Discovery of N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (FD274) as a highly potent PI3K/mTOR dual inhibitor for the treatment of acute myeloid leukemia.
PI3K-Akt-mTOR pathway is a highly activated signal transduction pathway in human hematological malignancies and has been validated as a promising target for acute myeloid leukemia (AML) therapy. Herein, we designed and synthesized a series of 7-azaindazole derivatives as potent PI3K/mTOR dual inhibitors based on our previously reported FD223. Among them, compound FD274 showed excellent dual PI3K/mTOR inhibitory activity, with IC50 values against PI3Kα/β/γ/δ and mTOR of 0.65 nM, 1.57 nM, 0.65 nM, 0.42 nM, and 2.03 nM, respectively, superior to compound FD223. Compared to the positive drug Dactolisib, FD274 exhibited significant anti-proliferation of AML cell lines (HL-60 and MOLM-16 with IC50 values of 0.092 μM and 0.084 μM, respectively) in vitro. Furthermore, FD274 demonstrated dose-dependent inhibition of tumor growth in the HL-60 xenograft model in vivo, with 91% inhibition of tumor growth at an intraperitoneal injection dose of 10 mg/kg and no observable toxicity. All of these results suggest that FD274 has potential for further development as a promising PI3K/mTOR targeted anti-AML drug candidate.


Hospital costs--the medical student component.
A study of indirect costs which could be attributed to undergraduate teaching in a large affiliated teaching hospital has shown that they are very small. Thus direct university costs in 1975 were $1,800,000 (7-6% of all expenditure at the hospital); indirect costs were $41,000 (approximately 0-2% of the hospital expenditure). It is concluded that the 45% difference in bed costs per day between teaching and non-teaching hospitals from a previous investigation is therefore not the result of the clinical school indirect demands on hospital expenditure.


Cyclic nucleotides control a system which regulates Ca2+ sensitivity of platelet secretion.
Cellular responses to extracellular signals are mediated by changes in the intracellular concentrations of one or more second messengers. In platelets, inhibitory agonists increase intracellular cyclic-3',5'-AMP [( cyclic AMP]i (refs 2, 3] whereas excitatory agonists increase [Ca2+]i and/or [1,2-diacylglycerol]i (refs 4-9), and in some cases decrease [cyclic AMP]i (refs 10, 11). Both activation and inhibition of platelet responses have been attributed to an increase in [cyclic-3',5'-GMP]i (refs 8, 12). The activity of protein kinase C, which is associated with the platelet secretory response, is increased by both 1,2-diacylglycerol and Ca2+ (refs 4, 7, 8). The role of cyclic AMP may involve either inhibition of Ca2+ mobilization to the cytosol or stimulation of intracellular Ca2+ uptake, and in addition inhibition of 1,2-diacylglycerol formation. The relationship between cyclic-3',5'-GMP (cyclic GMP) and other second messengers in platelet activation has not been defined. Using platelets made permeable by exposure to an intense electric field, we demonstrate here modulation of the Ca2+ sensitivity of platelet secretion by thrombin, and by 12-O-tetradecanoylphorbol-13-acetate (TPA) and 1-oleyl-2- acetylglycerol ( OAG ), both potent activators of protein kinase C. The effect of thrombin is selectively modified by cyclic GMP and cyclic AMP. The response to OAG and TPA is also modulated by cyclic AMP but to a much lesser extent.


Identification and occurrence of phenylethanoid and iridoid glycosides in six Polish broomrapes (Orobanche spp. and Phelipanche spp., Orobanchaceae).
There are about 200 holoparasitic broomrapes (Orobanchaceae) known worldwide, however, only several species have been so far investigated phytochemically. Among Orobanche s.l. are both rare and endangered species, as well as onerous crop pests. This study aims to give a phytochemical description, both qualitative and quantitative, of six broomrape species (Orobanche and Phelipanche taxa) growing in Poland, including species that have not been tested in detail (O. caryophyllacea, O. lutea, O. picridis, and P. arenaria). Sixteen metabolites, including 14 phenylethanoid glycosides (PhGs) and 2 iridoid glycosides (IrGs), were isolated and identified using NMR spectroscopy and hydrolysis, revealing the presence of two previously undescribed PhGs in P. ramosa, named ramoside A and 2'-acetylramoside A. In addition, in the example of O. caryophyllacea, we have reported as the first occurrence of IrGs in broomrapes. Concentrations of phenylethanoids, the main constituents of broomrapes, in the studied plant material (flowering shoots with haustoria) were determined using the UHPLC-PDA method. It was found that P. ramosa has been the richest source of PhGs. In addition, the differences between broomrapes have been visualized using principal component and cluster analysis. The results of the antiradical DPPH test of 13 PhGs confirmed previous findings on the relation of the antioxidant potential with the structure of phenolic moieties - phenolic acid and phenylethanoid unit.


Reliability of lens implant power formulas in hyperopes and myopes.
Calculations were made comparing a variety of formulas in patients who required unusually high and low power intraocular lenses. Of the formulas tested, the author found the Colenbrander formula to be more accurate for myopic patients and the SRK formula to be more accurate for hyperopic patients.


Effects of acrylamide and other sulfhydryl compounds in vivo and in vitro on staining of motor nerve terminals by the zinc iodide-osmium technique.
The zinc iodide-osmium technique blackens motor nerve terminals by selectively staining synaptic vesicles. Intraperitoneal injections of acrylamide (30 mg/kg/day, 5 times each week) cause inhibition of staining by this technique so that approximately one third of the end-plates in rat sternocostalis muscle are unstained after 24 hours, and by 17 days more than 70% are unstained. This is not associated with nerve fiber degeneration. A similar inhibition of staining can also be shown after prior incubation of the sternocostalis muscle in 4 mM acrylamide in oxygenated Ringer's solution. Intraperitoneal injection of the thiol group blocker N-ethylmaleimide also causes marked inhibition of staining of motor end-plates by this method. Dithiothreitol, which prevents the oxidation of thiol groups, will partly prevent the inhibition of staining by both acrylamide and N-ethylmaleimide, when given in vivo.


Gill-specific (Na(+), K(+))-ATPase activity and α-subunit mRNA expression during low-salinity acclimation of the ornate blue crab Callinectes ornatus (Decapoda, Brachyura).
We evaluate (Na(+), K(+))-ATPase activity, and protein and gene expression of the α-subunit in posterior gills 6 and 7 of Callinectes ornatus, a euryhaline crab, during a 10-day acclimation period from seawater (33‰ S) to low salinity (21‰ S). (Na(+), K(+))-ATPase activity decreased within 1h after transfer to 21‰ S, values recovering by 24h and attaining a maximum of ≈180 nmol Pi min(-1) mg(-1) after 10 days (≈2.5-fold increase). (Na(+), K(+))-ATPase activity is ≈1.5-fold greater in gill 6 than in gill 7, independently of salinity. Relative expression of (Na(+), K(+))-ATPase α-subunit mRNA increased in both gills within 1- to 2-h exposure to low salinity, reaching an ≈8-fold maximum after 24-h exposure, decreasing slightly by 10 days acclimation to low salinity. This increase in α-subunit mRNA expression may underpin the increased (Na(+), K(+))-ATPase activity seen after 10 days acclimation to low salinity. Enzyme affinity for ATP was greater in gill 6 than in gill 7, in contrast to ouabain affinity that was greater in gill 7. Western blotting analysis identified a single immunoreactive band against the (Na(+), K(+))-ATPase α-subunit with an Mr of ≈105 kDa, independently of gill number and low salinity acclimation. Despite these differences, gills 6 and 7 appear to perform similar functions in salt uptake from the dilute medium. The partial cDNA sequence obtained for the gill (Na(+), K(+))-ATPase of C. ornatus (GenBank deposit KF056804) showed 97 to 91% identities with similar sequences from other portunid crab gills. The regulation of gill (Na(+), K(+))-ATPase activity during acclimation to low salinity is discussed.


Climate determines transmission hotspots of Polycystic Echinococcosis, a life-threatening zoonotic disease, across Pan-Amazonia.
Polycystic Echinococcosis (PE), a neglected life-threatening zoonotic disease caused by the cestode Echinococcus vogeli, is endemic in the Amazon. Despite being treatable, PE reaches a case fatality rate of around 29% due to late or missed diagnosis. PE is sustained in Pan-Amazonia by a complex sylvatic cycle. The hunting of its infected intermediate hosts (especially the lowland paca Cuniculus paca) enables the disease to further transmit to humans, when their viscera are improperly handled. In this study, we compiled a unique dataset of host occurrences (~86000 records) and disease infections (~400 cases) covering the entire Pan-Amazonia and employed different modeling and statistical tools to unveil the spatial distribution of PE's key animal hosts. Subsequently, we derived a set of ecological, environmental, climatic, and hunting covariates that potentially act as transmission risk factors and used them as predictors of two independent Maximum Entropy models, one for animal infections and one for human infections. Our findings indicate that temperature stability promotes the sylvatic circulation of the disease. Additionally, we show how El Niño-Southern Oscillation (ENSO) extreme events disrupt hunting patterns throughout Pan-Amazonia, ultimately affecting the probability of spillover. In a scenario where climate extremes are projected to intensify, climate change at regional level appears to be indirectly driving the spillover of E. vogeli. These results hold substantial implications for a wide range of zoonoses acquired at the wildlife-human interface for which transmission is related to the manipulation and consumption of wild meat, underscoring the pressing need for enhanced awareness and intervention strategies.


The effects of histamine on the concentrations of immunoreactive thyrotropin-releasing hormone in the stomach and hypothalamus in rats.
The effects of histamine and its related compounds on the concentrations of immunoreactive thyrotropin-releasing hormone (ir-TRH) in the stomach, gastric juice and hypothalamus in rats were studied. Histamine, ranitidine or ethanolamine was injected intraperitoneally, and the rats were decapitated at various times after the injection. Ir-TRH concentrations in the stomach, gastric juice and hypothalamus were measured by a radioimmunoassay. Ir-TRH concentrations in the stomach decreased significantly after histamine injection and increased significantly after ranitidine injection in a dose-dependent manner, but did not change with ethanolamine. Ir-TRH concentrations in the gastric juice increased in a dose-dependent manner, peaking at 30 min after histamine injection, and its effect was blocked with ranitidine. Ir-TRH concentrations in the hypothalamus elevated significantly after histamine injection and reduced significantly after ranitidine injection, but did not change with ethanolamine. The effects of histamine on ir-TRH concentrations in the stomach and hypothalamus were significantly blocked with ranitidine, but not with ethanolamine. These findings suggest that histamine stimulates ir-TRH release from the stomach and inhibits ir-TRH release from the hypothalamus, and that these effects of histamine on ir-TRH release are mediated via an H2-receptor.


