Prophylactic salpingectomy for prevention of ovarian cancer at the time of elective laparoscopic cholecystectomy.

BACKGROUND: Most serous ovarian cancers are now understood to originate in the fallopian tubes. Removing the tubes (salpingectomy) likely reduces the risk of developing high-grade serous ovarian cancer. Numerous gynaecological societies now recommend prophylactic (or opportunistic) salpingectomy at the time of gynaecological surgery in appropriate women, and this is widely done. Salpingectomy at the time of non-gynaecological surgery has not been explored and may present an opportunity for primary prevention of ovarian cancer. METHODS: This study investigated whether prophylactic salpingectomy with the intention of reducing the risk of developing ovarian cancer would be accepted and could be accomplished at the time of elective laparoscopic cholecystectomy. Women aged at least 45 years scheduled for elective laparoscopic cholecystectomy were recruited. They were counselled and offered prophylactic bilateral salpingectomy at the time of cholecystectomy. Outcome measures were rate of accomplishment of salpingectomy, time and procedural steps needed for salpingectomy, and complications. RESULTS: A total of 105 patients were included in the study. The rate of acceptance of salpingectomy was approximately 60 per cent. Salpingectomy was performed in 98 of 105 laparoscopic cholecystectomies (93·3 per cent) and not accomplished because of poor visibility or adhesions in seven (6·7 per cent). Median additional operating time was 13 (range 4-45) min. There were no complications attributable to salpingectomy. One patient presented with ovarian cancer 28 months after prophylactic salpingectomy; histological re-evaluation of the tubes showed a previously undetected, focal serous tubal intraepithelial carcinoma. CONCLUSION: Prophylactic salpingectomy can be done during elective laparoscopic cholecystectomy.

ANTECEDENTES: La mayoría de carcinomas serosos de ovario se originan en las trompas de Falopio. La exéresis de las trompas (salpingectomía) probablemente reduce el riesgo de desarrollar un carcinoma seroso ovárico de alto grado. Numerosas sociedades ginecológicas recomiendan efectuar una salpingectomía profiláctica (u oportunista) en el momento de una cirugía ginecológica en determinadas mujeres, y esta conducta está ampliamente difundida. Sin embargo, no se ha analizado la realización de la salpingectomía durante cirugías no ginecológicas como forma de prevención primaria del carcinoma ovárico. MÉTODOS: Determinar si la salpingectomía profiláctica con intención de reducir el riesgo de desarrollar cáncer de ovario sería aceptada y podría llevarse a cabo durante una colecistectomía laparoscópica electiva. Se reclutaron mujeres ≥ 45 años de edad programadas para colecistectomía laparoscópica electiva. A todas ellas se les aconsejó y ofreció la realización de una salpingectomía bilateral profiláctica en el momento de su colecistectomía. Las variables analizadas fueron la tasa de realización de la salpingectomía, la duración y las etapas quirúrgicos para efectuar este procedimiento, y las complicaciones. RESULTADOS: La aceptación de la salpingectomía fue aproximadamente del 60%. La salpingectomía se realizó en 98 de 105 colecistectomías laparoscópicas (93%) y no se pudo realizar en 7 pacientes (7%) por escasa visibilidad o adherencias. La mediana del tiempo quirúrgico adicional fue de 13 (rango 4-45) minutos. No hubo complicaciones atribuibles a la salpingectomía. Una paciente presentó cáncer de ovario 28 meses después de la salpingectomía profiláctica; la reevaluación histológica de las trompas mostró un carcinoma intraepitelial seroso focal tubárico (serous tubal intraepithelial carcinoma, STIC) no detectado previamente. CONCLUSIÓN: La salpingectomía profiláctica se puede realizar durante la colecistectomía laparoscópica electiva.

CRISPR-Cas9: A New Addition to the Drug Metabolism and Disposition Tool Box.

Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein 9 (Cas9), i.e., CRISPR-Cas9, has been extensively used as a gene-editing technology during recent years. Unlike earlier technologies for gene editing or gene knockdown, such as zinc finger nucleases and RNA interference, CRISPR-Cas9 is comparably easy to use, affordable, and versatile. Recently, CRISPR-Cas9 has been applied in studies of drug absorption, distribution, metabolism, and excretion (ADME) and for ADME model generation. To date, about 50 papers have been published describing in vitro or in vivo CRISPR-Cas9 gene editing of ADME and ADME-related genes. Twenty of these papers describe gene editing of clinically relevant genes, such as ATP-binding cassette drug transporters and cytochrome P450 drug-metabolizing enzymes. With CRISPR-Cas9, the ADME tool box has been substantially expanded. This new technology allows us to develop better and more predictive in vitro and in vivo ADME models and map previously underexplored ADME genes and gene families. In this mini-review, we give an overview of the CRISPR-Cas9 technology and summarize recent applications of CRISPR-Cas9 within the ADME field. We also speculate about future applications of CRISPR-Cas9 in ADME research.

Caco-2 cells - expression, regulation and function of drug transporters compared with human jejunal tissue.

BACKGROUND: Induction or inhibition of drug transporting proteins by concomitantly administered drugs can cause serious drug-drug interactions (DDIs). However, in vitro assays currently available are mostly for studying the inhibitory potential of drugs on intestinal transporter proteins, rather than induction. Therefore, this study investigated the suitability of the frequently used intestinal Caco-2 cell line to predict transporter-mediated DDIs as caused by induction via activation of nuclear receptors. METHODS: TaqMan® low density arrays and LC-MS/MS based targeted proteomics were used to evaluate transporter expression in Caco-2 cells in comparison with jejunal tissue, in culture-time dependence studies and after incubation with different known inducers of drug metabolism and transport. Additionally, studies on ABCB1 function were performed using Transwell® assays with [3 H]-digoxin and [3 H]-talinolol as substrates after incubation with the prototypical inducers rifampicin, St John's wort, carbamazepine and efavirenz. RESULTS: The gene and protein expression pattern of drug transporters in Caco-2 cells and jejunal tissue differed considerably. For some transporters culture-time dependent differences in mRNA expression and/or protein abundance could be determined. Finally, none of the studied prototypical inducers showed an effect either on mRNA expression and protein abundance or on the function of ABCB1. CONCLUSION: Differences in transporter expression in Caco-2 cells compared with jejunal tissue, as well as expression dependence on culture time must be considered in in vitro studies to avoid under- or overestimation of certain transporters. The Caco-2 cell model is not suitable for the evaluation of DDIs caused by transporter induction. Copyright © 2016 John Wiley & Sons, Ltd.

[Catheter-related thrombosis during intravascular temperature management]. / Katheterthrombose während intravaskulärem Temperaturmanagement.

We report on a case of catheter-related thrombosis after 7­day catheter placement during intravascular temperature management (IVTM), in spite of the use of prophylactic anticoagulants. There were no clinical sequelae. According to the literature, occult thrombosis during ITVM could be more frequent than previously reported and dedicated monitoring for potential thrombosis may be indicated. However, a study comparing IVTM with surface cooling found no differences in clinical outcome. Therefore, n either of the methods can be recommended over the other. Further studies should evaluate the rate of occult thrombosis during the use of both cooling methods.

Thin film growth of Fe-based superconductors: from fundamental properties to functional devices. A comparative review.

Fe-based superconductors bridge a gap between MgB2 and the cuprate high temperature superconductors as they exhibit multiband character and transition temperatures up to around 55 K. Investigating Fe-based superconductors thus promises answers to fundamental questions concerning the Cooper pairing mechanism, competition between magnetic and superconducting phases, and a wide variety of electronic correlation effects. The question addressed in this review is, however, is this new class of superconductors also a promising candidate for technical applications? Superconducting film-based technologies range from high-current and high-field applications for energy production and storage to sensor development for communication and security issues and have to meet relevant needs of today's society and that of the future. In this review we will highlight and discuss selected key issues for Fe-based superconducting thin film applications. We initially focus our discussion on the understanding of physical properties and actual problems in film fabrication based on a comparison of different observations made in the last few years. Subsequently we address the potential for technological applications according to the current situation.

