N-Heterocyclic Olefins on a Silicon Surface.

The adsorption of N-heterocyclic olefins (NHOs) on silicon is investigated in a combined scanning tunneling microscopy, X-ray photoelectron spectroscopy, and density functional theory study. We find that both of the studied NHOs bind covalently, with ylidic character, to the silicon adatoms of the substrate and exhibit good thermal stability. The adsorption geometry strongly depends on the N-substituents: for large N-substituents, an upright adsorption geometry is favored, while a flat-lying geometry is found for the NHO with smaller wingtips. These different geometries strongly influence the quality and properties of the obtained monolayers. The upright geometry leads to the formation of ordered monolayers, whereas the flat-lying NHOs yield a mostly disordered, but denser, monolayer. The obtained monolayers both show large work function reductions, as the higher density of the flat-lying monolayer is found to compensate for the smaller vertical dipole moments. Our findings offer new prospects in the design of tailor-made ligand structures in organic electronics and optoelectronics, catalysis, and material science.

Case report: metoclopramide induced acute dystonic reaction in adolescent CYP2D6 poor metabolizers.

Metoclopramide is indicated for the management of gastroesophageal reflux, gastric stasis, nausea, and vomiting. Metoclopramide-induced acute dystonic reactions (MIADRs), along with repetitive involuntary protrusion of the tongue, are well-known phenomena in children and young adults that may appear after the first dose. The drug is primarily metabolized via oxidation by the cytochrome P450 enzyme CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2. A recommendation to decrease metoclopramide dosing in patients with severely limited to no CYP2D6 activity (i.e., poor metabolizers, PMs) is included in the drug label. It is important to note, however, that a requirement or recommendation for pre-emptive testing for CYP2D6 metabolizer status is not included in the drug label. We present two cases of acute dystonia in two non-consanguineous male adolescents: one following metoclopramide and cimetidine administration in a 14-year-old to treat gastroesophageal reflux, and another following metoclopramide and pantoprazole administration in a 17-year-old with acute gastroenteritis. A retrospective pharmacogenetic analysis revealed both patients as CYP2D6 PMs.

Robotically Assisted Surgery in Children-A Perspective.

The introduction of robotically assisted surgery was a milestone for minimally invasive surgery in the 21st century. Currently, there are two CE-approved robotically assisted surgery systems for use and development in pediatrics. Specifically, tremor filtration and optimal visualization are approaches which can have enormous benefits for procedures in small bodies. Robotically assisted surgery in children might have advantages compared to laparoscopic or open approaches. This review focuses on the research literature regarding robotically assisted surgery that has been published within the past decade. A literature search was conducted to identify studies comparing robotically assisted surgery with laparoscopic and open approaches. While reported applications in urology were the most cited, three other fields (gynecology, general surgery, and "others") were also identified. In total, 36 of the publications reviewed suggested that robotically assisted surgery was a good alternative for pediatric procedures. After several years of experience of this surgery, a strong learning curve was evident in the literature. However, some authors have highlighted limitations, such as high cost and a limited spectrum of small-sized instruments. The recent introduction of reusable 3 mm instruments to the market might help to overcome these limitations. In the future, it can be anticipated that there will be a broader range of applications for robotically assisted surgery in selected pediatric surgeries, especially as surgical skills continue to improve and further system innovations emerge.

Combination of Ceramic Laser Micromachining and Printed Technology as a Way for Rapid Prototyping Semiconductor Gas Sensors.

The work describes a fast and flexible micro/nano fabrication and manufacturing method for ceramic Micro-electromechanical systems (MEMS)sensors. Rapid prototyping techniques are demonstrated for metal oxide sensor fabrication in the form of a complete MEMS device, which could be used as a compact miniaturized surface mount devices package. Ceramic MEMS were fabricated by the laser micromilling of already pre-sintered monolithic materials. It has been demonstrated that it is possible to deposit metallization and sensor films by thick-film and thin-film methods on the manufactured ceramic product. The results of functional tests of such manufactured sensors are presented, demonstrating their full suitability for gas sensing application and indicating that the obtained parameters are at a level comparable to those of industrial produced sensors. Results of design and optimization principles of applied methods for micro- and nanosystems are discussed with regard to future, wider application in semiconductor gas sensors prototyping.