Spatiotemporal heterogeneity of the relationships between PM2.5 concentrations and their drivers in China's coastal ports.
PM2.5 is one of the primary air pollutants that affect air quality and threat human health in the port areas. To prevent and control air pollution, it is essential to understand the spatiotemporal distributions of PM2.5 concentrations and their key drivers in ports. 19 coastal ports of China are selected to examine the spatiotemporal distributions of PM2.5 concentrations during 2013-2020. The annual average PM2.5 concentration decreases from 61.03 μg/m3 to 30.17 μg/m3, with an average decrease rate of 51.57%. Significant spatial autocorrelation exists among PM2.5 concentrations of ports. The result of the geographically and temporally weighted regression (GTWR) model shows significant spatiotemporal heterogeneity in the effects of meteorological and socioeconomic factors on PM2.5 concentrations. The effects of boundary layer height on PM2.5 concentrations are found to be negative in most ports, with a stronger effect found in the Pearl River Delta, Yangtze River Delta and some ports of the Bohai Rim Area. The total precipitation shows negative effects on PM2.5 concentrations, with the strongest effect found in ports of the Southeast Coast. The effects of surface pressure on PM2.5 concentrations are positive, with stronger effects found in Beibu Gulf Port and Zhanjiang Port. The effects of wind speed on PM2.5 concentrations generally increase from south to north. Cargo throughput shows strong and positive effects on PM2.5 concentrations in ports of Bohai Rim Area; the positive effects found in Beibu Gulf Port increased from 2013 to 2018 and decreased since 2019. The positive effects of GDP and nighttime light on PM2.5 concentrations gradually decrease and turn negative from south to north. Understandings obtained from this study can potentially support the prevention and control of air pollution in China's coastal ports.


GDF15-mediated upregulation of ferroportin plays a key role in the development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis.
Growth differentiation factor 15 (GDF15), a divergent TGFβ superfamily, has recently been implicated in the modulation of iron homeostasis, acting as an upstream negative regulator of hepcidin, the key iron regulatory hormone produced primarily by hepatocytes. However, little is known about possible roles that GDF15 might play in the regulation of iron homeostasis and development of hyperferritinemia in children with hemophagocytic lymphohistiocytosis (HLH). We compared serum GDF15 level and mRNA expressions of GDF15 and key molecules of iron metabolism, and made correlations between their expressions in children with HLH and control children. Serum GDF15 level was remarkably higher in HLH group than that in controls, with median serum concentration of 1,700 and 260 pg/ml, respectively (P < 0.001). In addition, GDF15 mRNA was significantly upregulated but independent of hypoxia-inducible factor-mediated oxygen signaling pathway. More importantly, GDF15 induction was positively correlated to upregulation of ferroportin, the only cellular iron exporter, and to upregulation of ferritin heavy chain. Our study suggests that GDF15 induction helps suppress further activation of macrophages in stressful physiologic states as HLH, and is intimately implicated in the development of hyperferritinemia by modulating the hepcidin-ferroportin axis, resulting in enhanced ferroportin-mediated iron efflux.


P7TP3 inhibits tumor development, migration, invasion and adhesion of liver cancer through the Wnt/β-catenin signaling pathway.
The effect of hepatitis C virus p7 trans-regulated protein 3 (P7TP3) in the development of hepatocellular carcinoma (HCC) is still unknown. The present study aimed to investigate the role and mechanism of P7TP3 in HCC. P7TP3 was significantly decreased in HCC tissues when compared with corresponding liver tissues immediately around the tumor (LAT) from seven HCC patients. Fewer and smaller colonies originated from HepG2-P7TP3 cells when compared to HepG2-NC cells. Overexpression of P7TP3 in HepG2 cells significantly repressed the growth of HCC xenografts in nude mice. Furthermore, wound-healing tests, Transwell assays, Matrigel Transwell assays, adhesion assays, CCK-8 assays, flow cytometry and western blotting analysis showed that P7TP3 protein expression inhibited migration, invasion, adhesion, proliferation and cell cycle progression in HCC cell lines. Moreover, P7TP3 suppressed the activity of the Wnt/β-catenin signaling pathway, and was restored by Wnt3a, which is an activator of the Wnt/β-catenin signaling pathway. Consistently, β-catenin was highly expressed by P7TP3 silencing, and restored by XAV939, an inhibitor of the Wnt/β-catenin signaling pathway. Finally, microRNA (miR)-182-5p suppressed the expression of target gene P7TP3 by directly interacting with the 3'-UTR region. Taken together, P7TP3, the direct target gene of miR-182-5p, inhibited HCC by regulating migration, invasion, adhesion, proliferation and cell cycle progression of liver cancer cell through the Wnt/β-catenin signaling pathway. These findings provide strong evidence that P7TP3 functions as a new promising tumor suppressor in HCC.


Ecology of SO2 resistance: II. Photosynthetic changes of shrubs in relation to SO2 absorption and stomatal behavior.
In an effort to predict SO2 sensitivity of plants from their morphological and physiological features, the effects of SO2 on photosynthesis were partitioned between stomatal and nonstomatal components for a drought deciduous shrub, Diplacus aurantiacus, and an evergreen shrub, Heteromeles arbutifolia. As predicted, the drought deciduous shrub had the higher gas conductance, and hence SO2 absorptance. However, nonstomatal components also play a role in determining SO2 sensitivity. Apparently a plant with a high intrinsic photosynthetic capacity will be more sensitive to SO2 than one with a lower capacity.


Malignant renal tumors of childhood.
The prognosis in nephroblastoma (Wilms' tumor) has been improved considerably by treatment protocols combining surgery, chemotherapy, radiation therapy, and, in some clinical trials, pre-operative chemotherapy. Cure is now achieved in most patients. All clinical trials have employed treatment strategies tailored to the individual risk of the patient, including the histological subtype of the tumor. In the National Wilms' Tumor Study (NWTS) of the United States these subtypes have been divided into two groups of tumors according to their "favorable" or "unfavorable" histology. At the Kiel Pediatric Tumor Registry we have devised a system which distinguishes three groups of tumors classified according to prognosis. The first group includes tumors with a favorable prognosis, even if only surgery is performed. These comprise congenital mesoblastic nephroma (CMN) and cystic, partially differentiated nephroblastoma (CPDN). The second group consists of tumors posing an intermediate risk, such as typical nephroblastoma and its histological variants characterized by variations in the relative proportions of the histological components. Fetal rhabdomyomatous nephroblastoma (FRN) is also included in this group. The third group comprises tumors of high risk such as anaplastic nephroblastoma, clear cell sarcoma of the kidney (CCSK), and malignant rhabdoid tumor of the kidney (MRTK). Since histological diagnosis plays a crucial role in the assignment of a patient to a particular type of treatment protocol, knowledge of the histological appearance of the various tumor types both with and without preoperative treatment is of utmost importance.


Correcting for regression in assessing the response to treatment in a selected population.
Previous work on the consequences of regression to the mean for the interpretation of responses to treatment is extended to the situation where the response measured is the proportional change in some variable. Methods for correcting for the bias are discussed.


Low phase angle in critically ill older patients is associated with late mortality: A prospective study.
The aim of this study was to ascertain the accuracy of phase angle (PhA) as a predictor of mortality during intensive care unit (ICU) stay (MICU) and at 28 (M28) and 60 d (M60) after ICU admission among patients aged >60 y. Patients aged >60 y who were under mechanical ventilation (MV) ≥48 h were included once they were hemodynamically stable. PhA was measured by single-frequency bioelectrical impedance analysis up to 48 h after admission. ICU prognostic scores, functional scale, and nutritional assessments were performed in the first 24 h. Patients were followed for 60 d after ICU admission. We enrolled 102 patients into the present study. PhA was significantly higher (P < 0.001) in survivors at MICU, M28, and M60. Areas under the receiving operator characteristic curves for MICU, M28, and M60 were 0.77 (95% confidence interval [CI], 0.67-0.86), 0.71 (95% CI, 0.60-0.82), and 0.71 (95% CI, 0.60-0.81), respectively. The PhA cutoff to predict mortality was 3.29° for males at MICU, M28, and M60 and lower for females at M28 (2.63°) and M60 (3.01°). PhA better discriminated M60 than conventional prognostic scores. Logistic regression showed that even after controlling for other factors, PhA was a protective factor against late mortality. Survival analysis at 60 d revealed that low PhA was associated with lower median survival (18 versus 58 d; log-rank P < 0.001). Low PhA values are associated with higher late mortality and a short survival time at 60 d in critically ill older adults. Low PhA values can be considered a useful ICU prognostic score in similar populations.


Small GTPase Rho5 is a functional homologue of Rho1, which controls cell shape and septation in fission yeast.
The small GTPase Rho1 plays an essential role in controlling the organization of the actin cytoskeleton and synthesis of the cell wall in the fission yeast Schizosaccharomyces pombe. Here we studied the role of Rho5 whose primary structure is very similar to that of Rho1. It was found that elevated expression of Rho5 was able to compensate for the lethality of cells lacking Rho1. Rho5 was localized to the ends of interphase cells and the mid-region of mitotic cells. Overexpression of Rho5 caused depolarization of F-actin patches and abnormal formation of the cell wall, as did Rho1. Although rho5(+) was not essential for maintaining the cell shape, rho1 rho5-double null cells showed more severe defects in cell viability than rho1-null cells. Thus, it is likely that Rho5 has an overlapping function with Rho1 in controlling cell growth and division in S. pombe.


