyelocytic leukemia zinc finger protein.
Go, one of the most abundant heterotrimeric G proteins in the brain, is classified as a member of the Gi/Go family based on its homology to Gi proteins. Recently, we identified promyelocytic leukemia zinc finger protein (PLZF) as a candidate downstream effector for the alpha subunit of Go (Galphao). Activated Galphao interacts with PLZF and augments its function as a repressor of transcription and cell growth. G protein-coupled receptor-mediated Galphao activation also enhanced PLZF function. In this study, we determined that the GTPase domain of Galphao contributes to Galphao:PLZF interaction. We also showed that the Galphao GTPase domain is important in modulating the function of PLZF. This data indicates that the GTPase domain of Galphao may be necessary for the functional interaction of Galphao with PLZF.


Use of prescription medications with cardiovascular adverse effects among older adults in the United States.
Many commonly used prescription medications have cardiovascular adverse effects, yet the cumulative risk of cardiovascular events associated with the concurrent use of these medications is unknown. We examined the association between the concurrent use of prescription medications with known risk of a major adverse cardiovascular event (MACE) ("MACE medications") and the risk of such events among older adults. A multi-center, population-based study from the Atherosclerosis Risk in Communities (ARIC) study of a cohort of 3669 community-dwelling adults aged 61-86 years with no history of cardiovascular disease who reported the use of at least one medication between September 2006 and August 2013 were followed up until August 2015. Exposure defined as time-varying and time-fixed use of 1, 2 or ≥3 MACE medications with non-MACE medications serving as negative control. Primary outcome was incident MACE defined as coronary artery revascularization, myocardial infarction, fatal coronary heart disease, stroke, cardiac arrest, or death. In fully adjusted models, there was an increased risk of MACE associated with use of 1, 2, or ≥3 MACE medications (1 MACE: hazards ratio [HR], 1.21; 95% confidence interval [CI], 0.94-1.57); 2 MACE: HR 1.89, CI 1.42-2.53; ≥3 MACE: HR 2.22, CI 1.61-3.07) compared to use of non-MACE medications. These associations persisted in propensity score-matched analyses and among new users of MACE medications, never users of cardiovascular medications and subgroups of participants with increased risk of MACE. There was no association between the number of non-MACE medications used and MACE. In this community-based cohort of older adults with no prior cardiovascular disease, the use of MACE medications was independently and consistently associated with an increased risk of such events in a dose-response fashion.


How do our brain hemispheres cooperate to avoid false memories?
Memories are not always as reliable as they may appear. The occurrence of false memories can be reduced, however, by enhancing the cooperation between the two brain hemispheres. Yet is the communication from left to right hemisphere as helpful as the information transfer from right to left? To address this question, 72 participants were asked to learn 16 word lists. Applying the Deese-Roediger-McDermott paradigm, the words in each list were associated with an unpresented prototype word. In the test condition, learned words and corresponding prototypes were presented along with non-associated new words, and participants were asked to indicate which of the words they recognized. Crucially, both study and test words were projected to only one hemisphere in order to stimulate each hemisphere separately. It was found that false recognitions occurred significantly less often when the right hemisphere studied and the left hemisphere recognized the stimuli. Moreover, only the right-to-left direction of interhemispheric communication reduced false memories significantly, whereas left-to-right exchange did not. Further analyses revealed that the observed reduction of false memories was not due to an enhanced discrimination sensitivity, but to a stricter response bias. Hence, the data suggest that interhemispheric cooperation does not improve the ability to tell old and new apart, but rather evokes a conservative response tendency. Future studies may narrow down in which cognitive processing steps interhemispheric interaction can change the response criterion.


Effects of glucose ingestion on autonomic and cardiovascular measures during rest and mental challenge.
High levels of dietary sugar consumption may result in dysregulated glucose metabolism and lead to elevated cardiovascular disease risk via autonomic nervous system and cardiovascular dysfunction. Altered cardiovascular function can be examined using perturbation tasks such as mental challenge. This study examined the effects of controlled glucose intake on cardiovascular measures at rest and in responses to mental challenge in a laboratory setting. Using a double blind within-subjects design, participants were monitored at baseline, following ingestion of a glucose or taste-control solution, during structured speech (SS), anger recall (AR) and recovery (N=24, 288 repeated measures; age = 21±2 years). Pre-ejection period (PEP), heart rate (HR), stroke index (SI), cardiac index (CI), blood pressure and total peripheral resistance (TPR) were measured throughout the protocol. Glucose resulted in sustained decreased PEP levels compared to control condition (Δ=11.98±9.52 vs. 3.27±7.65 m·s, P<.001) and transient increases in resting HR (P=.011), CI (P=.040) and systolic blood pressure (P=.009). Glucose did not result in increased cardiovascular reactivity to mental challenge tasks, but was associated with a delayed HR recovery following AR (P=.032). Glucose intake resulted in a drop in PEP indicating increased sympathetic nervous system activity. No evidence was found for glucose-related exaggerated cardiovascular responses to mental challenge. Dysregulated glucose metabolism may result in elevated cardiovascular disease risk as a result of repeated glucose-induced elevations of sympathetic nervous system activity.


Reproducibility of mtDNA analysis between laboratories: a report of the European DNA Profiling Group (EDNAP).
The aim of this collaborative exercise was to determine whether uniformity of mtDNA sequencing results could be achieved among different EDNAP laboratories. Laboratories were asked to sequence mtDNAHV1 region (16024-16365) from three bloodstains, proceeding in accordance with the protocol and strategies currently used in each individual laboratory. Cycle sequencing was used by 11 laboratories and solid phase single stranded sequencing was used by one laboratory. Different PCR strategies and PCR conditions were used by the different laboratories. Three laboratories used semi-nested PCR, two nested PCR, three direct amplification of HV1 and four amplification of overlapping fragments covering the HV1 region. Despite the diversity of methodologies used, all the laboratories reported the same results. The successful result of this exercise shows that PCR based mtDNA typing by automated sequencing is a valid, robust and reliable means of forensic identification despite the different strategies and methodologies used by the different laboratories.