Automated regenerable microarray-based immunoassay for rapid parallel quantification of mycotoxins in cereals.

An automated flow-through multi-mycotoxin immunoassay using the stand-alone Munich Chip Reader 3 platform and reusable biochips was developed and evaluated. This technology combines a unique microarray, prepared by covalent immobilization of target analytes or derivatives on diamino-poly(ethylene glycol) functionalized glass slides, with a dedicated chemiluminescence readout by a CCD camera. In a first stage, we aimed for the parallel detection of aflatoxins, ochratoxin A, deoxynivalenol, and fumonisins in cereal samples in a competitive indirect immunoassay format. The method combines sample extraction with methanol/water (80:20, v/v), extract filtration and dilution, and immunodetection using horseradish peroxidase-labeled anti-mouse IgG antibodies. The total analysis time, including extraction, extract dilution, measurement, and surface regeneration, was 19 min. The prepared microarray chip was reusable for at least 50 times. Oat extract revealed itself as a representative sample matrix for preparation of mycotoxin standards and determination of different types of cereals such as oat, wheat, rye, and maize polenta at relevant concentrations according to the European Commission regulation. The recovery rates of fortified samples in different matrices, with 55-80 and 58-79%, were lower for the better water-soluble fumonisin B1 and deoxynivalenol and with 127-132 and 82-120% higher for the more unpolar aflatoxins and ochratoxin A, respectively. Finally, the results of wheat samples which were naturally contaminated with deoxynivalenol were critically compared in an interlaboratory comparison with data obtained from microtiter plate ELISA, aokinmycontrol® method, and liquid chromatography-mass spectrometry and found to be in good agreement.

Developments in nanostructured LiMPO4 (M = Fe, Co, Ni, Mn) composites based on three dimensional carbon architecture.

Nanostructured materials lie at the heart of fundamental advances in efficient energy storage and/or conversion, in which surface processes and transport kinetics play determining roles. This review describes recent developments in the synthesis and characterization of composites which consist of lithium metal phosphates (LiMPO(4), M = Fe, Co, Ni, Mn) coated on nanostructured carbon architectures (unordered and ordered carbon nanotubes, amorphous carbon, carbon foams). The major goal of this review is to highlight new progress in using different three dimensional nanostructured carbon architectures as support for the phosphate based cathode materials (e.g.: LiFePO(4), LiCoPO(4)) of high electronic conductivity to develop lithium batteries with high energy density, high rate capability and excellent cycling stability resulting from their huge surface area and short distance for mass and charge transport.

Intracerebral gadolinium deposition following blood-brain barrier disturbance in two different mouse models.

To evaluate the influence of the blood-brain barrier on neuronal gadolinium deposition in a mouse model after multiple intravenous applications of the linear contrast agent gadodiamide. The prospective study held 54 mice divided into three groups: healthy mice (A), mice with iatrogenic induced disturbance of the blood-brain barrier by glioblastoma (B) or cerebral infarction (C). In each group 9 animals received 10 iv-injections of gadodiamide (1.2 mmol/kg) every 48 h followed by plain T1-weighted brain MRI. A final MRI was performed 5 days after the last contrast injection. Remaining mice underwent MRI in the same time intervals without contrast application (control group). Signal intensities of thalamus, pallidum, pons, dentate nucleus, and globus pallidus-to-thalamus and dentate nucleus-to-pons ratios, were determined. Gadodiamide complex and total gadolinium amount were quantified after the last MR examination via LC-MS/MS and ICP-MS. Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios showed no significant increase over time within all mice groups receiving gadodiamide, as well as compared to the control groups at last MR examination. Comparing healthy mice with group B and C after repetitive contrast administration, a significant SI increase could only be detected for glioblastoma mice in globus pallidus-to-thalamus ratio (p = 0.033), infarction mice showed no significant SI alteration. Tissue analysis revealed significantly higher gadolinium levels in glioblastoma group compared to healthy (p = 0.013) and infarction mice (p = 0.029). Multiple application of the linear contrast agent gadodiamide leads to cerebral gadolinium deposition without imaging correlate in MRI.