The effects of the antiresorptive agents calcitonin and pamidronate on spine fusion in a rabbit model.
As the population ages, the number of individuals undergoing pharmacotherapy to prevent or treat osteoporosis is increasing. Drugs of the bisphosphonate family prevent bone resorption, as does calcitonin, though by different mechanisms. Bisphosphonates are deposited in bone, preventing resorption by osteoclasts. Calcitonin is a direct inhibitor of osteoclasts, but is not itself incorporated in bone. The same late middle-aged and elderly patients who are being treated for osteoporosis frequently come to spine fusion. Bone remodelling is a vital part of graft incorporation. Interventions that interfere with remodelling may have a detrimental effect on the rate, time course, and strength of the fusion mass. To delineate the effects of these anti-osteoporosis medications on the fusion process. Randomized, prospective, double-blind, animal model. Posterolateral arthrodesis was performed at L5/6 in 60 skeletally mature 4.0-4.5 kg New Zealand white rabbits, using 3 cc of autologous iliac crest graft per side. Rabbits were randomized to one of three groups: PAM--pamidronate 1.2 mg subcutaneously 3 times/week for 4 weeks preoperatively, then 0.6 mg/day via miniosmotic pump for 4 weeks postoperatively; CAL--calcitonin 14 IU/day via pump for 4 weeks postoperatively only; CON--no drug intervention. All animals were killed 5 weeks after surgery. Fusion, defined by absolute lack of intersegmental motion, was assessed by manual palpation by two spine surgeons. Where there was disagreement, a third surgeon made the final determination. Stiffness and peak load to failure were determined by mechanical testing of each operated motion segment, and normalized to the adjacent, unoperated level. Four rabbits excluded (1 each: death; euthanasia for hind-limb palsy; infection; incorrect level). Number fused at 5 weeks: CON 10/18 (56%), PAM 7/19 (37%), CAL 13/19 (68%). Fisher exact test showed no significant differences between groups. Analysis of variance (ANOVA) showed no significant differences in mechanical testing between CAL and CON, but PAM specimens had significantly less peak load than CON or CAL animals (p<.01) and were less stiff than CON (p<.01) or CAL (p<.05) animals. Though one must be careful in extrapolating animal data to humans, this study suggests that calcitonin is not detrimental to spine fusion. Pamidronate, however, does lead to a mechanically less robust fusion. Based on this study, there is no evidence to support a recommendation to stop antiresorptive therapy for osteoporosis in the spine fusion patient.


To treat or not to treat: a rare case of pseudo-thrombotic thrombocytopenic purpura in a Jehovah's Witness.
Thrombotic thrombocytopenic purpura (TTP) is a rare microvascular occlusive disorder characterized by systemic intravascular aggregation of platelets, thrombocytopenia, and mechanical injury to red blood cells. We report a rare case of pernicious anemia presenting as TTP in a Jehovah's Witness. A 46-year-old Jehovah's Witness female presented with epigastric pain, vomiting, and diarrhea for 2 days and fatigue and paresthesias for 4 weeks. Initial laboratory evaluation showed severe anemia and thrombocytopenia with elevated total bilirubin and lactate dehydrogenase. Peripheral blood smear showed schistocytes, macroovalocytes, and hypersegmented neutrophils. TTP was suspected and plasmapheresis was offered. The patient refused it due to her religious beliefs. Due to the presence of macroovalocytes and hypersegmented neutrophils, vitamin B12 level was checked and found to be extremely low. Anti-intrinsic factor antibodies and anti-parietal cell antibodies were also positive; hence a diagnosis of pernicious anemia was established. Treatment with intramuscular vitamin B12 was initiated, which resulted in dramatic neurologic and hematologic improvement. Vitamin B12 deficiency can lead to elevated levels of homocysteine in the blood. Homocysteine can cause endothelial dysfunction, which can lead to formation of microvascular thrombi. Due to this phenomenon, vitamin B12 deficiency can rarely present with schistocytes and thrombocytopenia, which combined with other stigmata of vitamin B12 deficiency, can be misdiagnosed as TTP.


Volume flows across gallbladder epithelium induced by small hydrostatic and osmotic gradients.
The hydraulic conductivity of rabbit gallbladder epithelium has been studied using a continuous volumetric method based on capacitance measurements. The time resolution for measuring osmotic flows is in the range of seconds. Volume flows have been induced by osmotic gradients between 0 and 100 mosmol. In this range the flow-force relation is linear and the Pf value is 9.3 X 10(-3) cm/sec. After correction for solute polarization effects, the Pf value amounts to 0.05 cm/sec. The observed flow is constant between 5 sec up to 20 min after a sudden increase in the osmolarity of the mucosal solution. The wet weight of the gallbladder tissue decreases by 22% and increases by 30% during osmotic flows from mucosa to serosa, respectively. Volume flows induced by hydrostatic pressure gradients on the mucosal surface are linearly related to the driving forces between 0 and 40 mbar. The Pf value is 0.15 cm/sec. The volume flows are constant between 2 sec and 15 min after pressure application. The flow-force relation for pressure gradients on the serosal surface is markedly nonlinear for gradients greater than 5 mbar. Below 5 mbar the Pf value is 4.5 cm/sec. From electrical measurements, e.g., resistance and streaming potentials, and from flux studies with inulin and polyethylene glycol 4000, it is concluded that hydrostatic and osmotic gradients are not comparable when they are applied to gallbladder epithelium. They induce volume flows across different pathways, e.g., osmosis predominantly across the cellular route and pressure filtration predominantly across paracellular routes.


Vaccinations for adult solid organ transplant recipient: current recommendations.
The need for immunization in solid organ transplant recipient can arise from three factors: immune deficit owing to underlying disease, rejection of the organ graft, and immunosuppressive therapy given after transplantation. As a general rule, primary immunizations should be given as early as possible before transplantation because the immune response to vaccines is decreased in patients with end-stage organ disease. There are three categories of vaccines: Live vaccines--oral polio, vaccinia, bacillus Calmette-Guerin, live oral typhoïd, and intranasal influenza vaccines--are contraindicated in solid organ transplant recipients. The use of varicella vaccine remains controversial. The use of rubella vaccine is recommended in young women of childbearing age. Of the killed vaccines or genetically engineered vaccines, the following are recommended: pneumococcal vaccine, influenza vaccine, hepatitis A vaccine, hepatitis B vaccine, diphtheria, and tetanus vaccine. Vaccination of household contacts and health care workers in transplant centers is recommended. However, live vaccine (with the exception of varicella vaccine) should be avoided in these contacts.


Electrophysiological behavior of microglia.
The present knowledge of voltage- and ligand-activated ion channels of cultured microglial cells is described and its relevance is discussed. All microglial cells cultured from rat or mouse brain express an inward rectifying K+ channel but no outward currents. This expression is not changed by the length of the cultivation period, nor is it different in freshly isolated cells. It makes the microglial cells distinct from peritoneal macrophages, which possess an outward rectifying K+ channel. In bone marrow, 2 populations of cells could be distinguished electrophysiologically, one with the channel pattern of macrophages and one with that of microglial cells. This finding is interesting in light of the fact that it is presently hypothesized that the differentiation of monocytes into microglia takes place exclusively during embryonic development but not in the adult. The available data thus support the hypothesis that within the bone marrow a population of macrophage precursor cells exists with a possible lineage relationship to brain macrophages. The lack of outward currents in the microglial cells has the functional consequence that even a small inward current leads to a large membrane depolarization, since K+ outward currents are not activated with the depolarization. The microglial cell is thus very sensitive to depolarizing events. We found that ATP induced an inward current and an increase in the conductance, whereas ADP, AMP, and adenosine did not. These relative potencies indicate that microglia possess a P2 purinoceptor linked to an ion channel. The amplitude of the inward current elicited by ATP is about 80 pA and is sufficient to depolarize microglial cells close to 0 mV.(ABSTRACT TRUNCATED AT 250 WORDS)


Parasites of the respiratory tract.
The author discusses the parasites that infect the nasal passages, trachea, bronchi, and lung parenchyma of dogs and cats. The clinical signs, diagnosis, epidemiology, treatment, and control of infection are also considered.


[Follow up of the CoDiM-Study: Cost of diabetes mellitus 2000-2009].
Cost of illness studies create transparency on the economic dimension of diseases. By now, the CoDiM study, based on administrative data of AOK Hesse und KV Hesse, identifies costs of people with diabetes and diabetes related excess costs in Germany for a period of 10 years. To date, additionally adjusted results are available by accounting for effects caused by inflation and ageing of the population. From 2000 to 2009 the number of treated patients with diabetes increased by 49 %, adjusted for age by 31 %. Mean cost of patients with diabetes and diabetes related excess costs per capita turned out to be relatively stable over the time period observed. The relation of cost per patient with diabetes to cost of patients without diabetes didn't change. Due to the increase of the number of treated patients with diabetes in the past 10 years, the total direct cost, dependant on the approach of calculation (adjusting or not for inflation and ageing effects), rose by 28 % to 70 %, the therein included diabetes excess cost by 24 % to 61 %.


Distribution of the major histocompatibility complex antigens in human and rat kidney.
We have compared the distribution of the major histocompatibility complex (MHC) antigens in human and rat kidney using monospecific antisera to class I and II antigens of the MHC. FITC/TRITC double immunofluorescence was used to demonstrate these antigens in frozen sections and the Staphylococcus aureus Cowan I rosette assay on the cell surface. In both species, the MHC antigens were prominently present on the passenger leukocytes. Immunofluorescence analysis of human kidney demonstrated that the class I, beta 2-microglobulin (beta 2m), and class II antigens were present in the vascular endothelial cells and class I antigens in the renal tubular cells. The Staphylococcus assay demonstrated that these antigens were also exposed on the respective cell surfaces. In clear contrast, in the rat, class I, the beta 2m, and class II antigens were absent from the kidney vascular endothelium of large vessels and intertubular capillaries; however, large amounts of class II antigens were seen inside the proximal renal tubular cells. The Staphylococcus assay indicated that none or very little of these antigens were exposed on the kidney parenchymal cell surface. These differences may explain why rat renal transplants are relatively non-immunogenic and easily accepted, whereas human renal transplant recipients must be immunosuppressed ad infinitum.


The function, composition and analysis of cerebrospinal fluid in companion animals: part I - function and composition.
Cerebrospinal fluid (CSF) is a clear, colourless ultrafiltrate of plasma with low protein content and few cells. The CSF is mainly produced by the choroid plexus, but also by the ependymal lining cells of the brain's ventricular system. CSF flows through the ventricular system and then into the subarachnoid space and it is subsequently absorbed through the subarachnoid villi into the venous system. CSF has several functions in the nervous system. It protects the brain during blood pressure fluctuations, regulates the chemical environment of the central nervous system and it is a vehicle for intracerebral transport. This two-part article reviews CSF function, physiology, analytical techniques and interpretations in disease states of companion animals. This first part will address the function and composition of CSF in companion animals.