The platinum (II) complex [Pt(O,O'-acac)(γ-acac)(DMS)] alters the intracellular calcium homeostasis in MCF-7 breast cancer cells.
It was previously demonstrated that [Pt(O,O'-acac)(γ-acac)(DMS)] exerted toxic effects at high doses, whilst sub-cytotoxic concentrations induced anoikis and decreased cell migration. Aim of this study was to investigate the hypothesis that [Pt(O,O'-acac)(γ-acac)(DMS)] alters the [Ca(2+)](i) and that this is linked to its ability to trigger rapid apoptosis in MCF-7 cells. Thus, cells were treated with [Pt(O,O'-acac)(γ-acac)(DMS)] and its effects on some of the systems regulating Ca(2+) homeostasis were studied, also in cells dealing with the complex changes occurring during the Ca(2+) signalling evoked by extracellular stimuli. [Pt(O,O'-acac)(γ-acac)(DMS)] caused the decrease of PMCA activity (but not SERCA or SPCA) and Ca(2+) membrane permeability. These two opposite effects on [Ca(2+)](i) resulted in its overall increase from 102±12nM to 250±24nM after 15min incubation. The effects of [Pt(O,O'-acac)(γ-acac)(DMS)] were also evident when cells were stimulated with ATP: the changes in Ca(2+) levels caused by purinergic stimulation resulted altered due to decreased PMCA activity and to the closure of Ca(2+) channels opened by purinergic receptor. Conversely, [Pt(O,O'-acac)(γ-acac)(DMS)] did not affect the store-operated Ca(2+) channels opened by thapsigargin or by ATP. [Pt(O,O'-acac)(γ-acac)(DMS)] provoked the activation of PKC-α and the production of ROS that were responsible for the Ca(2+) permeability and PMCA activity decrease, respectively. The overall effect of [Pt(O,O'-acac)(γ-acac)(DMS)] is to increase the [Ca(2+)](i), an effect that is likely to be linked to its ability to trigger rapid apoptosis in MCF-7 cells. These data reinforce the notion that [Pt(O,O'-acac)(γ-acac)(DMS)] would be a promising drug in cancer treatment.


An individualized administration model of vancomycin in elderly patients with sepsis and factors influencing augmented renal clearance.
Vancomycin efficacy is dependent on appropriate dosing, which should aim to achieve a target serum trough level. The purpose of this study was to determine the variables that predicted vancomycin serum trough concentrations in elderly patients with sepsis. This retrospective cohort study, which was conducted in the medical ICU of a university-affiliated teaching hospital in China, included 87 medical patients with sepsis who were enrolled from January 2014 to December 2017. All the patients were at least 60 years old (mean age = 74.8 ± 8.2 years), and 51.7% (n = 45) of them were male. The most common primary site of infection was the lungs (67.8%), followed by the abdomen (12.6%). Patients with septic shock accounted for 21.8% (n = 19) of the cases. The proportion of patients with vancomycin serum trough concentrations reaching target concentrations (≥15 mg/L) was 47.1% (41 cases). Multivariate linear regression showed that the creatinine clearance rate (CCR) and the daily dosage of vancomycin were independent predictors of vancomycin serum trough concentrations (both p's < 0.05), and the model for predicting vancomycin trough concentrations should be: serum trough concentration (mg/L) = 15.942 - 0.101 × CCR (mL/min) + 0.347 × vancomycin daily doses (mg/kg/d). Augmented renal clearance (ARC) was present in 13 patients (14.9%), and logistic regression revealed body mass index (OR = 1.420, p = .002) and serum creatinine level (OR = 0.883, p = .002) were independent predictors of ARC. The CCR and daily dosage of vancomycin were significantly correlated with vancomycin serum trough concentrations in elderly patients with sepsis, and the individualized administration model should be verified through further clinical trials. BMI and serum creatinine level were identified to be independent predictors of ARC in elderly patients.


Influence of and optimal insulin therapy for a low-glycemic index meal in children with type 1 diabetes receiving intensive insulin therapy.
The purpose of this study was to quantify the effects of glycemic index on postprandial glucose excursion (PPGE) in children with type 1 diabetes receiving multiple daily injections and to determine optimal insulin therapy for a low-glycemic index meal. Twenty subjects consumed test breakfasts with equal macronutrient contents on 4 consecutive days; high-and low-glycemic index meals (glycemic index 84 vs. 48) were consumed with preprandial ultra-short-acting insulin, and the low-glycemic index meal was also consumed with preprandial regular insulin and postprandial ultra-short-acting insulin. Each child's insulin dose was standardized. Continuous glucose monitoring was used. The PPGE was significantly lower for the low-glycemic index meal compared with the high-glycemic index meal at 30-180 min (P < 0.02) when preprandial ultra-short-acting insulin was administered. The maximum difference occurred at 60 min (4.2 mmol/l, P < 0.0001). Regular insulin produced a 1.1 mmol/l higher PPGE at 30 min compared with ultra-short-acting insulin (P = 0.015) when the low-glycemic index meal was consumed. Postprandial ultra-short-acting insulin produced a higher PPGE at 30 and 60 min compared with preprandial administration when the low-glycemic index meal was consumed. The maximum difference was 2.5 mmol/l at 60 min (P < 0.0001). Low-glycemic index meals produce a lower PPGE than high-glycemic index meals. Preprandial ultra-short-acting insulin is the optimal therapy for a low-glycemic index meal.


Control of vitamin B12 release from poly(ethylene glycol)/poly(butylene terephthalate) multiblock copolymers.
The release of vitamin B12 (1355 Da) from matrices based on multiblock copolymers was studied. The copolymers were composed of hydrophilic poly(ethylene glycol)-terephthalate (PEGT) blocks and hydrophobic poly(butylene terephthalate) (PBT) blocks. Vitamin B12 loaded films were prepared by using a water-in-oil emulsion method. The copolymer properties, like permeability, could be varied by increasing the PEG-segment length from 300 up to 4,000 g/mol and by changing the wt% of PEGT. From permeation and release experiments. the diffusion coefficient of vitamin B12 through PEGT/PBT films of different compositions was determined. The diffusion coefficient of Vitamin B12 was strongly dependent on the composition of the copolymers. Although an increased wt% of PEGT (at a constant PEG-segment length) resulted in a higher diffusion coefficient, a major effect was observed at increasing PEG-segment length. By varying the copolymer composition, a complete release of vitamin B12 in 1 day up to a constant release for over 12 weeks was obtained. The release rate could be effectively tailored by blending copolymers with different PEG-segment lengths. The swelling and the crystallinity of the matrix could explain the effect of the matrix composition on the release behavior.