New Members of the Cinchona Alkaloids Family: Assembly of the Triazole Heterocycle at the 6' Position.

The substance class of the well-known Cinchona alkaloids is widened by 6'-Amino-cinchonine and 6'-Amino-cinchonidine, novel compounds which incorporate a primary amino function in the quinolinic ring system. These key intermediates open the field for a range of fruitful chemistry. Here is described a short and direct pathway for the synthesis of triazole containing derivatives of the above-mentioned substances using the [3 + 2] Huisgen cycloaddition. For this purpose, the amines were first converted into the corresponding azides. Based on this, non-substituted and silyl-protected triazoles were synthesized as examples. Furthermore, didehydrated derivatives of quincorine and quincoridine were used as addition partners, resulting in compounds that carry the quinuclidine ring of the cinchona alkaloids at both ends. Some of these compounds were examined radiographically to investigate the position of the quinuclidine ring to the triazole. The solid-state structures of compounds 10, 11 and 28 were determined by X-ray diffraction analyses.

Controlled growth of ordered monolayers of N-heterocyclic carbenes on silicon.

N-Heterocyclic carbenes (NHCs) are promising modifiers and anchors for surface functionalization and offer some advantages over thiol-based systems. Because of their strong binding affinity and high electron donation, NHCs can dramatically change the properties of the surfaces to which they are bonded. Highly ordered NHC monolayers have so far been limited to metal surfaces. Silicon, however, remains the element of choice in semiconductor devices and its modification is therefore of utmost importance for electronic industries. Here, a comprehensive study on the adsorption of NHCs on silicon is presented. We find covalently bound NHC molecules in an upright adsorption geometry and demonstrate the formation of highly ordered monolayers exhibiting good thermal stability and strong work function reductions. The structure and ordering of the monolayers is controlled by the substrate geometry and reactivity and in particular by the NHC side groups. These findings pave the way towards a tailor-made organic functionalization of silicon surfaces and, thanks to the high modularity of NHCs, new electronic and optoelectronic applications.

Rapid responding to the COVID-19 crisis: Assessing the resilience in the German restaurant and bar industry.

The COVID-19 pandemic has fundamentally impacted the restaurant and bar industry. Simultaneously, this industry is already undergoing structural change. Using the concept of organisational resilience, we analyse the impact of the COVID-19 crisis on owner's assessment of resilience in the German restaurant and bar industry. Findings from an online survey with 623 owners and managers show that ex-ante business problems, and financing by loans or credit, reduce the likelihood of owners perceiving their business as resilient; while, delivery and takeaway service, ownership of property and higher age of owners, increase the likelihood of enterprise resilience. The paper contributes to understanding how restaurants and bars absorb and cope with the COVID-19 crisis. Furthermore, we make recommendation for future research on the recovery and adaptability of the business sector.

[Management of intra-abdominal dysgerminoma During pregnancy - A Case Report and Literature Review]. / Management Unterbauchraumforderungen in der Schwangerschaft ­ Fallbeschreibung eines extraovariell-intraabdominalen Dysgerminoms mit Überblick über die Literatur.