Forecasting seizure likelihood from cycles of self-reported events and heart rate: a prospective pilot study.
Seizure risk forecasting could reduce injuries and even deaths in people with epilepsy. There is great interest in using non-invasive wearable devices to generate forecasts of seizure risk. Forecasts based on cycles of epileptic activity, seizure times or heart rate have provided promising forecasting results. This study validates a forecasting method using multimodal cycles recorded from wearable devices. Seizure and heart rate cycles were extracted from 13 participants. The mean period of heart rate data from a smartwatch was 562 days, with a mean of 125 self-reported seizures from a smartphone app. The relationship between seizure onset time and phases of seizure and heart rate cycles was investigated. An additive regression model was used to project heart rate cycles. The results of forecasts using seizure cycles, heart rate cycles, and a combination of both were compared. Forecasting performance was evaluated in 6 of 13 participants in a prospective setting, using long-term data collected after algorithms were developed. The results showed that the best forecasts achieved a mean area under the receiver-operating characteristic curve (AUC) of 0.73 for 9/13 participants showing performance above chance during retrospective validation. Subject-specific forecasts evaluated with prospective data showed a mean AUC of 0.77 with 4/6 participants showing performance above chance. The results of this study demonstrate that cycles detected from multimodal data can be combined within a single, scalable seizure risk forecasting algorithm to provide robust performance. The presented forecasting method enabled seizure risk to be estimated for an arbitrary future period and could be generalised across a range of data types. In contrast to earlier work, the current study evaluated forecasts prospectively, in subjects blinded to their seizure risk outputs, representing a critical step towards clinical applications. This study was funded by an Australian Government National Health & Medical Research Council and BioMedTech Horizons grant. The study also received support from the Epilepsy Foundation of America's 'My Seizure Gauge' grant.


Imaging a boa constrictor--the incomplete double aortic arch syndrome.
Incomplete double aortic arch is a rare anomaly resulting from atresia rather than complete involution in the distal left arch resulting in a non-patent fibrous cord between the left arch and descending thoracic aorta. This anatomic anomaly may cause symptomatic vascular rings, leading to stridor, wheezing, or dysphagia, requiring surgical transection of the fibrous cord. Herein, we describe an asymptomatic 59 year-old man presenting for contrast-enhanced CT angiography to assess cardiac anatomy prior to radiofrequency ablation, who was incidentally found to have an incomplete double aortic arch with hypoplasia of the left arch segment and an aortic diverticulum. Recognition of this abnormality by imaging is important to inform both corrective surgery in symptomatic patients, as well as assist in the planning of percutaneous coronary and vascular interventions.


Role of CaMKII in post acidosis arrhythmias: a simulation study using a human myocyte model.
Postacidotic arrhythmias have been associated to increased sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activation. However, the molecular mechanisms underlying these arrhythmias are still unclear. To better understand this process, acidosis produced by CO2 increase from 5% to 30%, resulting in intracellular pH (pHi) change from 7.15 to 6.7, was incorporated into a myocyte model of excitation-contraction coupling and contractility, including acidotic inhibition of L-type Ca(2+) channel (I(CaL)), Na(+)-Ca(2+) exchanger, Ca(2+) release through the SR ryanodine receptor (RyR2) (I(rel)), Ca(2+) reuptake by the SR Ca(2+) ATPase2a (I(up)), Na(+)-K(+) pump, K(+) efflux through the inward rectifier K(+) channel and the transient outward K(+) flow (I(to)) together with increased activity of the Na(+)-H(+) exchanger (I(NHE)). Simulated CaMKII regulation affecting I(rel), I(up), I(CaL), I(NHE) and I(to) was introduced in the model to partially compensate the acidosis outcome. Late Na(+) current increase by CaMKII was also incorporated. Using this scheme and assuming that diastolic Ca(2+) leak through the RyR2 was modulated by the resting state of this channel and the difference between SR and dyadic cleft [Ca(2+)], postacidotic delayed after depolarizations (DADs) were triggered upon returning to normal pHi after 6 min acidosis. The model showed that DADs depend on SR Ca(2+) load and on increased Ca(2+) leak through RyR2. This postacidotic arrhythmogenic pattern relies mainly on CaMKII effect on I(CaL) and I(up), since its individual elimination produced the highest DAD reduction. The model further revealed that during the return to normal pHi, DADs are fully determined by SR Ca(2+) load at the end of acidosis. Thereafter, DADs are maintained by SR Ca(2+) reloading by Ca(2+) influx through the reverse NCX mode during the time period in which [Na(+)]i is elevated.


Rilonacept (interleukin-1 trap) for prevention of gout flares during initiation of uric acid-lowering therapy: results from a phase III randomized, double-blind, placebo-controlled, confirmatory efficacy study.
To evaluate the efficacy and safety of the interleukin-1 inhibitor rilonacept (interleukin-1 Trap) for gout flare prevention during initiation of uric acid-lowering therapy (ULT). In total, 241 adult patients with gout, ≥2 gout flares within the past year, and a serum urate level ≥7.5 mg/dl were initiated on allopurinol 300 mg daily and randomly allocated in a 1:1:1 ratio to receive 16 once-weekly subcutaneous injections of placebo, rilonacept 80 mg, or rilonacept 160 mg, with a double (loading) dose on day 1. Allopurinol was titrated to achieve a serum urate level of <6.0 mg/dl. The study was powered for the primary efficacy end point, the number of gout flares per patient through week 16. More patients in the rilonacept groups (80.0% in the rilonacept 80 mg group, 86.4% in the rilonacept 160 mg group) completed the study than in the placebo group (72.5%; P < 0.05 for the rilonacept 160 mg group versus the placebo group). Over 16 weeks, the mean number of gout flares per patient was significantly reduced by rilonacept treatment (placebo: 1.06, rilonacept 80 mg: 0.29 [P < 0.001], rilonacept 160 mg: 0.21 [P < 0.001]). Significantly lower proportions of patients reported ≥1 gout flares with rilonacept 80 mg (18.8%) and rilonacept 160 mg (16.3%) relative to placebo (46.8%; P < 0.001 for both). Except for injection site reactions (1.3% in the placebo group versus 8.8% in the rilonacept 80 mg group [P = 0.0635, post hoc analysis] and 19.8% in the rilonacept 160 mg group [P = 0.0001, post hoc analysis]), the incidence of adverse events was generally balanced among the treatment groups. Rilonacept markedly reduced the occurrence of gout flares associated with the initiation of ULT. The efficacy and safety profile suggests that rilonacept may have the potential to improve long-term disease control for some patients by improving adherence to ULT by reducing flares during the first months after ULT initiation.


Energy at Origins: Favorable Thermodynamics of Biosynthetic Reactions in the Last Universal Common Ancestor (LUCA).
Though all theories for the origin of life require a source of energy to promote primordial chemical reactions, the nature of energy that drove the emergence of metabolism at origins is still debated. We reasoned that evidence for the nature of energy at origins should be preserved in the biochemical reactions of life itself, whereby changes in free energy, ΔG, which determine whether a reaction can go forward or not, should help specify the source. By calculating values of ΔG across the conserved and universal core of 402 individual reactions that synthesize amino acids, nucleotides and cofactors from H2, CO2, NH3, H2S and phosphate in modern cells, we find that 95-97% of these reactions are exergonic (ΔG ≤ 0 kJ⋅mol-1) at pH 7-10 and 80-100°C under nonequilibrium conditions with H2 replacing biochemical reductants. While 23% of the core's reactions involve ATP hydrolysis, 77% are ATP-independent, thermodynamically driven by ΔG of reactions involving carbon bonds. We identified 174 reactions that are exergonic by -20 to -300 kJ⋅mol-1 at pH 9 and 80°C and that fall into ten reaction types: six pterin dependent alkyl or acyl transfers, ten S-adenosylmethionine dependent alkyl transfers, four acyl phosphate hydrolyses, 14 thioester hydrolyses, 30 decarboxylations, 35 ring closure reactions, 31 aromatic ring formations, and 44 carbon reductions by reduced nicotinamide, flavins, ferredoxin, or formate. The 402 reactions of the biosynthetic core trace to the last universal common ancestor (LUCA), and reveal that synthesis of LUCA's chemical constituents required no external energy inputs such as electric discharge, UV-light or phosphide minerals. The biosynthetic reactions of LUCA uncover a natural thermodynamic tendency of metabolism to unfold from energy released by reactions of H2, CO2, NH3, H2S, and phosphate.


Production and characterization of cost-effective magnetic pine bark biochar and its application to remove tetracycline from water.
Low-cost adsorbent, pine bark biochar (PBB) from the forest residue, was produced and applied to remove tetracycline (TC) from aqueous solution via adsorption pathway. The PBB, hence obtained, was modified using aqueous ferric and ferrous ion solutions to obtain magnetic pine bark biochar (M-PBB). Batch adsorption experiments were conducted to examine the adsorption of TC by PBB and M-PBB in the variation of pH, contact time, dosage, and temperature. The adsorbents were characterized by SEM/EDX, TGA, and pHpzc. The adsorption mechanism was evaluated by fitting Langmuir, Freundlich, Temkin, and Dubinin-Radushkevich (D-R) isotherms model. Also, the experimental data were analyzed by kinetics models (pseudo-first-order, pseudo-second-order, intra-particle diffusion, and Elovich) and thermodynamics. The maximum adsorption capacity (qm) of M-PBB was 15.3 mg/g from the experiment at pH 6. A high correlation coefficient (R2 ≈ 0.9) of Freundlich isotherm postulated multi-layer adsorption of TC on M-PBB at pH 6. The kinetic studies showed that the pseudo-first-order was more suitable for representing the adsorption of TC molecules on the surface. The thermodynamic analysis was showed that the adsorption process is favorable, spontaneous, and endothermic at studied temperatures. M-PBB demonstrated a potential for removal of TC from water as a low-cost and convenient adsorbent.


Effects of load on the guidance of visual attention from working memory.
An active recent line of research on working memory and attention has shown that the visual attention can be top-down guided by working memory contents. The present study examined whether the guidance effect is modulated by memory load, i.e., the amount of information maintained in working memory. In a set of three experiments, participants were asked to perform a visual search task while maintaining several objects in working memory. The memory-driven attentional guidance effect was observed in all experiments when there were spare working memory resources. When memory load was increased from one item to two items, there was no sign that the guidance effect was attenuated. When load was further increased to four items, the guidance effect disappeared completely, indicating a clear impact of memory load on attentional guidance.


Magnesium Depletion Score Predicts Diabetic Retinopathy Risk among Diabetes: Findings from NHANES 2005-2018.
Magnesium is essential for material and energy metabolism. The magnesium depletion score (MDS) is recognized as a more valuable and reliable predictor of body magnesium status than any other clinical used markers such as serum and urine magnesium. However, research on the relationship between MDS and diabetic retinopathy (DR) is limited. As a result, the current study sought to assess this issue in diabetic samples from a large population-based database in the United States. Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2005-2018. MDS was calculated, and multivariate logistic regression analysis was applied to evaluate the presence of association between variables and DR risk. A total of 4308 participants was comprised in this study. Samples with DR consumed less magnesium (259.1 ± 113.6 vs 269.8 ± 113.2 mg, P < 0.001), and their MDS levels differed significantly from non-DR participants (P < 0.001). Increased dietary magnesium was linked to a lower incidence of DR (all P for trend < 0.05), and patients with a high level of MDS were more prone to DR (P = 0.001). Furthermore, subgroup analysis revealed that high (Q3) amount magnesium supplements was associated with lower DR risk when MDS was none to low or middle level (both P = 0.02). Our results indicated that MDS levels are associated with DR risk and that magnesium supplementation is benefit to DR prevention.


