Newer Oral Anticoagulants in the Treatment of Acute Portal Vein Thrombosis in Patients with and without Cirrhosis.

BACKGROUND: Newer oral anticoagulants (NOACs) are being utilized increasingly for the treatment of venous thromboembolism (VTE). NOAC use is the standard of care for stroke prophylaxis in nonvalvular atrial fibrillation and treatment of acute VTE involving extremities and pulmonary embolism. In contrast, most guidelines in the literature support the treatment of acute portal vein thrombosis (PVT) with low molecular weight heparin (LMWH) and vitamin K antagonists (VKA). Literature evaluating NOAC use in the treatment of acute portal vein thrombosis is sparse. This review focuses on the safety and efficacy of the use of NOACs in the treatment of acute PVT in patients, with or without concomitant cirrhosis, based on the most recent data available in the current literature. METHODS: A systematic review was conducted through a series of advanced searches in the following medical databases: PubMed, BioMed Central, Cochrane, and Google Scholar. Keywords utilized were as follows: NOAC, DOAC (direct oral anticoagulants), portal vein thrombosis, rivaroxaban, apixaban, dabigatran, and edoxaban. Articles related to newer anticoagulant use in patients with portal vein thrombosis were included. RESULTS: The adverse events, including bleeding events (major and minor) and the failure of anticoagulation (propagation of thrombus or recurrence of PVT), are similar between the NOACs and traditional anticoagulants for the treatment of acute PVT, irrespective of the presence of cirrhosis. CONCLUSIONS: Newer oral anticoagulants are safe and efficacious alternatives to traditional anticoagulation with low molecular weight heparin and vitamin K antagonists in the treatment of acute portal vein thrombosis with or without cirrhosis.

Impact of the spacer on the condensing effect of fluorinated chains investigated by grazing incidence X-ray diffraction on ultrathin Langmuir monolayers.

Langmuir monolayers of double perfluoroalkyl(alkyl) chain amphiphiles fitted with a monomorpholinophosphate polar head, [C(n)F(2n+1)(CH(2))(m)O](2)P(O)[N(CH(2)CH(2))(2)O] (di(FnHm)MP with n = 6, 8, or 9; and m = 1 or 2), were investigated by surface pressure (π)/molecular area (A(0)) compression isotherms for temperatures ranging from 15 to 50 °C, and by grazing-incidence X-ray diffraction (GIXD) at 25 °C. Ultrathin monolayers were obtained for these short surfactants. Though the hydrocarbon spacer is short, it has a remarkable impact on the monolayer's organization. At 25 °C, whereas di(F8H2)MP monolayer presents a liquid expanded (LE)/liquid condensed (LC) transition, simply replacing one CH(2) by a CF(2) in the latter compound's structure at constant chain length, i.e. shortening the spacer from 2 to 1 CH(2) (as in di(F9H1)MP), suppresses the LE phase. At 25°, GIXD established that for both di(F8H2)MP and di(F9H1)MP, the chains form an hexagonal lattice in the LC phase. The collective tilt of the two compounds is close to zero. The lattice of the dense phase can be compressed, as assessed by the continuous linear decrease of the d spacing with increasing pressure. This indicates that the azimuthal distribution of the molecular tilts is progressively reduced upon compression. The d value for di(F9H1)MP is significantly lower than that of di(F8H2)MP, providing evidence for strong condensing effect of the fluorinated chains. Molecular areas were determined directly from the compression curves and also from the X-ray data, the latter allowing reconstruction of the compression isotherms. The calculated lattice compressibilities are ~30% and 50% of the macroscopic compressibilities for di(F9H1)MP and di(F8H2)MP, respectively. Comparison with the experimentally determined isotherms shows that the monolayer of di(F9H1)MP is more stable than that of di(F8H2)MP. The enthalpies and entropies determined for di(F9H1)MP and di(F8H2)MP, derived from the Clausius-Clapeyron equation, confirm that the observed transitions are both of the LE/LC type, although the triple point temperatures are strikingly different (27 °C vs -18 °C); this large difference further illustrates the stabilizing effect of the fluorinated chains. Disorder is hindered by the fluorinated chains and facilitated by a hydrocarbon spacer when larger than 1 CH(2).