[Ways of increasing the effectiveness of tuberculosis control].
Ways for improving quality of tuberculosis control at the present stage are discussed. The necessity for estimating the quality of the activities of medical institutions by the final results with respect to all the parameters is grounded. Such results should be the level of tuberculosis incidence, susceptibility to tuberculosis, death rate due to tuberculosis, temporary and stable invalidity.


Reducing the risk of foaming and decreasing viscosity by two-stage anaerobic digestion of sugar beet pressed pulp.
Anaerobic digestion (AD) of sugar beet pressed pulp (SBPP) is a promising treatment concept. It produces biogas as a renewable energy source making sugar production more energy efficient and it turns SBPP from a residue into a valuable resource. In this study one- and two-stage mono fermentation at mesophilic conditions in a continuous stirred tank reactor were compared. Also the optimal incubation temperature for the pre-acidification stage was studied. The fastest pre-acidification, with a hydraulic retention time (HRT) of 4 days, occurred at a temperature of 55 °C. In the methanogenic reactor of the two-stage system stable fermentation at loading rate of 7 kg VS/m³ d was demonstrated. No artificial pH adjustment was necessary to maintain optimum levels in both the pre-acidification and the methanogenic reactor. The total HRT of the two-stage AD was 36 days which is considerably lower compared to the one-stage AD (50 days). The frequently observed problem of foaming at high loading rates was less severe in the two-stage reactor. Moreover the viscosity of digestate in the methanogenic stage of the two-stage fermentation was in average tenfold lower than in the one-stage fermentation. This decreases the energy input for the reactor stirring about 80 %. The observed advantages make the two-stage process economically attractive, despite higher investments for a two reactor system.


Pit pattern analysis with high-definition chromoendoscopy and narrow-band imaging for optical diagnosis of dysplasia in patients with ulcerative colitis.
Patients with longstanding ulcerative colitis (UC) are at increased risk of developing colorectal neoplasia. Chromoendoscopy (CE) increases detection of lesions, and Kudo pit pattern classification I and II have been suggested to be predictive of benign polyps in UC. Little is known on the use of this classification in nonmagnified high-definition (HD) (virtual) CE and narrow-band Imaging (NBI) or on the interobserver agreement. The aim of this pilot study was to assess the diagnostic accuracy and the interobserver agreement of the Kudo pit pattern classification in UC patients undergoing surveillance with methylene blue CE or NBI in a multicenter study. Fifty images of lesions identified in 27 UC patients (13 neoplastic) either with classical CE (methylene blue .1%; n = 24) or NBI (n = 26) were selected by an independent investigator. Images were selected from a randomized controlled trial to compare CE and NBI. All nonmagnified images were obtained with a processor and mounted in a PowerPoint file in a standardized way (same size; black background). Ten endoscopists with extensive experience in NBI/CE were asked to assess the lesions for the predominant Kudo pit pattern (I, II, IIIL, IIIS, IV, and V) to indicate if they believed the lesion was neoplastic and how confident they were about the diagnosis. Histology was used as the criterion standard. Median sensitivity, specificity, negative predictive value, and positive predictive value for diagnosing neoplasia based on the presence of pit pattern other than I or II was 77%, 68%, 88%, and 46%, respectively. Diagnostic accuracy was significantly higher when a diagnosis was made with a high level of confidence (77% vs 21%, P < .001). The overall interobserver agreement for any pit pattern was only fair (κ = .282), with CE being significantly better than NBI (.322 vs .224, P < .001). From a clinical viewpoint the difference between neoplastic and non-neoplastic lesions is important. The agreement for differentiation between non-neoplastic patterns (I, II) and neoplastic patterns (IIIL, IIIS, IV, or V) was moderate (κ = .587) and even significantly better for NBI in comparison with CE (κ = .653 vs .495, P < .001). Differentiation between non-neoplastic and neoplastic pit patterns in UC lesions shows a moderate to substantial agreement among expert endoscopists. The agreement for differentiating neoplastic from non-neoplastic lesions is significantly better for NBI in comparison with HD CE. The assessment of pit pattern I or II with nonmagnified HD CE or NBI has a high negative predictive value to rule out neoplasia. (Clinical trial registration number: NCT01882205.).


Structure and absolute configuration of (Z)-(+)-2-bromo-2-cycloundecenyl camphanate.
C21H31BrO4, Mr = 427.38, monoclinic, P2(1), a = 8.050 (1), b = 12.703 (3), c = 10.658 (1) A, beta = 102.56 (2) degrees, V = 1063.80 A3, Z = 2, Dx = 1.334 g cm-3, lambda(Cu K alpha) = 1.5418 A, mu = 28.09 cm-1, experimental temperature 296 K. F(000) = 448, R = 0.045 for 2015 unique reflections with I greater than or equal to sigma(I). The conformation of the 11-membered ring in this compound and its absolute configuration (1R) have been determined.


Sweet cherry flesh cells burst in non-random clusters along minor veins.
Sweet cherry flesh cells burst when exposed to water but they do so in clusters indicating heterogeneity with respect to osmotic concentration, which depends on proximity to a minor vein. Water plays a key role in cracking in sweet cherry fruit. Magnetic resonance imaging has previously indicated preferential partitioning of water along veins. A more negative osmotic potential along veins seems the likely explanation. Here we establish if cell bursting in mature sweet cherry fruit is also associated with the veins. Cell bursting was identified by a novel light microscope technique involving exposure of a cut fruit surface to water or to sucrose solutions. Upon exposure to water there was no bursting of skin cells but for cells of the flesh (mesocarp) bursting increased with time. When the cut surface was exposed to sucrose solutions of decreasing osmotic concentrations (increasing water potentials) the incidence of cell bursting increased from hypertonic (no bursting), to isotonic, to hypotonic. Cell bursting in the outer mesocarp occurred primarily in the vicinity of minor veins that in the inner mesocarp was primarily between radial veins. The median distance between a minor vein and a bursting cell (mean diameter 0.129 mm) was about 0.318 mm that between a radial vein and a bursting cell was about 0.497 mm. In contrast, the distance between adjacent minor veins averaged 2.57 mm, that between adjacent radial veins averaged 0.83 mm. Cell bursting tends to occur in clusters. Mapping of cell bursting indicates (1) that a seemingly uniform population of mesocarp cells actually represents a heterogeneous population with regard to their cell osmotic potentials and (2) cell bursting afflicts clusters of neighbouring cells in the vicinities of minor veins.