Construction of perineuronal net-like structure by cortical neurons in culture.
Perineuronal nets consisting of chondroitin sulfate proteoglycans and hyaluronic acid are associated with distinct neuronal populations in mammalian brain. Whether neurons or glia cells produce these surface-associated chondroitin sulfate proteoglycan perineuronal nets has remained in question. In the present study, we observed perineuronal net-like structure by rat cortical neurons in dissociated culture using Wisteria floribunda aggulutinin, hyaluronic acid binding protein, and the antibodies recognizing chondroitin sulfate proteoglycans. The double labeling experiments showed that perineuronal net-like structure labeled with Wisteria floribunda aggulutinin was observed often at parvalbumin-positive neurons in dissociated cortical culture without glia. Perineuronal net-like structure was not seen at the early stage of culture, but they became visible concomitantly with neuronal maturation after longer culture. High magnification observation further demonstrated that Wisteria floribunda aggulutinin labeling on cortical neurons was seen as numerous puncta along surface of somata and proximal dendrites, but not axons and synapses. Perineuronal net-like structure on cultured neurons was also visualized using chondroitin sulfate proteoglycan-specific antibodies and hyaluronic acid binding protein. Double labeling study demonstrated that perineuronal net-like structure in cultured cortical neurons was composed of chondroitin sulfate proteoglycans such as neurocan and phosphacan. The hyaluronidase treatment of live neurons abolished cellular labeling of hyaluronic acid binding protein and concomitantly diminished that of Wisteria floribunda aggulutinin. These results indicate that cultured cortical neurons are able to construct perineuronal net-like structure without glial cells.


Status of higher TGF-β1 and TGF-β2 levels in the aqueous humour of patients with diabetes and cataracts.
Transforming growth factor (TGF) is a cytokine that acts on the proliferation, migration, differentiation, and apoptosis of cells and the accumulation of extracellular matrix components. Very few studies have precisely evaluated the concentration of TGF-β in the aqueous humour (AH) of diabetic and cataract (DMC) eyes due to the low expression of proteins in the AH or other reasons. The concentrations of TGF-β1, -β2, and -β3 in the AH of the DMC group were compared with those of the age-related cataract (ARC) group. We collected AH and lens epithelium samples from 33 DMC patients and 36 ARC patients. Luminex liquid suspension chip detection was applied to detect the concentration of TGF-β1, -β2, and -β3 in the AH samples. The expression of TGFB1/2/3 in lens epithelium samples was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The concentrations of TGF-β1 and TGF-β2 in AH samples of DMC eyes were higher than those of ARC eyes. The differences in TGF-β1 and TGF-β2 between the two groups were statistically significant (P value = 0.001 for TGF-β1, P value = 0.023 for TGF-β2). The difference of the correlation between TGF-β1 and glycosylated haemoglobin was significant (P value = 0.011, and Pearson correlation coefficient = 0.306). The difference of the correlation between TGF-β2 and glycosylated haemoglobin was significant (P value = 0.026, and Pearson correlation coefficient = 0.269). The mRNA expression levels of TGFB1 and TGFB2 were upregulated in DMC epithelium samples compared with ARC epithelium samples. The differences in TGFB1 and TGFB2 between the two groups were statistically significant (P value for TGFB1 = 0.041, P value for TGFB2 = 0.021). The concentrations of TGF-β1 and TGF-β2 in AH samples were significantly higher in DMC eyes than in ARC eyes. The higher the glycosylated haemoglobin was, the higher the concentrations of TGF-β1 and -β2 were. The mRNA expression of TGFB1 and TGFB2 was significantly upregulated in DMC epithelial samples compared with ARC epithelial samples, suggesting the proinflammatory status of the anterior chamber of DMC eyes.


Fixation augmentation using titanium cage packing with xenograft in the treatment of tibial plateau fractures.
To evaluate a new surgical technique concerning titanium cage packing with xenograft demineralized bone matrix bovine augmentation in the management of subchondral bone defects associated with tibial plateau fractures. All patients underwent plate fixation augmentation using titanium cage packing with xenograft, with the help of digital medical software of Mimics and 3-matic preoperatively. Duration of the surgical procedure, intraoperative bleeding volume, bone union time, quality of reduction and alignment, fracture healing, complications, and functional outcomes based on Oxford knee outcome score were recorded. A total of 18 patients were followed for average 18.1 months (range, 12-24 months). The average radiographic bony union time was 12.8 weeks (range, 11-17 weeks) and full weight bearing time was 13.4 weeks (range, 11-16 weeks) respectively. At one-year follow-up, the mean degrees of knee extension were 2.7° (range, 0-6) and the mean degrees of knee flexion were 122.0° (range, 112-134). The articular step-off was unchanged from 0.9 ± 0.6 mm (range, 0-1.8 mm) to 1.0 ± 0.6 mm (0-1.9 mm) (P = 0.512). All the cases had satisfactory reduction. No secondary loss of reduction was found over the time period studied. Superficial infection was found in one case, and resolved with closed treatment. No implant failures were noted. The average Oxford knee score was 19.9 ± 5.4 (range, 12-30) at the final follow-up. Fixation augmentation using titanium cage packing with xenograft augmentation is a safe and effective way to treat the depressed tibial plateau fractures.


Research on the effectiveness of intermittent cervical traction therapy, using short-latency somatosensory evoked potentials.
Short-latency somatosensory evoked potentials (SSEPs) were measured before and after intermittent cervical traction therapy to serve as objective indicators of therapy effectiveness. The subjects were 29 patients with myelopathy, 23 with cervical radiculopathy, 28 with cervical sprain, and 26 healthy individuals. SSEPs were recorded by stimulating the median nerve, and the negative potentials elicited from the brachial plexus (N9), neck (N11, lcN13, ucN13), and somatosensory area (N18) were measured to determine interpeak latencies and then corrected latency. As to the changes in SSEPs following traction, the N11-lcN13 and lcN13-ucN13 interpeak latencies for patients with type I and II myelopathy decreased, and the severity of myelopathy was inversely related to the degree of decrease. The ucN13-N18 interpeak latency for some patients with severe myelopathy increased. The N9-N11 and N11-lcN13 interpeak latencies for patients with cervical radiculopathy decreased, and the ucN13-N18 for patients with cervical sprain accompanied by autonomic nervous symptoms also decreased. Traction therapy might improve conduction disturbance primarily by increasing the amount of blood flow from the nerve roots to the spinal parenchyma.


Pharmacology and toxicology of ATOA, an AMPA receptor antagonist and a partial agonist at GluR5 receptors.
(RS)-2-Amino-3-[3-(carboxymethoxy)-5-tert-butyl-4-isoxazolyl]propi onic acid (ATOA) has previously been described as an antagonist at (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptors with an IC50 value of 150 microM towards AMPA-induced depolarisation in the rat cortical wedge preparation. ATOA has now been shown also to be a partial agonist at recombinant GluR5 receptors, expressed in Xenopus oocytes, with an EC50 value of 170 microM and a relative efficacy of 0.17 +/- 0.04 compared with responses produced by kainic acid (1.0). Using cultured cerebral cortical neurones as a test system and leakage of lactate dehydrogenase (LDH) as an indicator of cell damage, ATOA was shown to be cytotoxic (ED50 > 300 microM), though much less toxic than the structurally related dual AMPA and GluR5 agonist, (RS)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid (ATPA) (ED50 = 14 +/- 2 microM). The toxic effect of ATPA was sensitive to 6,7-dinitroquinoxaline-2,3-dione (DNQX) but was not significantly reduced by the selective AMPA receptor antagonist, (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA). The toxicity of ATOA (1 mM) could not be significantly attenuated by co-administration of AMOA (300 microM) or DNQX (25 microM). A structure-activity analysis indicates that the tert-butyl group of ATPA and ATOA facilitates the interaction of these compounds with GluR5 receptors.


Treatment of Fractures of the Thoracolumbar Spine: Recommendations of the Spine Section of the German Society for Orthopaedics and Trauma (DGOU).
consensus paper with systematic literature review. The aim of this study was to establish recommendations for treatment of thoracolumbar spine fractures based on systematic review of current literature and consensus of several spine surgery experts. The project was initiated in September 2008 and published in Germany in 2011. It was redone in 2017 based on systematic literature review, including new AOSpine classification. Members of the expert group were recruited from all over Germany working in hospitals of all levels of care. In total, the consensus process included 9 meetings and 20 hours of video conferences. As regards existing studies with highest level of evidence, a clear recommendation regarding treatment (operative vs conservative) or regarding type of surgery (posterior vs anterior vs combined anterior-posterior) cannot be given. Treatment has to be indicated individually based on clinical presentation, general condition of the patient, and radiological parameters. The following specific parameters have to be regarded and are proposed as morphological modifiers in addition to AOSpine classification: sagittal and coronal alignment of spine, degree of vertebral body destruction, stenosis of spinal canal, and intervertebral disc lesion. Meanwhile, the recommendations are used as standard algorithm in many German spine clinics and trauma centers. Clinical presentation and general condition of the patient are basic requirements for decision making. Additionally, treatment recommendations offer the physician a standardized, reproducible, and in Germany commonly accepted algorithm based on AOSpine classification and 4 morphological modifiers.


Four-amino acid segment in steroid 5 alpha-reductase 1 confers sensitivity to finasteride, a competitive inhibitor.
The 4-azasteroid 17 beta-(N-t-butyl)carbamoyl-4-aza-5 alpha-androst-1-en-3-one (finasteride) is 100-fold more potent as a competitive inhibitor of the rat NADPH:delta 4-3-oxosteroid-5-alpha- oxidoreductase (steroid 5 alpha-reductase) type 1 enzyme (Ki = 3-5 nM) than of the human type 1 enzyme (Ki greater than or equal to 300 nM). In this study, we exploit this differential sensitivity to map a major determinant of finasteride sensitivity in steroid 5 alpha-reductase. Chimeric steroid 5 alpha-reductase cDNAs composed of different combinations of rat and human exon sequences were created by genetic engineering, expressed in human embryonic kidney 293 cells, and assayed for their sensitivity to finasteride. Hybrid proteins containing sequences encoded by rat exon 1 were found to be as sensitive to finasteride as the parental enzyme. The exchange of progressively smaller protein segments encoded within exon 1 identified a tetrapeptide sequence (Val-Ser-Ile-Val) in the rat enzyme that conferred sensitivity to finasteride. The analogous sequence in the human enzyme (Ala-Val-Phe-Ala) conferred partial resistance to the drug. Finasteride was a competitive inhibitor of the native and all chimeric enzymes tested, suggesting that the tetrapeptide segments form a portion of the substrate-binding domain of steroid 5 alpha-reductase.