XPS investigations of electrolyte/electrode interactions for various Li-ion battery materials.

For future Li-ion battery applications the search for both new design concepts and materials is necessary. The electrodes of the batteries are always in contact with electrolytes, which are responsible for the transport of Li ions during the charging and discharging process. A broad range of materials is considered for both electrolytes and electrodes so that very different chemical interactions between them can occur, while good cycling behavior can only be obtained for stable solid-electrolyte interfaces. X-ray photoelectron spectroscopy (XPS) was used to study the most relevant interactions between various electrode materials in contact with different electrolyte solutions. It is shown how XPS can provide useful information on reactivities and thus preselect suitable electrode/electrolyte combinations, prior to electrochemical performance tests.

Delivery of carboplatin by carbon-based nanocontainers mediates increased cancer cell death.

Since the activity of several conventional anticancer drugs is restricted by resistance mechanisms and dose-limiting side-effects, the design of nanocarriers seems to be an efficient and promising approach for drug delivery. Their chemical and mechanical stability and their possible multifunctionality render tubular nanomaterials, such as carbon nanotubes (CNTs) and carbon nanofibres (CNFs), promising delivery agents for anticancer drugs. The goal of the present study was to investigate CNTs and CNFs in order to deliver carboplatin in vitro. No significant intrinsic toxicity of unloaded materials was found, confirming their biocompatibility. Carboplatin was loaded onto CNTs and CNFs, revealing a loading yield of 0.20 mg (CNT-CP) and 0.13 mg (CNF-CP) platinum per milligram of material. The platinum release depended on the carrier material. Whereas CNF-CP marginally released the drug, CNT-CP functioned as a drug depot, constantly releasing up to 68% within 14 days. The cytotoxicity of CNT-CP and CNF-CP in urological tumour cell lines was dependent on the drug release. CNT-CP was identified to be more effective than CNF-CP concerning the impairment of proliferation and clonogenic survival of tumour cells. Moreover, carboplatin, which was delivered by CNT-CP, exhibited a higher anticancer activity than free carboplatin.

Application of angle-resolved X-ray photon electron spectroscopy for interface and layer growth studies demonstrated on Ti/Ta-based films deposited on SiO2.

X-ray photoelectron spectroscopy (XPS) is one of the main methods for elemental and bonding-state characterization in the near-surface region. Applying it as angle-resolved XPS (ARXPS), it is promising for non-destructive depth profiling in the nanometre-thickness range. The challenges for the application of ARXPS are discussed for the early film growth of Ti and Ta on SiO(2) produced by in situ magnetron sputtering. The measurements showed several phase-formation processes at the interfaces, which were used as the basis for the ARXPS data analysis and resulted in different interlayer growth information for Ti and Ta. From a systematic ARXPS data interpretation in combination with simulations, limits of the method are critically discussed.

Oxygen nonstoichiometry of tetragonal La2-xSr(x)CuO4-δ (x = 0.15-1.2) and in situ XPS studies at elevated temperatures.

The peculiarities of oxygen nonstoichiometry (δ) in tetragonal La(2-x)Sr(x)CuO(4-δ) solid solution with x(Sr) = 0.15-1.2 were studied by XRD, NPD, in situ high-temperature XPS, and chemical analysis. Temperature dependences of oxygen nonstoichiometry, δ = δ(T), were obtained for different Sr contents at 1 bar of O(2). Two types of charge compensation during replacement of lanthanum by strontium are discussed: an increase of the average copper oxidation state and a formation of oxygen vacancies. The average copper oxidation state V(Cu) exhibits a maximum of 2.32 at x(Sr) = 0.6, while δ increases with x(Sr). Oxygen vacancies are unambiguously located on the 4c site ({CuO(2)} plane) for compositions with different strontium contents, which electronic state is described by the O 2p core electron peak at about 531 eV. Thermal stability of the solid solution in a vacuum is associated with the extraction of practically the entire oxygen from CuO(2) layers and the formation of Cu(+) at least in the near-surface region. The higher average copper oxidation state after synthesis in the Sr-rich phases in comparison with the Sr-poor compositions prevents oxygen removal and the formation of Cu(+) and, therefore, stabilizes the structure during heating in a vacuum.