Effect of recombinant serine protease from newborn larval stage of Trichinella spiralis on 2,4,6-trinitrobenzene sulfonic acid-induced experimental colitis in mice.
Inflammatory bowel disease (IBD) is a complex immune-mediated disease of gastrointestinal tract that is mainly driven by Th1/Th17 immune response. "Helminth therapy" has emerged, and helminth-derived immunoregulatory molecules are being used as safe and new therapeutic antigens for IBD. Recombinant serine protease (SP) from newborn Trichinella spiralis (T. spiralis) larvae (NBL) was expressed and purified. BALB/c mice were immunized with NBL-SP at 100 µg three times at an interval of 5 days. Experimental colitis was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) administration. The disease activity index (DAI) and macroscopic and microscopic scores of the colon were assessed to identify the effect of NBL-SP on experimental colitis. Cytokine production in the serum was analysed by meso scale discovery (MSD). Cytokine production in the colon was detected by ELISA. CD4+T cell differentiation was measured by flow cytometry. NBL-SP alleviated TNBS-induced colitis in mice. The DAI, macroscopic and microscopic scores and colon length all showed a positive intervention effect of NBL-SP on experimental colitis. NBL-SP can weaken the increase in IFN-γ, TNF-α and IL-17 production as well as CD4+ IFN-γ+T cell and CD4+IL-17+T cell populations induced by colitis. Furthermore, the levels of Th2-related cytokines (IL-4, IL-5) and regulatory cytokines (IL-10, TGF-β) were elevated meanwhile the ratio of regulatory T cells (Tregs) and CD4+ IL-4 + T cells were increased by NBL-SP. NBL-SP of T. spiralis had a potential protective effect against IBD. NBL-SP skewed the Th1 and Th17-mediated response towards the Th2 and Treg response.


Multivariable regression: understanding one of medicine's most fundamental statistical tools.
Multivariable regression is a fundamental tool that drives observational research in orthopaedic surgery. However, regression analyses are not always implemented correctly. This study presents a basic overview of regression analyses and reviews frequent points of confusion. Topics include linear, logistic, and time-to-event regressions, causal inference, confounders, overfitting, missing data, multicollinearity, interactions, and key differences between multivariable versus multivariate regression. The goal is to provide clarity regarding the use and interpretation of multivariable analyses for those attempting to increase their statistical literacy in orthopaedic research.


The trematode Podocotyle atomon modulates biochemical responses of Gammarus locusta to thermal stress but not its feeding rate or survival.
Although parasitism is one of the most common species interactions in nature, the role of parasites in their hosts' thermal tolerance is often neglected. This study examined the ability of the trematode Podocotyle atomon to modulate the feeding and stress response of Gammarus locusta towards temperature. To accomplish this, infected and uninfected females and males of Gammarus locusta were exposed to temperatures (2, 6, 10, 14, 18, 22, 26, 30 °C) for six days. Shredding (change in food biomass) and defecation rates (as complementary measure to shredding rate) were measured as proxies for feeding activity. Lipid and glycogen concentrations (energy reserves), catalase (oxidative stress indicator), and phenoloxidase (an immunological response in invertebrates) were additionally measured. Gammarid survival was optimal at 10 °C as estimated by the linear model and was unaffected by trematode infection. Both temperature and sex influenced the direction of infection effect on phenoloxidase. Infected females presented lower phenoloxidase activity than uninfected females at 14 and 18 °C, while males remained unaffected by infection. Catalase activity increased at warmer temperatures for infected males and uninfected females. Higher activity of this enzyme at colder temperatures occurred only for infected females. Infection decreased lipid content in gammarids by 14 %. Infected males had significantly less glycogen than uninfected, while infected females showed the opposite trend. The largest infection effects were observed for catalase and phenoloxidase activity. An exacerbation of catalase activity in infected males at warmer temperatures might indicate (in the long-term) unsustainable, overwhelming, and perhaps lethal conditions in a warming sea. A decrease in phenoloxidase activity in infected females at warmer temperatures might indicate a reduction in the potential for fighting opportunistic infections. Results highlight the relevance of parasites and host sex in organismal homeostasis and provide useful insights into the organismal stability of a widespread amphipod in a warming sea.


Pregabalin in the discontinuation of long-term benzodiazepines' use.
Tolerance, dependence, and adverse effects on cognitive functions are well-known consequences of long-term use of benzodiazepines (BDZ), especially at high doses, raising thorny therapeutic problems in their discontinuation. One promising pharmacological agent in BDZ discontinuation might be the newer anti-epileptic pregabalin, already successfully tested in the treatment of anxiety disorders. We report on a sample of 15 patients with long-term, mostly high-dose dependence from BDZ, treated with pregabalin in an open-label study at doses 225-900 mg. All patients discontinued successfully BDZ in 3-14 weeks, moreover with a significant reduction of their previous anxiety levels under BDZ. In addition, patients showed also a significant amelioration in their cognitive functioning. Pregabalin's side-effects were mild and transient, lasting only during the first 2 weeks of treatment. Although preliminary, our findings suggest that pregabalin may be one new promising agent in the treatment of BDZ dependence.


An in vitro study on the stimulatory effects of extracellular glutamate on astrocytes.
In our previous research, it was found that the cerebrospinal fluid had higher levels of glutamate, astrocytes were stimulated and released pro-inflammatory factors in a subarachnoid hemorrhage model. Glutamate is a neurotransmitter produced in abundance by excitatory neurons in the central nervous system, residual glutamate can cause neurotoxicity. Recent studies indicate that most glutamate is absorbed by astrocytes, to optimize neurological functions and prevent excitotoxicity. However, it is still unclear if astrocytes could be stimulated by glutamate, and the concentration range of glutamate transportable by astrocytes. Thus, further research is necessary. This study aimed to clarify these scientific questions by stimulating primary astrocytes at different glutamate concentrations (0, 25, 50, and 100 µM) for 24 h. The results showed that glutamate induced an increased response in astrocytes, the protein levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were upregulated in treatment groups with 50 and 100 µM. Additionally, the protein expression of complement component 3 (C3) significantly increased following glutamate stimulation (50 and 100 µM) for 24 h. Furthermore, the supernatant of the 100 µM treatment group significantly decreased the viability of HT-22 (an immortalized mouse hippocampal neuronal cell line). In summary, our results indicate that increased extracellular glutamate levels can activate astrocytes and promote pro-inflammatory factor production. Moreover, the concentration range of glutamate transported by astrocytes is approximately less than 50-100 µM. Therefore, our study suggests that experimental antagonization of glutamate excitotoxicity is feasible.