Interleukin-2 production by human fetal lymphocytes.
IL-2 production by PHA-stimulated human lymphocytes in umbilical blood was studied ontogenetically. Lymphocytes from the 16-week-old fetus produced appreciable amounts of interleukin-2 (IL-2). In 16- to 36-week-old fetuses the IL-2 production rate was found to be significantly higher than that in adults. When signal transduction, which is mediated by high affinity IL-2 receptors (IL-2R), was studied after adding exogenous IL-2 to PHA-blast lymphocytes, the response of the 24-week-old fetus was similar to that of adults. These results indicate that the attainment of IL-2 production and the function of IL-2 receptors are completed at a relatively early stage of fetal development.


Extending the Reach of Early Intervention Training for Practitioners: A Preliminary Investigation of an Online Curriculum for Teaching Behavioral Intervention Knowledge in Autism to Families and Service Providers.
Early behavioral intervention, based on the methods of applied behavior analysis, has the strongest and most consistent scientific support as a means of teaching skills to young children with Autism Spectrum Disorder and reducing their restricted and maladaptive behavior. Though individual ABA-based treatment plans are usually developed, designed and supervised by a senior-level clinician, they are most often implemented by a practitioner, such as a parent, direct service provider, aide, or an early childhood professional from a related discipline. Unfortunately, few practitioner-orientated training programs are available to geographically disparate persons. Online distance-learning education offers a potential solution to this problem. Fifty-one individuals participated in an initial study of a short, three-module online course. The results showed a highly statistically significant difference between the mean pre-test and post-test score. The outcomes suggest the feasibility and user satisfaction of teaching BI knowledge acquisition online, and thus bolster confidence that future, larger-scale curricula aimed at teaching BI in a distance-learning format is warranted.


Multi-Aspect enhanced Graph Neural Networks for recommendation.
Graph neural networks (GNNs) have achieved remarkable performance in personalized recommendation, for their powerful data representation capabilities. However, these methods still face several challenging problems: (1) the majority of user-item interaction graphs only utilize the interaction information, which cannot reflect the users' specific preferences for different aspects, making it difficult to capture user preferences in a fine-grained manner. (2) there is no effective way to integrate multi-aspect preferences into a unified model to capture the comprehensive user interests. To address these challenges, we propose a Multi-Aspect enhanced Graph Neural Networks (MA-GNNs) model for item recommendation. Specifically, we learn the aspect-based sentiments from reviews and use them to construct multiple aspect-aware user-item graphs, thus giving the edge practical meaning. And aspect semantic features are introduced into the information aggregation process to adjust users' preferences for different items. Furthermore, we design a routing-based fusion mechanism, which adaptively allocates weights to different aspects to realize the dynamic fusion of aspect preferences. We conduct experiments on four publicly available datasets, and the experimental results show that the proposed MA-GNNs model outperforms state-of-the-art methods. Further analysis proves that fine-grained interest modeling can improve the interpretability of recommendations.


Determination of oxcarbazepine and its metabolites in postmortem blood and hair by means of liquid chromatography with mass detection (HPLC/APCI/MS).
A typical use of hair analysis in forensic toxicology is the documentation of previous drug administration. This is illustrated in a suicidal death of a 58-year-old epileptic patient who was treated with oxcarbazepine and probably with levomepromazine. The toxicological analysis carried out by HPLC/APCI/MS included also the hair (6 cm length) besides postmortem blood. The method was validated for levomepromazine, oxcarbazepine (OXCBZ) and its two metabolites, 10-hydroxycarbazepine (CBZ-10OH) and trans-diol-carbazepine (CBZ-diOH) in various biological matrices. The analysis of the postmortem blood indicated oxcarbazepine and its two main metabolites were present at therapeutic concentrations; levomepromazine was detected at a fatal concentration. In three 2-cm segments of hair, oxcarbazepine and its two metabolites were detected; however, levomepromazine was not detected in this specimen. As a result of complex chemical-toxicological investigation it was confirmed the information that the decedent. was an epileptic patient and was treated with oxcarbazepine for at least 6 months before death. In addition, he took a toxic dose of levomepromazine in order to commit suicide. The analysis revealed differences between the concentration levels of oxcarbazepine and its active metabolite CBZ-10OH in postmortem specimens and hair, suggesting different mechanisms of penetration of metabolites and their precursors into this matrix.


The importance of perceived helplessness and emotional health in understanding the relationship among pain, function, and satisfaction following revision knee replacement surgery.
Little is known about the relationships among pain, function, psychological variables like perceived helplessness and emotional health, and patient satisfaction in people with revision knee replacement surgery. We hypothesized that pain and function would have a direct association with satisfaction as well as an indirect association through patient perceptions of helplessness and emotional health. This longitudinal study included 145 participants undergoing revision knee replacement surgery. Demographic data and expectation of benefit from surgery were recorded prior to surgery. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Arthritis Helplessness Scale (AHS) and the Mental Component Scale (MCS) of the SF-36 (emotional health) were collected prior to and 2 years post-surgery. Satisfaction was recorded 2 years post-surgery. Regression analyses were conducted to test for mediation effects of helplessness and MCS. Participants were on average 69 years old and 54% were women. Participants were satisfied with the results of the surgery (mean ± standard deviation (SD) = 70.42 ± 31.46). Less pain and functional disability were associated with increased patient satisfaction and, the effect of pain or function was also mediated through helplessness whereby more pain and disability were associated with perceptions of helplessness and helplessness was associated with lower satisfaction. MCS did not mediate the relationship of pain and function with satisfaction. Helplessness plays an important role in understanding patient satisfaction. Interventions aimed at improving patient outcome should target not only pain and function but also should address strategies to support people in managing following knee revision surgery to maximize satisfaction with outcome.


Behavioral avoidance of contagion in childhood.
Although there is a large literature on children's reasoning about contagion, there has been no empirical research on children's avoidance of contagious individuals. This study is the first to investigate whether children avoid sick individuals. Participants (4- to 7-year-old children) were invited to play with two confederates-one of whom was "sick." Afterward, their knowledge of contagion was assessed. Overall, children avoided proximity to and contact with the sick confederate and her toys, but only 6- and 7-year-olds performed above chance. The best predictor of avoidance behavior was not age but rather children's ability to make predictions about illness outcomes. This provides the first evidence of behavioral avoidance of contagious illness in childhood and suggests that causal knowledge underlies avoidance behavior.


Movement of the ankle joint after driving a screw across the inferior tibiofibular joint.
Twenty-eight patients with fracture-subluxation of the ankle were studied for at least 1 year after fixation with an oblique fibulotibial screw, supplemented when necessary by a screw in the medial malleolus and loops of wire around the fibula. The range of movement at each ankle was measured at 6 weeks and 1 year after operation. The patient's comments on mobility and symptoms were also noted. Irrespective of the radiological severity of the injury, 6 of the 28 had full movement at 6 weeks, and 13 at 1 year, and a further 9 had movement reduced by less than 5 mm, at 1 year, at which time 22 were free from symptoms.


Genome Sequence of the Banana Plant Growth-Promoting Rhizobacterium Bacillus amyloliquefaciens BS006.
Bacillus amyloliquefaciens is an important plant growth-promoting rhizobacterium (PGPR). We report the first whole-genome sequence of PGPR Bacillus amyloliquefaciens evaluated in Colombian banana plants. The genome sequences encode genes involved in plant growth and defense, including bacteriocins, ribosomally synthesized antibacterial peptides, in addition to genes that provide resistance to toxic compounds.


DNA damage response-related alterations define the genetic background of patients with chronic lymphocytic leukemia and chromosomal gains.
The presence of chromosomal gains other than trisomy 12 suggesting a hyperdiploid karyotype is extremely rare in chronic lymphocytic leukemia (CLL) and is associated with a dismal prognosis. However, the genetic mechanisms and mutational background of these patients have not been fully explored. To improve our understanding of the genetic underpinnings of this subgroup of CLL, seven CLL patients with several chromosomal gains were sequenced using a next-generation sequencing (NGS)-targeted approach. The mutational status of 54 genes was evaluated using a custom-designed gene panel including recurrent mutated genes observed in CLL and widely associated with CLL pathogenesis. A total of 21 mutations were detected; TP53 (42.8%), ATM (28.5%), SF3B1 (28.5%), and BRAF (28.5%) were the most recurrently mutated genes. Of these mutations, 61.9% were detected in genes previously associated with a poor prognosis in CLL. Interestingly, five of the seven patients exhibited alterations in TP53 or ATM (deletion and/or mutation), genes involved in the DNA damage response (DDR), which could be related to a high genetic instability in this subgroup of patients. In conclusion, CLL patients with several chromosomal gains exhibit high genetic instability, with mutations in CLL driver genes and high-risk genetic alterations involving ATM and/or TP53 genes.


Thieno[3,4-b]-1,4-oxathiane: an unsymmetrical sulfur analogue of 3,4-ethylenedioxythiophene (EDOT) as a building block for linear pi-conjugated systems.
[reaction: see text] An unsymmetrical analogue of 3,4-ethylenedioxythiophene (EDOT) has been synthesized by transetherification of 3,4-dimethoxythiophene. Electropolymerization leads to a stable electroactive polymer with electrochemical and electronic properties intermediate between those of the two symmetrical parent polymers poly(EDOT) and poly(3,4-ethylenedithiathiophene). Experimental work shows that the 2- and 5-positions possess a different reactivity, thus opening the possibility of synthesizing regioregular oligomers or polymers.


Complete atrio-ventricular block due to cardiac echinococcosis.
A 33-year-old man presented a complete antrio-ventricular block due to two hydatid cysts localized in the interventricular septum and interrupting both bundle branches. Intracardiac rupture within the right ventricle led to extensive pulmonary hydatidosis and death.


Diffusion tensor imaging for long-term follow-up of corticospinal tract degeneration in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a predominantly clinical and electromyographic diagnosis. Conventional MRI reveals atrophy of the motor system, particularly the pyramidal tract, in the advanced stages but does not provide a sensitive measure of disease progression. Three patients with different principal symptoms of ALS, i.e., with predominant involvement of the upper (UMN) or lower (UMN) motor neurons, or bulbar disease, respectively, underwent serial clinical examination including lung function tests, conventional MRI, and diffusion tensor imaging (DTI). MRI demonstrated changes in of the pyramidal tract without measurable variation on follow-up. The patient with UMN involvement showed remarkable progressive loss of diffusion anisotropy in the pyramidal tract. DTI might be useful, together with clinical follow-up, as an objective morphological marker in therapeutic trials.