INTRODUCTION: Dysgerminomas are rare malignant germ cell tumors. They usually arise from the ovary, but case reports describing extraovarian dysgerminomas do exist. When treated adequately the disease has a good prognosis. Dysgerminomas diagnosed during pregnancy are very rare. METHODOLOGY: Report of extraovarian intra-abdominal dysgerminoma during pregnancy. Systematic literature review. CASE REPORT: A 35-year-old second gravida was diagnosed with a suspected intra-abdominal mass at 20 gestational weeks. During an exploratory laparotomy, a tumor infiltrating the transverse colon and histologically identified as a dysgerminoma was resected. Ovaries were clinically unremarkable. The induction of chemotherapy was postponed until after delivery. At 34 gestational weeks the patient underwent cesarean section and tumor debulking. Four cycles of bleomycin, etoposide and cisplatin were administered. After 12 months, cystic ovaries were found. Hysterectomy with bilateral adnexectomy was performed but no malignancy found. After 16 months, the patient was still in complete remission. CONCLUSION: We describe the first-ever published dysgerminoma in gravida primarily evolving intraabdominally and not affecting the ovaries. The decision for cytoreductive surgery, prolongation of pregnancy and postponing chemotherapy until after delivery combined the best benefit for the baby with a good maternal prognosis. Due to limited data regarding dysgerminomas in pregnancy, individual interdisciplinary concepts are mandatory.

Annealing of Gadolinium-Doped Ceria (GDC) Films Produced by the Aerosol Deposition Method.

Solid oxide fuel cells need a diffusion barrier layer to protect the zirconia-based electrolyte if a cobalt-containing cathode material like lanthanum strontium cobalt ferrite (LSCF) is used. This protective layer must prevent the direct contact and interdiffusion of both components while still retaining the oxygen ion transport. Gadolinium-doped ceria (GDC) meets these requirements. However, for a favorable cell performance, oxide ion conducting films that are thin yet dense are required. Films with a thickness in the sub-micrometer to micrometer range were produced by the dry room temperature spray-coating technique, aerosol deposition. Since commercially available GDC powders are usually optimized for the sintering of screen printed films or pressed bulk samples, their particle morphology is nanocrystalline with a high surface area that is not suitable for aerosol deposition. Therefore, different thermal and mechanical powder pretreatment procedures were investigated and linked to the morphology and integrity of the sprayed films. Only if a suitable pretreatment was conducted, dense and well-adhering GDC films were deposited. Otherwise, low-strength films were formed. The ionic conductivity of the resulting dense films was characterized by impedance spectroscopy between 300 °C and 1000 °C upon heating and cooling. A mild annealing occurred up to 900 °C during first heating that slightly increased the electric conductivity of GDC films formed by aerosol deposition.

A Normal Preoperative Lipase Serum Level Is an Easy and Objective Risk Factor of Pancreatic Fistula After Pancreaticoduodenectomy.

OBJECTIVES: The evaluation of the risk of postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy is crucial to optimize perioperative strategies. Many risk factors of POPF have been identified and were included in scores. Performances of these scores have to be improved because of the use of subjective and/or intraoperative factors. We tried to identify new risk factors of POPF that could improve the performance of validated scores. METHODS: We analyzed data from a prospective database of 191 consecutive patients who underwent a pancreaticoduodenectomy. Recorded data included a comprehensive inventory of pre-, intra- and postoperative clinical, biological and radiological data. RESULTS: The rate of POPF was significantly increased in patients with a normal preoperative lipase serum level (LSL) (29.8% vs 6.8%; P = 0.001). After multivariate analysis, a normal preoperative LSL was a strong independent risk factor of both POPF (odds ratio, 7.06; P = 0.001) and clinically relevant POPF (odds ratio, 3.11; P = 0.036). The addition of the normality of the preoperative LSL to the Fistula Risk Score significantly improved its performance (P < 0.001). CONCLUSIONS: A normal preoperative LSL was a strong, easy, and objective preoperative risk factor of POPF. Its addition to the Fistula Risk Score improved its performance and allows a more accurate evaluation of the risk of POPF.

The metalloproteinase ADAM8 promotes leukocyte recruitment in vitro and in acute lung inflammation.