Leptin and perioperative neuroendocrine stress response with two different anaesthetic techniques.
Stress response to surgery is modulated by several factors, including magnitude of the injury, pain, type of procedure and choice of anaesthesia. Our purpose was to compare intra- and post-operative hormonal changes during total intravenous anaesthesia (TIVA) using propofol and remifentanil vs. sevoflurane anaesthesia in a low stress level surgical model (laparoscopy). We randomly allocated 18 patients undergoing laparoscopic surgery for benign ovarian cysts in two groups to receive either TIVA (group A=9) or sevoflurane anaesthesia (group B=9). Perioperative plasma levels of norepinephrine (NE), epinephrine (E), adrenocorticotropic hormone (ACTH), cortisol and leptin were measured. Blood samples were collected pre-operatively (time 0), 30 min after the beginning of surgery (time 1), after extubation (time 2), and 2 h (time 3) and 4 h after surgery (time 4). The comparative analysis between the groups shows significantly higher values of NE (P<0.001 at time 1 and P<0.01 at time 3), E (P<0.001 at times 1 and 2; P<0.01 at time 3 and P<0.05 at time 4), ACTH (P<0.001 at times 1 and 2; P<0.05 at time 3) and cortisol (P<0.001 at times 1 and 2; P<0.01 at time 3; P<0.05 at time 4) in group B. The serum values of leptin were not significantly different between the two groups. The choice of anaesthesia does not seem to affect the leptin serum levels but influences the release of stress response markers: ACTH, cortisol, NE and E.


Trypanosoma cruzi: Genome characterization of phosphatidylinositol kinase gene family (PIK and PIK-related) and identification of a novel PIK gene.
Chagas disease is caused by the protozoan Trypanosoma cruzi which affects 10 million people worldwide. Very few kinases have been characterized in this parasite, including the phosphatidylinositol kinases (PIKs) that are at the heart of one of the major pathways of intracellular signal transduction. Recently, we have classified the PIK family in T. cruzi using five different models based on the presence of PIK conserved domains. In this study, we have mapped PIK genes to the chromosomes of two different T. cruzi lineages (G and CL Brener) and determined the cellular localization of two PIK members. The kinases have crucial roles in metabolism and are assumed to be conserved throughout evolution. For this reason, they should display a conserved localization within the same eukaryotic species. In spite of this, there is an extensive polymorphism regarding PIK localization at both genomic and cellular levels, among different T. cruzi isolates and between T. cruzi and Trypanosomabrucei, respectively. We showed in this study that the cellular localization of two PIK-related proteins (TOR1 and 2) in the T. cruzi lineage is distinct from that previously observed in T. brucei. In addition, we identified a new PIK gene with peculiar feature, that is, it codes for a FYVE domain at N-terminal position. FYVE-PIK genes are phylogenetically distant from the groups containing exclusively the FYVE or PIK domain. The FYVE-PIK architecture is only present in trypanosomatids and in virus such as Acanthamoeba mimivirus, suggesting a horizontal acquisition. Our Bayesian phylogenetic inference supports this hypothesis. The exact functions of this FYVE-PIK gene are unknown, but the presence of FYVE domain suggests a role in membranous compartments, such as endosome. Taken together, the data presented here strengthen the possibility that trypanosomatids are characterized by extensive genomic plasticity that may be considered in designing drugs and vaccines for prevention of Chagas disease.


Training high school counselors on the use of motivational interviewing to screen for substance abuse.
Interdisciplinary faculty implemented a project to enhance school personnel's knowledge and skills in screening and motivational interviewing for substance abuse in two Boston high schools.


Tissue-selective estrogen complex bazedoxifene and conjugated estrogens for the treatment of menopausal vasomotor symptoms.
Menopause occurs on average at age 51.4 years. Most, but not all, women who undergo menopause experience significant vasomotor symptoms (VMS). Although single agent estrogen therapy can relieve VMS, over time estrogen can stimulate the endometrial lining leading to an increased risk for endometrial hyperplasia and adenocarcinoma. Although a progestin has traditionally been given in combination with estrogen to 'protect' the endometrium, a new and innovative approach to this traditional combination hormone therapy is to substitute the progestin with an alternative agent. One such alternative agent is bazedoxifene, an estrogen agonist-antagonist. Based on data from randomized trials, when bazedoxifene is given in combination with oral conjugated estrogens to post-menopausal women, the risk of estrogen-associated endometrial stimulation is significantly reduced. The combination of bazedoxifene and conjugated estrogens has also been shown to relieve menopause-associated VMS and vaginal atrophy, and has been shown to be safe for short-term use. Long-term studies of this combination are needed to determine if the combination of conjugated estrogens/bazedoxifene can be used for >3 years without increasing the risk of breast cancer, stroke, cognitive deficit, pulmonary embolism or coronary heart disease. Short-term data regarding this combination has been submitted to the FDA and is currently under review for clinical use, with the relief of VMS as its primary indication. Data regarding the effects of combination conjugated estrogens/bazedoxifene therapy on bone are promising in terms of the prevention and treatment of post-menopausal osteoporosis.


Symptom trajectories in the months before and after a suicide attempt in individuals with bipolar disorder: A STEP-BD study.
The suicide crisis is a relatively short-lived psychiatric emergency, with transient symptoms that ebb and flow around the suicide attempt. Understanding the dynamic processes of symptoms before and after suicide attempt may aid future prevention efforts. Data were drawn from the NIMH STEP-BD study, which followed 4,360 patients with bipolar disorder; a subset attempted suicide during the trial (245/4100 or 5.97% of the sample eligible for analysis). This analysis focused on change in suicidal ideation (SI) in the 120 days before and 120 days after suicide attempt; similar analyses were conducted for other depressive symptoms. Generalized linear mixed models with a two-piece linear function of time corresponding to pre- and post-suicide attempt trends were used. SI ratings from 216 individuals were analyzed (n = 1,231 total; n = 395 pre-attempt, n = 126 circa-attempt, n = 710 post-attempt) and compared to data from a matched sample of 648 non-attempters. SI worsened in the 120 days pre-attempt but improved afterwards, reaching non-attempter levels by 90 days post-attempt. A similar pattern was found for other depressive symptoms, including depressed mood, loss of interest, guilt, and self-esteem. Pre/post differences in tension/activating symptoms of depression-anxiety, agitation, and irritability-were less pronounced and more time-limited. The suicide crisis is dynamic, and the days before and after suicide attempt may be particularly critical. The findings extend previous research on proximal symptoms of suicide and underscore that some SI and affective/cognitive symptoms of depression can remain elevated up to 90 days post-attempt in individuals with bipolar disorder.