Linkage of a tumor immune function and cell cycle de-regulation via a gene regulatory network subcircuit.
Gene regulatory network (GRN) subcircuits have been described for cell fate progressions in animal development. The hallmark of these subcircuits is the integration of promoters, and positive- and negative-acting promoter binding proteins, such that an alteration in function of any one member of the defined subcircuit, occurring with a change in cell fate, defines a change in status for all other members of the subcircuit. Here we describe a GRN subcircuit that links a tumor immune function with cell cycle de-regulation. All members of this subcircuit have a predictable status change in response to rescue of the growth-controlled phenotype. Given the similarities between the molecular mechanisms underlying cell status changes in tumorigenesis and development, application of GRN paradigms to tumor progression is particularly apt and offers the hope of providing a more concise, reliable, and therapeutically useful series of predictions linking gene regulation and tumor progression.


The impact of revascularization on myocardial blood flow as assessed by positron emission tomography.
Revascularization aims to improve myocardial perfusion. However, changes in regional artery-specific quantitative perfusion after revascularization have not been systematically investigated. It is unclear whether artery-specific thresholds for coronary flow capacity (CFC) and/or relative perfusion predict improved stress perfusion after revascularization. We sought to determine the impact of revascularization based on predefined, artery-specific, severity size thresholds for CFC and/or relative perfusion defects. Fifty patients underwent PET imaging before revascularization and then prospectively within 90 days after revascularization. Changes in regional myocardial blood flow (MBF) were stratified based on baseline perfusion abnormalities, baseline reduced CFC, and whether revascularization was performed in that region. Following angiographic stenosis-directed revascularization, in regions with relative perfusion abnormalities and decreased CFC, stress MBF (sMBF) increased by 0.51 cm3/min/g (59%) from baseline (p < 0.001). In regions without baseline perfusion abnormalities and yet decreased CFC, sMBF increased by 0.35 cm3/min/g (40%) from baseline (p < 0.001). In regions without perfusion abnormalities and normal CFC, sMBF did not increase significantly (+0.07 cm3/min/g, p = 0.56). Patients in whom revascularization was concordant with abnormal PET findings showed increased whole-heart sMBF (+0.22 cm3/min/g, p < 0.001), but in patients in whom revascularization was targeted only to regions without perfusion abnormalities or low CFC, sMBF did not change significantly (-0.06 cm3/min/g, p = 0.38). Revascularization targeted to regions with reduced CFC and relative perfusion abnormalities on baseline PET yielded significant improvements in sMBF. When revascularization was performed in regions without reduced CFC, sMBF did not improve.


Nitrogen removal via short-cut simultaneous nitrification and denitrification in an intermittently aerated moving bed membrane bioreactor.
An intermittently aerated moving bed membrane bioreactor (MBMBR) was developed and crucial parameters affecting nitrogen removal from wastewater by simultaneous nitrification and denitrification via nitrite were investigated, without strict control of solids retention time. Changes in the microbiological community and distribution in the reactor were monitored simultaneously. The intermittent-aeration strategy proved effective in achieving nitrition and the chemical oxygen demand (COD) to total nitrogen (TN) ratio was an important factor affecting TN removal. In the MBMBR, the nitrite accumulation rate reached 79.4% and TN removal efficiency averaged at 87.8% with aeration 2 min/mix 4 min and an influent COD/TN ratio of 5. Batch tests indicated that under the intermittently aerated mode, nitrite-oxidizing bacteria (NOB) were not completely washed out from the reactor but NOB activity was inhibited. The intermittently aerated mode had no effect on the activities of ammonia-oxidizing bacteria. Fluorescence in situ hybridizations (FISH) results also suggested that NOBs remained within the system.


In vivo evidence for tibial plateau slope as a risk factor for anterior cruciate ligament injury: a systematic review and meta-analysis.
In vivo studies reporting tibial plateau slope as a risk factor for anterior cruciate ligament (ACL) injury have been published with greatly increasing frequency. To examine and summarize the in vivo evidence comparing tibial slope in ACL-injured and uninjured populations. Systematic review and meta-analysis. We reviewed publications in Scopus, SPORTDiscus, CINAHL, and PubMed to identify all studies reporting a measure of tibial plateau slope between ACL-injured groups and controls. A meta-analysis was performed including calculation of effect size and 95% confidence interval as well as 95% confidence intervals for the mean values of the measurement in each study. Fourteen studies met our inclusion/exclusion criteria. Five of 6 radiographic studies reporting medial tibial plateau slope (MTPS) demonstrated significant differences between controls and ACL-injured groups, while only 1 of 7 magnetic resonance imaging (MRI) studies reported significant differences between groups. Mean MTPS measurements and standard deviations reported for controls ranged from 2.9° ± 2.8° anterior to 9.5° ± 3° posterior. For ACL-injured patients, MTPS ranged from 1.8° ± 3.5° anterior to 12.1° ± 3.3° posterior. Lateral tibial plateau slope (LTPS) was reported to be significantly greater in ACL-injured groups in all 5 MRI-based studies reporting group comparisons. Mean values for LTPS in controls ranged from 0.3° ± 3.6° anterior slope to 9° ± 4° posterior slope. In ACL-injured groups, mean reported LTPS values ranged from 1.8° ± 3.2° to 11.5° ± 3.54° posterior slope. Despite high measures of reliability for the various methods reported in current studies, there is vast disagreement regarding the actual values of the slope that would be considered "at risk." Reported tibial slope values for control groups vary greatly between studies. In many cases, the study-to-study differences in "normal" tibial slope exceed the difference between controls and ACL-injured patients. The clinical utility of imaging-based measurement methods for the determination of ACL injury risk requires more reliable techniques that demonstrate consistency between studies.


Long term assessment of factors affecting nitrifying bacteria communities and N-removal in a full-scale biological process treating high strength hazardous wastewater.
Over a 3 year period, interactions between nitrifying bacterial communities and the operational parameters of a full-scale wastewater treatment plant were analyzed to assess their impact on nitrification performance. Throughout the study period, nitrification fluctuated while Nitrosomonas europaea and Nitrosomonas nitrosa, the two major ammonia oxidizing bacteria (AOB) communities, showed resistance to changes in operational and environmental conditions. Nitrobacter populations mostly exceeded those of Nitrospira within nitrite oxidizing bacteria (NOB). Meanwhile, principal component analysis (PCA) results revealed that a close association between Nitrobacter and nitrite concentration as well as a direct correlation between the quantity of AOB and influent SCN- concentration. The serial shifts of data points over time showed that the nitrification of a full-scale treatment plant has been gradually suppressed by the influence of influent COD and phenol concentrations.


Vitamin E-blended versus conventional polyethylene liners in prostheses : Prospective, randomized trial with 3-year follow-up.
Despite continuous technical improvements, polyethylene wear debris induced periprosthetic osteolysis remains the main cause for failure of hip arthroplasty. Progressive oxidation of polyethylene was identified as another risk factor for material failure. To overcome this problem, antioxidants such as vitamin E (alpha-tocopherol) were supplemented by diffusion into the latest generation of polyethylene liners. The purpose of the present study was to investigate the clinical outcome of patients treated with vitamin E blended highly cross-linked ultra-high molecular weight polyethylene liners (UHMWPE-XE) in comparison with conventional UHMWPE‑X liners by evaluating patient-reported outcome measures (PROM's) at 3‑year follow-up. A total of 143 patients were recruited into this prospective, randomized trial in our academic center. Three years after implantation, 101 patients were examined in the outpatient clinic for follow-up. Of these, 51 (50.5%) received UHMWPE-XE and 50 (49.5%) UHMWPE‑X liners. Clinical outcome was evaluated using Harris-Hip-Score (HHS) UCLA-Score and Hip Disability and Osteoarthritis Outcome Score (HOOS). There was a significant improvement in all PROM's at one- and three-year follow-up compared to the status before implantation. PROM's did not differ significantly between the first and third year follow-up. Both liner groups showed an equal clinical outcome. The present study demonstrates that the supplementation of vitamin E to polyethylene liners is reliable and safe without showing higher complication rates compared with conventional polyethylene liners. The shortterm clinical outcome of vitamin E-blended (UHMWPE‑XE) is equivalent to those of conventional highly cross-linked polyethylene liners.


A facile regio- and stereoselective synthesis of mannose octasaccharide of the N-glycan in human CD2 and mannose hexasaccharide antigenic factor 13b.
A highly concise and effective synthesis of the mannose octasaccharide of the N-linked glycan in the adhesion domain of human CD2 was achieved via TMSOTf-promoted selective 6-glycosylation of a trisaccharide 4,6-diol acceptor with a pentasaccharide donor, followed by deprotection. The pentasaccharide was constructed by selective 3,6-diglycosylation of 1,2-O-ethylidene-beta-D-mannopyranose with 2-O-acetyl-3,4,6-tri-O-benzoyl-alpha-D-mannopyranosyl-(1-->2)-3,4,6-tri-O-benzoyl-alpha-D-mannopyranosyl trichloroacetimidate, while the trisaccharide was obtained by selective 3-O-glycosylation of allyl 4,6-O-benzylidene-alpha-D-mannopyranoside with the same disaccharide trichloroacetimidate, followed by debenzylidenation. The mannose hexasaccharide antigenic factor 13b was synthesized by condensation of a trisaccharide donor, 2-O-acetyl-3,4,6-tri-O-benzoyl-alpha-D-mannopyranosyl-(1-->2)-3,4,6-tri-O-benzoyl-alpha-D-mannopyranosyl-(1-->3)-4,6-di-O-acetyl-2-O-benzoyl-alpha-D-mannopyranosyl trichloroacetimidate, with a trisaccharide acceptor, methyl 3,4,6-tri-O-benzoyl-alpha-D-mannopyranosyl-(1-->2)-3,4,6-tri-O-benzoyl-alpha-D-mannopyranosyl-(1-->2)-3,4,6-tri-O-benzoyl-alpha-D-mannopyranoside, followed by deprotection.