How is wettability of titanium surfaces influenced by their preparation and storage conditions?

The effect of two different etching procedures with inorganic acids (HSE and CSE)-one using additionally strongly oxidising conditions due to the presence of CrO(3) (CSE)-and consecutive storage conditions (dry methanol and air) for previous corundum blasted titanium surfaces is compared with respect to their wettability behaviour and the potential of the etching processes for removing remaining blasting material. The etching procedures result in distinct different surface morphologies. Whereas the HSE surface shows sub-mm to sub-mum structures but neither porosity nor undercuts, the CSE surface is extremely rugged and porous with structures protruding the more homogeneously attacked areas by several micrometers. By EDX analysis both remaining blasting material and chromium and sulphur from the etching treatment has been detected on the CSE surfaces only. Both surfaces states show super-hydrophilic behaviour immediately after etching and storage up to 28 days in dry methanol. Whereas contact with air does not change super-hydrophilicity for the CSE samples, wettings angles of the HSE samples increase within minutes and reach about angles of about 60 degrees and 90 degrees after one and 2 days exposure to air, respectively. The increasing hydrophobicity is discussed with respect to the formation of a surface coverage from hydrocarbons originating from aromatic compounds present in traces in air.

Quasi in situ XPS investigations on intercalation mechanisms in Li-ion battery materials.

New concepts for Li-ion batteries are of growing interest for high-performance applications. One aim is the search for new electrode materials with superior properties and their detailed characterization. We demonstrate the application of X-ray photoelectron spectroscopy (XPS) to investigate electrode materials (LiCoO(2), LiCrMnO(4)) during electrochemical cycling. The optimization of a "quasi in situ" analysis, by transferring the samples with a transport chamber from the glove box to the XPS chamber, and the reliability of the experiments performed are shown. The behavior of characteristic chemical species at the electrodes and the changes in oxidation states of LiCrMnO(4) during cycling is discussed. The formation of Cr(6+) is suspected as a possible reason for irreversible capacity loss during charging up to complete Li deintercalation (approximately 5.2 V).

Application of FTIR spectra for evaluating interfacial reactions in metal matrix composites.

Manufacturing of Saffil/MgLi metal matrix composites by the melt infiltration process is accompanied by extensive interfacial redox reaction between delta-Al(2)O(3) fibers (Saffil) and lithium. The present paper deals with the Fourier transform infrared spectroscopy examination of Saffil fibers isolated from Mg-8 wt% Li alloy by the bromine/methylacetate agent focusing on the insertion of Li(+) ions into delta-Al(2)O(3) and their influence on water adsorption. Insertion of Li(+) into delta-Al(2)O(3) is monitored by gradual change of Al-O stretching bands (400-900 cm(-1)) towards more simple patterns of a spinel-like product assigned as delta(Li) which transforms to LiAl(5)O(8) during subsequent annealing. Rapid increase in the water adsorption with increase in Li content, indicated by the changes in H-O-H bending (about 1,650 cm(-1)) and O-H stretching (about 3,500 cm(-1)), is connected with the ionicity of the delta(Li) phase, which attracts polar water molecules.

Fracture configurations of the equine radius and tibia after a simulated kick.