Muscarinic and gamma-aminobutyric acid-ergic receptor changes during vestibular compensation. A quantitative autoradiographic study of the vestibular nuclei complex in the rat.
Involvement of the neurotransmitters acetyl choline and gamma-aminobutyric acid (GABA) in vestibular compensation has been suggested by electrophysiological and pharmacological experiments. In this investigation we used quantitative autoradiography to study the modification of muscarinic and benzodiazepine receptors in each nucleus of the rat's vestibular nucleus complex. Tissues were examined 3, 14, 23 h and 3, 12, 37 and 90 days after unilateral surgical labyrinthectomies. The present results demonstrated a muscarinic receptor supersensitivity in the deafferented side in the superior vestibular nucleus 90 days after surgery. This increase was not large enough to support the cholinergic receptor supersensitivity hypothesis for vestibular compensation. The changes in the benzodiazepine receptors observed for a short time following surgery were reversed after a few days. These findings support a transient involvement of GABAergic pathways in vestibular compensation.


Prevalence of invasive cytomegalovirus disease with administration of muromonab CD-3 in patients undergoing orthotopic liver transplantation.
To assess the association of cytomegalovirus (CMV) disease with the administration of muromonab CD-3 (OKT-3) in patients undergoing liver transplant; specifically, to assess the risk of OKT-3 use as an agent for rejection prophylaxis and as an agent for therapy of rejection. Retrospective review of medical records. 83 liver transplant recipients (43 men, 40 women) with a mean age of 41.5 years (range 16-62). The medical record for each liver transplant recipient was reviewed and analyzed for the following variables: (1) preoperative recipient CMV serology, (2) donor CMV serology, (3) incidence of invasive CMV disease, (4) administration of OKT-3, (5) postoperative administration time of OKT-3, and (6) the relationship between the administration of OKT-3 and the prevalence of invasive CMV disease. OKT-3 was administered to 34 of 83 (40.9 percent) liver remainder received OKT-3 as rejection rescue. All patients received OKT-3 5 mg iv for 14 days. Seventeen of the 34 patients receiving OKT-3 (50 percent) developed invasive CMV disease; 58.8 percent of the patients (20/34) receiving OKT-3 were given the agent within the first 14 postoperative days. Sixteen of these 20 patients (80 percent) developed invasive CMV disease. One of 14 patients (7.1 percent) who received OKT-3 after the first 14 postoperative days developed invasive CMV disease. Of those patients 94 percent (16/17) received OKT-3 in the first 14 postoperative days. This prevalence differed significantly from those receiving OKT-3 after the 14th postoperative day and those who did not receive OKT-3 at any time during their hospital course. The patients who received early administration of OKT-3 in our study had a greater risk of invasive CMV disease than did those who received OKT-3 later in the hospital course.


Effect of educational intervention using the Internet on quantitative ultrasound parameters in prevention of osteoporosis: a randomized controlled trial in young Japanese women.
The objective of this study was to determine whether or not educational intervention using the Internet, to prevent osteoporosis, is able to increase bone strength in young women. Subjects were 253 healthy female university and junior college students aged 18-25 years. After initial measurements of bone stiffness index, a bone formation marker, and a bone absorption marker, the minimization method was used to allocate the subjects to an intervention group (n = 126) or a control group (n = 127) according to whether the measurements were above or below average. Subjects in the intervention group were instructed to perform osteoporosis prevention activities, ie, jump on the spot as high as possible ten times per day and increase calcium intake by 300 mg per day to a total of 800 mg or more per day on average. In addition, they were instructed to report the implementation status of the recommended measures via email. The researcher sent out information on osteoporosis and preventive behaviors to the subjects five times via email. A total of 182 subjects, comprising 87 (69.0%) in the intervention group and 95 (74.8%) in the control group, underwent remeasurement 6 months later. Of the subjects in the intervention group, 54 (42.9%) reported their daily additional calcium intake amount and number of jumps via email. The mean amount of additional calcium taken was 216.3 ± 85.9 mg per day, and mean number of jumps performed was 6.4 ± 4.2 per day. Subjects in the intervention group were further divided into an implementation group (n = 54), consisting of subjects who sent in reports and a nonimplementation group (n = 72) who did not. No significant difference was found among the groups for rate of change in bone stiffness index and speed of sound, but there was a significant difference for broadband ultrasound attenuation (BUA) (P = 0.017). Sheffe's multiple comparison test was performed using baseline body weight and BUA values as covariates, and revealed that the rate of decrease in bone strength in the control group was larger than that in the implementation group (P = 0.049). Health education for preventing osteoporosis via Internet email was performed over 6 months for women aged 18 to 25 and a comparison was performed between the intervention group and control group. The intervention consisted of high jumps on the spot (ten times a day), which reduced the drop in BUA, and thus indicates robustness of the trabecular structure. This suggests that a longer intervention period may maintain or improve bone strength.


Transcriptome analysis reveals the impact of arbuscular mycorrhizal symbiosis on Sesbania cannabina expose to high salinity.
Arbuscular mycorrhiza can improve the salt-tolerance of host plant. A systematic study of mycorrhizal plant responses to salt stress may provide insights into the acquired salt tolerance. Here, the transcriptional profiles of mycorrhizal Sesbania cannabina shoot and root under saline stress were obtained by RNA-Seq. Using weighted gene coexpression network analysis and pairwise comparisons, we identified coexpressed modules, networks and hub genes in mycorrhizal S. cannabina in response to salt stress. In total, 10,371 DEGs were parsed into five coexpression gene modules. One module was positively correlated with both salt treatment and arbuscular mycorrhizal (AM) inoculation, and associated with photosynthesis and ROS scavenging in both enzymatic and nonenzymatic pathways. The hub genes in the module were mostly transcription factors including WRKY, MYB, ETHYLENE RESPONSE FACTOR, and TCP members involved in the circadian clock and might represent central regulatory components of acquired salinity tolerance in AM S. cannabina. The expression patterns of 12 genes involved in photosynthesis, oxidation-reduction processes, and several transcription factors revealed by qRT-PCR confirmed the RNA-Seq data. This large-scale assessment of Sesbania genomic resources will help in exploring the molecular mechanisms underlying plant-AM fungi interaction in salt stress responses.