Alveolar leukocyte recruitment is a hallmark of acute lung inflammation and involves transmigration of leukocytes through endothelial and epithelial layers. The disintegrin and metalloproteinase (ADAM) 8 is expressed on human isolated leukocytic cells and can be further upregulated on cultured endothelial and epithelial cells by proinflammatory cytokines. By shRNA-mediated knockdown we show that leukocytic ADAM8 is required on monocytic THP-1 cells for chemokine-induced chemotaxis as well as transendothelial and transepithelial migration. Furthermore, ADAM8 promotes αL-integrin upregulation and THP-1 cell adhesion to endothelial cells. On endothelial cells ADAM8 enhances transendothelial migration and increases cytokine-induced permeability. On epithelial cells the protease facilitates migration in a wound closure assay but does not affect transepithelial leukocyte migration. Blood leukocytes and bone marrow-derived macrophages (BMDM) from ADAM8-deficient mice show suppressed chemotactic response. Intranasal application of LPS to mice is accompanied with ADAM8 upregulation in the lung. In this model of acute lung inflammation ADAM8-deficient mice are protected against leukocyte infiltration. Finally, transfer experiments of BMDM in mice indicate that ADAM8 exerts a promigratory function predominantly on leukocytes. Our study provides in vitro and in vivo evidence that ADAM8 on leukocytes holds a proinflammatory function in acute lung inflammation by promoting alveolar leukocyte recruitment.

CXCL10 triggers early microglial activation in the cuprizone model.

A broad spectrum of diseases is characterized by myelin abnormalities and/or oligodendrocyte pathology. In most, if not all, of these diseases, early activation of microglia occurs. Our knowledge regarding the factors triggering early microglia activation is, however, incomplete. In this study, we used the cuprizone model to investigate the temporal and causal relationship of oligodendrocyte apoptosis and early microglia activation. Genome-wide gene expression studies revealed the induction of distinct chemokines, among them Cxcl10, Ccl2, and Ccl3 in cuprizone-mediated oligodendrocyte apoptosis. Early microglia activation was unchanged in CCL2- and CCL3-deficient knockouts, but was significantly reduced in CXCL10-deficient mice, resulting in an amelioration of cuprizone toxicity at later time points. Subsequent in vitro experiments revealed that recombinant CXCL10 induced migration and a proinflammatory phenotype in cultured microglia, without affecting their phagocytic activity or proliferation. In situ hybridization analyses suggest that Cxcl10 mRNA is mainly expressed by astrocytes, but also oligodendrocytes, in short-term cuprizone-exposed mice. Our results show that CXCL10 actively participates in the initiation of microglial activation. These findings have implications for the role of CXCL10 as an important mediator during the initiation of neuroinflammatory processes associated with oligodendrocyte pathology.

Nitric Oxide And Hypoxia Response In Pluripotent Stem Cells.

The expansion of pluripotent cells (ESCs and iPSCs) under conditions that maintain their pluripotency is necessary to implement a cell therapy program. Previously, we have described that low nitric oxide (NO) donor diethylenetriamine/nitric oxide adduct (DETA-NO) added to the culture medium, promote the expansion of these cell types. The molecular mechanisms are not yet known. We present evidences that ESC and iPSCs in normoxia in presence of low NO triggers a similar response to hypoxia, thus maintaining the pluripotency. We have studied the stability of HIF-1α (Hypoxia Inducible Factor) in presence of low NO. Because of the close relationship between hypoxia, metabolism, mitochondrial function and pluripotency we have analyzed by q RT-PCR the expression of genes involved in the glucose metabolism such as: HK2, LDHA and PDK1; besides other HIF-1α target gene. We further analyzed the expression of genes involved in mitochondrial biogenesis such as PGC1α, TFAM and NRF1 and we have observed that low NO maintains the same pattern of expression that in hypoxia. The study of the mitochondrial membrane potential using Mito-Tracker dye showed that NO decrease the mitochondrial function. We will analyze other metabolic parameters, to determinate if low NO regulates mitochondrial function and mimics Hypoxia Response. The knowledge of the role of NO in the Hypoxia Response and the mechanism that helps to maintain self-renewal in pluripotent cells in normoxia, can help to the design of culture media where NO could be optimal for stem cell expansion in the performance of future cell therapies.

Leukocytes require ADAM10 but not ADAM17 for their migration and inflammatory recruitment into the alveolar space.