"Dancing inside the ball": the structures and nonlinear optical properties of three Sc2S@C3v(8)-C82 isomers.
Recently, the crystal structures and electrochemical properties of the isomers (Sc2S "trapped" in C82) have been reported, in which the Sc2S is located inside the different positions of the C82 cage. In the present work, three isomers of endohedral metallofullerenes Sc2S@C3v(8)-C82 (A, B, and C) have been designed to explore the effect of the position of Sc2S on their interaction energies and nonlinear optical properties. Among three isomers, the Sc2S is located in different positions of the C82 cage: the angles of Sc-S-Sc in A, B, and C are 104.9, 114.8, and 115.7°, respectively. Furthermore, the analysis of natural bond orbital (NBO) charge indicates that the electron-transfer is from the Sc2S to the adjacent carbon atoms of the C82 cage. The interaction energy of B is the smallest among three isomers which is -226.2 kcal mol(-1). It was worth mentioning that their first hyperpolarizabilities (β tot) were studied, we found that their β tot values were related to the positions of Sc2S: C (2100) > B (1191) > A (947 au). We hope that the present work can provide a new strategy to promote the nonlinear optical properties of endohedral metallofullerenes by changing the positions of the encapsulated molecular. Graphical abstract Three isomers of endohedral metallofullerenes Sc2S@C3v(8)-C82 (A, B, and C) have been designed to explore the position effect of Sc2S on the interaction energies and nonlinear optical properties. Among three isomers, the Sc2S in B has the most stable position. Significantly, the first hyperpolarizability is related to the position of Sc2S inside the C82 cage, which provides a novel strategy to enhance the first hyperpolarizability by the Sc2S revolving inside the C82 cage.


Electrochemical behavior of uric acid and epinephrine at an electrochemically activated glassy carbon electrode.
A pretreated glassy carbon electrode by electrochemical activation has been proposed for simultaneous investigation and determination of epinephrine and uric acid by differential pulse voltammetry. This pretreated glassy carbon electrode exhibits a potent and persistent electron-mediating behavior followed by well-separated oxidation peaks towards epinephrine and uric acid with a potential difference of 161 mV, which is large enough to determine epinephrine and uric acid individually and simultaneously. Under the optimum condition, the detection limit of epinephrine is 8.9 x 10(-8)mol L(-1) and that of uric acid is 1.6 x 10(-7)mol L(-1). The proposed method was successfully used for the determination of epinephrine and uric acid in real samples with satisfactory results.


The impact of the pneumococcal conjugate vaccines on the incidence of community-acquired alveolar pneumonia in premature compared with in term-born infants.
Preterm-born children are prone to respiratory infections and complications during infancy and early childhood. In Israel, pneumococcal conjugated vaccines (PCVs) were introduced in 2009-2010, with high vaccination coverage. We assessed the impact of PCV implementation on community-acquired alveolar pneumonia (CAAP) in children < 2 years old born prematurely, in comparison with term born infants. We conducted a prospective, active, population-based surveillance of children < 2 years old with radiologically-proven CAAP, visiting the only regional medical center. CAAP incidence in the pre-PCV and post-PCV eras were compared in early premature (29-32 weeks gestational age [WGA]), late premature (33-36 WGA) and term-born infants (>36 WGA). Of 214,947 births during the study period, 6'791 CAAP episodes were diagnosed; 211, 653 and 5,806 were in early premature, late premature and term infants, respectively. After PCV implementation, overall CAAP visits were reduced by 44% (95% CI 36-51): 60%, 21% and 45% among those born early preterm, late preterm and at term, respectively (statistically significant for children born early preterm and at term). For outpatients, the respective rate reductions were 79%, 40% and 65% (statistically significant for the children born at term). Importantly, the mean annual rates in the post-PCV period became similar in all 3 groups. The rate reductions among the hospitalized children were lower those that among the non-hospitalized children, with reductions of 56%, 16% and 33% for the three groups, respectively (statistically significant for early preterm and at term children). CAAP reduction trends after PCV implementation for preterm-born infants were similar to those for term-born infants. Whether this was because of similar direct PCV- protection, because of indirect (herd) protection or both, is unclear. Post-PCV implementation, the gaps in CAAP rates between infants born prematurely and at term were reduced.


Kaempferol targets Krt-14 and induces cytoskeletal mineralization in osteoblasts: A mechanistic approach.
Kaempferol (KEM) has been observed to stimulate Krt-14 protein which subsequently contributes to matrix maturation and mineralization in rat primary osteoblast cells. Incorporation of Krt-14 siRNA results in reduced mRNA and protein expression after 48h post transfection and remained low for 9days. At day 9 Krt-14 siRNA significantly reduced mineralization without concomitant change in the cell number. ColI and OCN gene expression was reduced in Krt-14 siRNA-treated osteoblast cells. Soluble osteocalcin and collagen levels were markedly decreased in conditioned medium as well as in acid-salt soluble cell-ECM layer treated with Krt-14 siRNA compared to control siRNA treated cells corroborated at the ultrastructral level by AFM. Further, knockdown of Krt-14 and inhibitors against AMPK and mTOR, repressed the activation of mTOR and mineralization attenuated by KEM confirmed the role of Krt-14 in mineralization. These findings strongly suggest that Krt-14 regulates osteoblast mineralization by organizing osteoblast derived ECM.


A stochastic model of active zone material mediated synaptic vesicle docking and priming at resting active zones.
Synaptic vesicles (SVs) fuse with the presynaptic membrane (PM) at specialized regions called active zones for synaptic transmission. SVs are associated with dense aggregates of macromolecules called active zone material (AZM) that has been thought to be involved in SV release. However, its role has recently begun to be elucidated. Several morphological studies proposed distinctively different AZM mediated SV docking and priming models: sequential and concurrent SV docking/priming. To explore ways to reconcile the contradictory models we develop a stochastic AZM mediated SV docking and priming model. We assume that the position of each connection site of the AZM macromolecules on their SV, directly linking the SV with the PM, varies by random shortening and lengthening of the macromolecules at resting active zones. We also perform computer simulations of SVs near the PM at resting active zones, and the results show that the distribution of the AZM connection sites can significantly affect the SV's docking efficiency and distribution of its contact area with the PM, thus priming and that the area correlates with the shape of the SVs providing a way to account for seemingly irreconcilable observations reported about the spatial relationship of SVs with the PM at active zones.


[Evaluation of pre-travel prevention, except vaccination, in children returning from Africa with fever].
Evaluating the frequency and modalities of transmissible infection prevention counseling in children before a stay in tropical or subtropical areas. Description of the frequency and modalities of transmissible infection prevention counseling (except specific vaccination) given prior to travel in children attending a tertiary care center in Paris, France, for fever occurring within 3 months following a return from Africa. Data were collected retrospectively from medical observations and telephone interviews with parents. A total of 173 children were included; 98 and 75 returned from sub-Saharan Africa and North Africa, respectively. Forty-one percent were less than 2 years old. Eighty-one percent of the children had consulted before leaving. Among children who returned from North Africa, the proportion of children who had a specific preventive consultation before travel was lower than among children who returned from sub-Saharan Africa (respectively, 72.1% versus 94.7%; p<0.001). In children having consulted before traveling, specific hygiene and diet advice had been given in 72% of cases but less frequently in children who traveled in North Africa compared to children who traveled to sub-Saharan Africa (respectively, 57.8% vs. 92.2%; p<0.001). Among children who returned from North Africa, those who had no preventive consultation before travel had febrile gastrointestinal infection more frequently than those who had a consultation before traveling (p=0.003). Although in this study the majority of children traveling to Africa receive transmissible infection prevention counseling before the travel, prevention could be improved, particularly before a stay in North Africa.


Comparing the selectivity and chiral separation of d- and l- fluorenylmethyloxycarbonyl chloride protected amino acids in analytical high performance liquid chromatography and supercritical fluid chromatography; evaluating throughput, economic and environmental impact.
The chiral separation of d- and l- FMOC amino acids was undertaken using the Lux Cellulose-1 polysaccharide based chiral column in HPLC (normal phase and reverse phase) and SFC conditions. This was done to compare the relative selectivity and separation between the three separation modes and to evaluate the potential benefits of SFC separations with regards to resolution, throughput, economic and environmental impact. It was established that the separation of d- and l- FMOC amino acids in SFC displayed behaviours that were similar to both normal phase and reversed phase, rather than distinctly one or the other. Additionally, although reversed phase conditions yielded significantly higher resolution values between enantiomers across the range of amino acids studied, improvements in selectivity in SFC via the introduction of higher concentrations of formic acid in the mobile phase allowed for better resolution per unit of time. Moreover since the SFC mobile phase is composed mostly of recyclable CO2, there is a reduction in organic solvent consumption, which minimises the economic and environmental costs.


Metastatic Mixed Germ Cell Tumour with Embryonal Carcinoma and Choriocarcinoma in a Female Eurasian Harvest Mouse (Micromys minutus).
Mixed germ cell tumours occur rarely in veterinary species. This report describes a case of metastatic mixed germ cell tumour in a female Eurasian harvest mouse (Micromys minutus). The tumour was extensive in one ovary and the uterus, and was characterized by two distinct tumour cell populations with features typical of embryonal carcinoma (EC) and choriocarcinoma (CC). Metastases of CC to the lungs and liver were observed. The exact origin of the CC was unclear, but the possibility of a non-gestational CC is favoured, given the context of a mixed germ cell tumour and lack of p53 expression. EC diagnosis was confirmed by immunohistochemical labelling of CD30 and lack of immunoreactivity for c-Kit. In addition, membranous β-catenin expression was present in the EC component, indicating an inactive Wnt/β-catenin pathway, which is required for the maintenance of pluripotency.


Andrology. Origin and development of a special discipline in medicine. Reflection and view in the future.
A general survey comments on the problems of andrology as a special medica discipline. A retrospective and an outlook concerning the different future possibilities of andrology is given. Special emphasis is placed on: examination of the ejaculate, morphology of the testicles, andrological training and further education; in the discussion of the future prospects special consideration is given to the responsibility of andrologists--also with respect to in-vitro-fertilization--and the significance of andrology for the inhabitants of the Third World.


A preliminary service evaluation of a personality disorder case management service.
The aim of this study is to assess the impact of establishing a specialized community personality disorder team on out of area placements, local hospital admissions and out of hours crisis contacts for service users with borderline personality disorder. This is a before-after interim evaluation of a new service. We tested, through a paired t-test, whether the intervention generated statistically significant differences over a range of measures of service usage, including out of area placements, local hospital admissions and out of hours crisis contacts. Data from 12 months after the intervention started were compared with the previous 12 months of routine care, to determine the effect on crisis contacts, days in hospital and those returning from/or sent out of area for care. Finally, we have assessed the likelihood to generate cost savings. All service users in out of area placements were repatriated to live in the community locally (100%), and there was a statistically significant decrease in inpatient admissions (80%). This was counterbalanced by a smaller but statistically significant increase in out of hours community crisis contacts (30%), although these reduced over time. Reorganizing local care pathways can lead to less out of area placements and less hospital admissions. © 2019 John Wiley & Sons, Ltd.