Different Gabapentin and Pregabalin Dosages for Perioperative Pain Control in Patients Undergoing Spine Surgery: A Systematic Review and Network Meta-Analysis.
Patients undergoing spine surgery often experience severe pain. The optimal dosage of pregabalin and gabapentin for pain control and safety in these patients has not been well established. To evaluate the associations of pain, opioid consumption, and adverse events with different dosages of pregabalin and gabapentin in patients undergoing spine surgery. PubMed/MEDLINE, Embase, Web of Science, Cochrane library, and Scopus databases were searched for articles until August 7, 2021. Randomized clinical trials conducted among patients who received pregabalin or gabapentin while undergoing spine surgery were included. Two investigators independently performed data extraction following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) reporting guideline. The network meta-analysis was conducted from August 2022 to February 2023 using a random-effects model. The primary outcome was pain intensity measured using the Visual Analog Scale (VAS), and secondary outcomes included opioid consumption and adverse events. Twenty-seven randomized clinical trials with 1861 patients (median age, 45.99 years [range, 20.00-70.00 years]; 759 women [40.8%]) were included in the systematic review and network meta-analysis. Compared with placebo, the VAS pain score was lowest with gabapentin 900 mg per day, followed by gabapentin 1200 mg per day, gabapentin 600 mg per day, gabapentin 300 mg per day, pregabalin 300 mg per day, pregabalin 150 mg per day, and pregabalin 75 mg per day. Additionally, gabapentin 900 mg per day was found to be associated with the lowest opioid consumption among all dosages of gabapentin and pregabalin, with a mean difference of -22.07% (95% CI, -33.22% to -10.92%) for the surface under the cumulative ranking curve compared with placebo. There was no statistically significant difference in adverse events (nausea, vomiting, and dizziness) among all treatments. No substantial inconsistency between direct and indirect evidence was detected for all outcomes. These findings suggest that gabapentin 900 mg per day before spine surgery is associated with the lowest VAS pain score among all dosages. In addition, no differences in adverse events were noted among all treatments.


A novel ABC transporter gene, PMR5, is involved in multidrug resistance in the phytopathogenic fungus Penicillium digitatum.
We have cloned a novel ABC transporter gene PMR5 from the phytopathogenic fungus Penicillium digitatum by RT-PCR using degenerate primers. The deduced amino acid sequence of PMR5 showed 37% identity to PMR1 from the same fungus, 71% identity to AtrB from Aspergillus nidulans, and 65% identity to BcatrB from Botrytis cinerea. Disruption mutants for PMR5 were generated in two independent P. digitatum strains and their phenotypes were characterized. These mutants displayed increased sensitivity to thiabendazole (a benzimidazole), benomyl (a benzimidazole), dithianon (a quinone), resveratrol (the phytoalexin of grape), and camptothecin (an alkaloid). Delta pmr1 disruption mutants were previously reported to show resistance to demethylation inhibitors (DMIs). These mutants were found also to display increased sensitivity to phloretin (the phytoanticipin of apples), camptothecin and oligomycin (an antibiotic). Transcription of PMR1 and PMR5 was strongly induced in response to several toxicants, including DMIs that specifically induced PMR1. In contrast, dithianon and resveratrol specifically induced PMR5 transcription. These findings indicate that expression of the two ABC transporter genes is regulated differently, and that they have complementary roles in multidrug resistance, with each having different substrate-specificities.


Intravesical mitoxantrone in superficial bladder tumours (Ta-T1).
36 patients with histologically proven grade G1-G2, Ta-T1 transitional cell carcinoma of the bladder were introduced, after transurethral resection (TUR), into a study of intravesical chemoprophylaxis with mitoxantrone (20 mg diluted in 50 ml). After a mean follow-up of 23 months, 16 (50%) patients showed a superficial recurrence with a mean recurrence rate of 0.56 per year. In 19 patients with recurring tumours the mean recurrence rate decreased from 1.65 to 0.58 per year. 9 patients (25.7%) suffered from a chemical cystitis that in 2 cases (5.7%) required treatment interruption.


HPV prophylactic vaccination in males improves the clearance of semen infection.
Semen represents a reservoir for human papillomavirus (HPV), rising concern in couples eligible for assisted reproduction techniques (ART). Humoral immunity against HPV is considered to protect from reinfection. We investigated the impact of vaccination on virus clearance in a cohort of infertile male patients showing HPV semen infection. 179 out of 619 infertile patients, showing HPV-DNA detection in semen by FISH analysis,were enrolled. Subjectswere split into 91 vaccine-sensitive (VSPs) and 88 nonvaccine-sensitive patients (NVSPs) by INNO-LiPA. 19 VSPs showed vaccine-type specific seroconvesion at recruitment. All patients underwent specific counselling. 42 seronegative VSPs were randomly assigned to receive quadrivalent vaccination in 6 months, whilst 49 VSPs, 19 seroconverted and 30 seronegative, served as controls. The prevalence of HPV-DNA semen infection and serology was studied in a follow-up of 24 months. Compared to seronegative patients, VSP seroconverted at recruitment showed absence of multiple infections and reduced prevalence of HPV semen infection at 12 (P = 0.039), 18 (P = 0.034) and 24 months (P = 0.034) of follow-up. Vaccinated VSP showed improved healing (P = 0.001 at 6 months and P b 0.001 at 12 months vs seroconverted VSP), achieving clearance in 12 months. Humoral immunity has a major role in healing from HPV infection. Elder ART patients with HPV semen infection may benefit by the union of both specific counselling and available prophylactic vaccination.


Red Phosphorus-Embedded Cross-Link-Structural Carbon Films as Flexible Anodes for Highly Reversible Li-Ion Storage.
Red phosphorus (P) is considered to be one of the most attractive anodic materials for lithium-ion batteries (LIBs) due to its high theoretical capacity of 2596 mAh g-1. However, intrinsic characteristics such as the poor electronic conductivity and large volume expansion at lithiation impede the development of red P. Here, we design a new strategy to embed red P particles into a cross-link-structural carbon film (P-C film), in order to improve the electronic conductivity and accommodate the volume expansion. The red P/carbon film is synthesized via vapor phase polymerization (VPP) followed by the pyrolysis process, working as a flexible binder-free anode for LIBs. High cycle stability and good rate capability are achieved by the P-C film anode. With 21% P content in the film, it displays a capacity of 903 mAh g-1 after 640 cycles at a current density of 100 mA g-1 and a capacity of 460 mAh g-1 after 1000 cycles at 2.0 A g-1. Additionally, the Coulombic efficiency reaches almost 100% for each cycle. The superior properties of the P-C films together with their facile fabrication make this material attractive for further flexible and high energy density LIB applications.