Inflammation is a key process in various diseases, characterized by leukocyte recruitment to the inflammatory site. This study investigates the role of a disintegrin and a metalloproteinase (ADAM) 10 and ADAM17 for leukocyte migration in vitro and in a murine model of acute pulmonary inflammation. Inhibition experiments or RNA knockdown indicated that monocytic THP-1 cells and primary human neutrophils require ADAM10 but not ADAM17 for efficient chemokine-induced cell migration. Signaling and adhesion events that are linked to cell migration such as p38 and ρ GTPase-family activation, F-actin polymerization, adhesion to fibronectin, and up-regulation of α5 integrin were also dependent on ADAM10 but not ADAM17. This was confirmed with leukocytes isolated from mice lacking either ADAM10 or ADAM17 in all hematopoietic cells (vav 1 guanine nucleotide exchange factor [Vav]-Adam10(-/-) or Vav-Adam17(-/-) mice). In lipopolysaccharide-induced acute pulmonary inflammation, alveolar recruitment of neutrophils and monocytes was transiently increased in Vav-Adam17(-/-) but steadily reduced in Vav-Adam10(-/-) mice. This deficit in alveolar leukocyte recruitment was also observed in LysM-Adam10(-/-) mice lacking ADAM10 in myeloid cells and correlated with protection against edema formation. Thus, with regard to leukocyte migration, leukocyte-expressed ADAM10 but not ADAM17 displays proinflammatory activities and may therefore serve as a target to limit inflammatory cell recruitment.

Modern GERD treatment: feasibility of minimally invasive esophageal sphincter augmentation.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common chronic disease requiring adequate treatment since it represents one major cause of development of Barrett's esophagus and eventually carcinoma. Novel laparoscopic magnetic sphincter augmentation for GERD was evaluated prospectively. PATIENTS AND METHODS: A total of 23 patients with GERD underwent minimally invasive implantation of LINX™ Reflux Management System. Primary outcome measures were overall feasibility, short-term procedure safety and efficacy. Secondary GERD-related quality of life was assessed. RESULTS: All implantations were performed without serious adverse events. A significant decrease in all major GERD complaints were found: heartburn: 96%-22% (p<0.001); bloating: 70%-30% (p=0.006); respiratory complaints: 57%-17% (p=0.039); sleep disturbance: 65%-4% (p<0.001). A four-week follow-up reduction of ≥50% of proton pump inhibitor (PPI) dose was achieved in over 80% of patients. Self-limiting difficulty in swallowing was found in 70% within four weeks. One patient required for endoscopic dilation. GERD-related quality of life improved significantly. CONCLUSION: LINX™ implantation is a standardized, technically simple, safe and well-tolerated expeditious procedure.

Development of treatment and clinical results in childhood AML in Austria (1993-2013).

BACKGROUND: Since the early 1990s, three consecutive pediatric acute myeloid leukemia (AML) trials have been performed in Austria (AML-Berlin-Frankfurt-Münster (BFM) 93, AML-BFM 98, and AML-BFM 2004) in close cooperation with the international BFM study center. Herein, we review the pertinent patient characteristics, therapy, and outcome data. PATIENTS AND METHODS: From January 1993 to April 2013, 249 children and adolescents (193 protocol patients) diagnosed with AML were enrolled in the three BFM studies. Patients were mainly treated in one of five pediatric hematology/oncology centers distributed over Austria. RESULTS: Many characteristics and outcome parameters were not statistically different between the three trials. Almost similar proportions of patients were stratified into two risk groups: standard risk (SR) (approximately 37 % overall) and high-risk (HR) (61 %). MLL rearrangements were found in 23 % of patients overall as the most frequent genetic aberration subtype. Complete remission (CR) was achieved by 84-95 % of patients. The most important type of event was leukemic relapse (5-year cumulative incidence 40 ± 8 %, 21 ± 5 %, and 39 ± 6 %; p = 0.058), with a trend to a higher rate specifically in SR patients of study AML-BFM 2004 compared with AML-BFM 98. Importantly, the frequency of death from causes other than relapse sequelae declined over the years (AML-BFM 93: 5/42 12 %, AML-BFM 98: 5/57 9 %, and AML-BFM 2004: 5/94 5 %). Altogether, event-free survival at 5 years varied insignificantly (48 ± 8 %, 61 ± 7 %, and 50 ± 6 %; p = 0.406). Nevertheless, survival (pSU) apparently improved from BFM 93 to subsequent studies, both overall (57 ± 8 %, 75 ± 6 %, and 62 ± 6 %; p = 0.046) and regarding the HR group (5-year-probability of survival (pSU) 40 ± 10 %, 66 ± 8 %, and 52 ± 8 %; p = 0.039). CONCLUSION: Treatment of pediatric AML in Austria renders survival rates in the range of international best practice. However, unambiguous statistical comparison of treatment periods is eventually hampered by small numbers and inequalities of recruitment. Hence, only internationally collaborative trials will allow developing treatment further to achieve higher cure rates with fewer events.