The objective of this postmortem study was to determine the fracture configurations of the equine radius and tibia after a simulated kick. Fracture configurations of 35 radii and 36 tibiae from 19 adult horses were evaluated after a simulated kick in an experimental ex-vivo study. The bones were dissected, the proximal and distal ends were embedded in resin, fixed horizontally and preloaded in compression, and a steel impactor, designed to simulate a shod equine hoof, was dropped from a height of three to six metres onto the diaphysis. The experiments were filmed with a high-speed camera (30,000 pictures/second). The bones were then photographed and radiographed using a C-arm based 3D imaging device. A software programme (Osirix) was used to reconstruct the fissured and fractured bones three-dimensionally on a computer screen for assessment of the fracture configuration and fissure lines. Incomplete fractures occurred in 26 bones and complete fractures in 42. The complete fractures included 22 butterfly and 20 simple fractures; the latter included 17 oblique, two transverse and one longitudinal fracture. Additional longitudinal fissures occurred in 98% of the fractures. The butterfly fragment was always located on the side opposite the impact. There was a significant correlation between the type of bone and the fracture configuration: butterfly and oblique fractures occurred more frequently in the tibia, and incomplete fractures occurred more frequently in the radius. The data collected can be used to optimize evaluation of fractures and fissures caused by a kick and thereby improve surgical stabilization.

Intestinal and hepatic contributions to the pharmacokinetic interaction between gamithromycin and rifampicin after single-dose and multiple-dose administration in healthy foals.

BACKGROUND: Standard treatment of foals with severe abscessing lung infection caused by Rhodococcus equi using rifampicin and a macrolide antibiotic can be compromised by extensive inhibition and/or induction of drug metabolising enzymes (e.g. CYP3A4) and transport proteins (e.g. P-glycoprotein), as has been shown for rifampicin and clarithromycin. The combination of rifampicin with the new, poorly metabolised gamithromycin, a long-acting analogue of azithromycin and tulathromycin with lower pharmacokinetic interaction potential, might be a suitable alternative. OBJECTIVES: To evaluate the pharmacokinetic interactions and pulmonary distribution of rifampicin and gamithromycin in healthy foals, and to investigate the cellular uptake of gamithromycin in vitro. STUDY DESIGN: Controlled, four-period, consecutive, single-dose and multiple-dose study. METHODS: Pharmacokinetics and lung distribution of rifampicin (10 mg/kg) and gamithromycin (6 mg/kg) were measured in nine healthy foals using LC-MS/MS. Enzyme induction was confirmed using the 4ß-OH-cholesterol/cholesterol ratio. Affinity of gamithromycin to drug transport proteins was evaluated in vitro using equine hepatocytes and MDCKII-cells stably transfected with human OATP1B1, OATP1B3 and OATP2B1. RESULTS: Rifampicin significantly (P<0.05) increased the plasma exposure of gamithromycin (16.2 ± 4.77 vs. 8.57 ± 3.10 µg × h/mL) by decreasing the total body clearance. Otherwise, gamithromycin significantly lowered plasma exposure of single- and multiple-dose rifampicin (83.8 ± 35.3 and 112 ± 43.1 vs. 164 ± 96.7 µg × h/mL) without a change in metabolic ratio and half-life. Gamithromycin was identified as an inhibitor of human OATP1B1, OATP1B3 and OATP2B1 and as a substrate of OATP2B1. In addition, it was extracted by equine hepatocytes via a mechanism which could be inhibited by rifampicin. MAIN LIMITATIONS: Influence of gamithromycin on pulmonary distribution of rifampicin was not evaluated. CONCLUSION: The plasma exposure of gamithromycin is significantly increased by co-administration of rifampicin which is most likely caused by inhibition of hepatic elimination.

An interspecific test of allen's rule: evolutionary implications for endothermic species.

Ecogeographical rules provide potential to describe how organisms are morphologically constrained to climatic conditions. Allen's rule (relatively shorter appendages in colder environments) remains largely unsupported and there remains much controversy whether reduced surface area of appendages provides energetic savings sufficient to make this morphological trend truly adaptive. By showing for the first time that Allen's rule holds for closely related endothermic species, we provide persuasive support of the adaptive significance of this trend for multiple species. Our results indicate that reduction of thermoregulatory cost during the coldest part of the breeding season is the most likely mechanism driving Allen's rule for these species. Because for 54% of seabird species examined, rise in seasonal maximum temperature over 100 years will exceed that for minimum temperatures, an evolutionary mismatch will arise between selection for limb length reduction and ability to accommodate heat stress.