Biosorption of heavy metals by lactic acid bacteria and identification of mercury binding protein.
Heavy metals cause various health hazards. Using lactic acid bacteria (LAB), we tested the biosorption of heavy metals e.g. cadmium (Cd) (II), lead (Pb) (II), arsenic (As) (III), and mercury (Hg) (II). Cd (II) sorption was tested in 103 strains using atomic absorption spectrophotometery (AAS). Weissella viridescens MYU 205 (1 × 10(8) cells/ml) decreased Cd (II) levels in citrate buffer (pH 6.0) from one ppm to 0.459 ± 0.016 ppm, corresponding to 10.46 μg of Cd (II). After screening, 11 LAB strains were tested using various pH (pH 4.0, 5.0, 6.0, 7.0) showing the sorption was acid sensitive; and was cell concentration dependent, where the Cd (II) concentration decreased from one ppm to 0.042 (max)/0.255 (min) ppm at 1 × 10(10) cells/ml. Additionally, the biosorption of Pb (II), As (III), and Hg (II) were tested using an inductively coupled plasma mass spectrometer (ICP-MS). The Hg (II) concentration was reduced the most followed by Pb (II) and As (III). Many of the bacterial cell surface proteins of W. viridescens MYU 205 showed binding to Hg (II) using the Hg (II) column assay. Having a CXXC motif, a ∼14 kDa protein may be one of the Hg (II) binding proteins. LAB biosorption may aid the detoxification of people exposed to heavy metals.


Minocycline produced antidepressant-like effects on the learned helplessness rats with alterations in levels of monoamine in the amygdala and no changes in BDNF levels in the hippocampus at baseline.
Previous studies have indicated that minocycline might function as an antidepressant drug. The aim of this study was to evaluate the antidepressant-like effects of minocycline, which is known to suppress activated microglia, using learned helplessness (LH) rats (an animal model of depression). Infusion of minocycline into the cerebral ventricle of LH rats induced antidepressant-like effects. However, infusion of minocycline into the cerebral ventricle of naïve rats did not produce locomotor activation in the open field tests, suggesting that the antidepressant-like effects of minocycline were not attributed to the enhanced locomotion. LH rats showed significantly higher serotonin turnover in the orbitofrontal cortex and lower levels of brain-derived neurotrophic factor (BDNF) in the hippocampus than control rats. However, these alterations in serotonin turnover and BDNF expression remained unchanged after treatment with minocycline. On the contrary, minocycline treatment of LH rats induced significant increases in the levels of dopamine and its metabolites in the amygdala when compared with untreated LH rats. Taken together, minocycline may be a therapeutic drug for the treatment of depression.


Prevalence of and factors associated with herpes zoster in England: a cross-sectional analysis of the Health Survey for England.
Herpes zoster (commonly called shingles) is caused by the reactivation of varicella zoster virus, and results in substantial morbidity. While the risk of zoster increases significantly with age and immunosuppression, relatively little is known about other risk factors for zoster. Moreover, much evidence to date stems from electronic healthcare or administrative data. Hence, the aim of this study was to explore potential risk factors for herpes zoster using survey data from a nationally-representative sample of the general community-dwelling population in England. Data were extracted from the 2015 Health Survey for England, an annual cross-sectional representative survey of households in England. The lifetime prevalence of self-reported herpes zoster was described by age, gender and other socio-demographic factors, health behaviours (physical activity levels, body mass index, smoking status and alcohol consumption) and clinical conditions, including; diabetes, respiratory, digestive and genito-urinary system and mental health disorders. Logistic regression models were then used to identify possible factors associated with shingles, and results were presented as odds ratios with 95% confidence intervals. The lifetime prevalence of shingles among the sample was 11.5% (12.6% among women, 10.3% among men), which increased with age. After adjusting for a range of covariates, increased age, female gender (odds ratio: 1.21; 95%CI: 1.03, 1.43), White ethnic backgrounds (odds ratio: 2.00; 95%CI: 1.40, 2.88), moderate physical activity 7 days per week (odds ratio: 1.29; 95%CI: 1.01, 1.66) and digestive disorders (odds ratio: 1.51; 95%CI: 1.13, 1.51) were each associated with increased odds of having had herpes zoster. Age, gender, ethnicity and digestive disorders may be risk factors for herpes zoster among a nationally representative sample of adults in England. These potential risk factors and possible mechanisms should be further explored using longitudinal studies.


Partial monosomy of the short arm of chromosome 9: a distinct clinical entity.
A 10-year-old girl with partial deletion of the short arm of chromosome 9 is reported; karyotype: 46,XX,del(9)(p22). This syndrome results in a distinctive craniofacial dysmorphism with trigonocephaly and contrasting midfacial hypoplasia. Partial monosomy 9p was the result of a paternal de novo germinal deletion in this case.


Knockdown of TRIM44 inhibits the proliferation and invasion in papillary thyroid cancer cells through suppressing the Wnt/β-catenin signaling pathway.
Tripartite motif 44 (TRIM44), a member of the TRIM family, functions as a critical regulator in several types of malignancy. However, the role of TRIM44 in thyroid cancer has never been revealed. Thus, in this study, to explore its role in PTC, we detected its expression patterns in human papillary thyroid cancer (PTC) tissues and cell lines, and investigated its effects on cell proliferation and invasion. Our results demonstrated that TRIM44 was highly expressed in human PTC tissues and cell lines. In addition, silencing of TRIM44 significantly suppressed the proliferation, migration/invasion, and the epithelial-mesenchymal transition (EMT) process in PTC cells. Furthermore, silencing of TRIM44 dramatically down-regulated the expression of β-catenin, cyclin-D1 and c-Myc in PEC cells, and the activator of the Wnt/β-catenin pathway LiCl rescued the anticancer effect of knockdown TRIM44 expression in PTC cells. In conclusion, this study reported here provided evidence that TRIM44 functions as an oncogene in PTC. Silencing of TRIM44 inhibits the proliferation, migration and invasion of PTC cells in part through suppression of the Wnt/β-catenin signaling pathway. Thus, TRIM44 may be a potential therapeutic target for the treatment of PTC.