Detection of PrP(Sc) in peripheral tissues of clinically affected cattle after oral challenge with bovine spongiform encephalopathy.

Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative prion disease that mainly affects cattle. Transmission of BSE to humans caused a variant form of Creutzfeldt-Jakob disease. Following infection, the protease-resistant, disease-associated isoform of prion protein (PrP(Sc)) accumulates in the central nervous system and in other tissues. Many countries have defined bovine tissues that may contain prions as specified risk materials, which must not enter the human or animal food chains and therefore must be discarded. Ultrasensitive techniques such as protein misfolding cyclic amplification (PMCA) have been developed to detect PrP(Sc) when present in minuscule amounts that are not readily detected by other diagnostic methods such as immunohistochemistry or Western blotting. This study was conducted to determine when and where PrP(Sc) can be found by PMCA in cattle orally challenged with BSE. A total of 48 different tissue samples from four cattle infected orally with BSE at various clinical stages of disease were examined using a standardized PMCA protocol. The protocol used brain homogenate from bovine PrP transgenic mice (Tgbov XV) as substrate and three consecutive rounds of PMCA. Using this protocol, PrP(Sc) was found in the brain, spinal cord, nerve ganglia, optic nerve and Peyer's patches. The presence of PrP(Sc) was confirmed in adrenal glands, as well as in mesenteric lymph nodes - a finding that was reported recently by another group. Interestingly, additional positive results were obtained for the first time in the oesophagus, abomasum, rumen and rectum of clinically affected cattle.

Elevated lipopolysaccharide in the colon evokes intestinal inflammation, aggravated in immune modulator-impaired mice.

Frequency of gram-negative bacteria is markedly enhanced in inflamed gut, leading to augmented LPS in the intestine. Although LPS in the intestine is considered harmless and, rather, provides protective effects against epithelial injury, it has been suggested that LPS causes intestinal inflammation, such as necrotizing enterocolitis. Therefore, direct effects of LPS in the intestine remain to be studied. In this study, we examine the effect of LPS in the colon of mice instilled with LPS by rectal enema. We found that augmented LPS on the luminal side of the colon elicited inflammation in the small intestine remotely, not in the colon; this inflammation was characterized by body weight loss, increased fluid secretion, enhanced inflammatory cytokine production, and epithelial damage. In contrast to the inflamed small intestine induced by colonic LPS, the colonic epithelium did not exhibit histological tissue damage or inflammatory lesions, although intracolonic LPS treatment elicited inflammatory cytokine gene expression in the colon tissues. Moreover, we found that intracolonic LPS treatment substantially decreased the frequency of immune-suppressive regulatory T cells (CD4(+)/CD25(+) and CD4(+)/Foxp3(+)). We were intrigued to find that LPS-promoted intestinal inflammation is exacerbated in immune modulator-impaired IL-10(-/-) and Rag-1(-/-) mice. In conclusion, our results provide evidence that elevated LPS in the colon is able to cause intestinal inflammation and, therefore, suggest a physiological explanation for the importance of maintaining the balance between gram-negative and gram-positive bacteria in the intestine to maintain homeostasis in the gut.