Perfluorocarbon emulsions prevent hypoxia of pancreatic ß-cells.

As oxygen carriers, perfluorocarbon emulsions might be useful to decrease hypoxia of pancreatic islets before transplantation. However, their hydrophobicity prevents their homogenisation in culture medium. To increase the surface of contact between islets and Perfluorooctyl bromide (PFOB), and consequently oxygen delivery, we tested effect of a PFOB emulsion in culture medium on ß-cell lines and rat pancreatic islets. RINm5F ß-cell line or pancreatic rat islets were incubated for 3 days in the presence of PFOB emulsion in media (3.5% w/v). Preoxygenation of the medium was performed before culture. Cell viability was assessed by apoptotic markers (Bax and Bcl-2) and by staining (fluoresceine diacetate and propidium iodide). ß-Cell functionality was determined by insulin release during a glucose stimulation test and. Hypoxia markers, HIF-1α and VEGF, were studied at days 1 and 3 using RT-PCR, Western blotting, and ELISA. PFOB emulsions preserved viability and functionality of RINm5F cells with a decrease of HIF-1α and VEGF expression. Islets viability was preserved during 3 days of culture. Secretion of VEGF was higher in untreated control (0.09 ± 0.041 µg VEGF/mg total protein) than in PFOB emulsion incubated islets (0.02 ± 0.19 µg VEGF/mg total protein, n = 4, p < 0.05) at day 1. At day 3, VEGF secretion was increased as compared to day 1 in control (0.23 ± 0.04 µg VEGF/mg total protein) but it was imbalance by the presence of PFOB emulsion (0.09 ± 0.03 µg VEGF/mg total protein, n = 5, p < 0.05). While insulin secretion was maintained in response to a glucose stimulation test until day 3 when islets were incubated in the presence of PFOB emulsion preoxygenated (0.81 ± 0.16 at day 1 vs. 0.75 ± 0.24 at day 3), the ability to secrete insulin in the presence of high glucose concentration was lost in islets controls (0.51 ± 0.18 at day 1 vs. 0.21 ± 0.13 at day 3). Atmospheric oxygen delivery by PFOB emulsion might be sufficient to decrease islets hypoxia. However, to improve islets functionality, overoxygenation is needed. Finally, maintenance of islet viability and functionality for several days after isolation could improve the outcome of islets transplantation.

The properties of Safety Performance Indicators in target setting, projections and safety design of the road transport system.

Road traffic Safety Performance Indicators (SPIs) are becoming increasingly used as an instrument for the planning and monitoring of safety progress. SPIs form an intermediate step between actions and final outcome in terms of casualties in road crashes. It is understood that SPIs are closely related to outcome; and that it is also possible to use them in calculations and predictions of both actions and final outcome. In the present study, it was found that some of the properties assigned to SPIs could be questioned. An assumption of linearity between SPIs and final outcome was partly rejected. It was also found that 100% fulfillment of a set of SPIs could lead to very low mortality, demonstrating the importance of handling SPIs simultaneously.

Improved in vivo two-photon imaging after blood replacement by perfluorocarbon.

Two-photon microscopy is a powerful method in biomedical research that allows functional and anatomical imaging at a subcellular resolution in vivo. The technique is seriously hampered by absorption and scattering of light by blood, which prevents imaging through large vessels. Here, we demonstrate in the rat cerebral cortex that blood replacement by perfluorocarbon emulsion, a compound also used in human critical care medicine, yields superior image quality, while preserving neuronal integrity. Shadows of large superficial vessels disappear completely and cells can be imaged underneath them. For the first time, it is possible to image complete populations of neurons and astrocytes in the upper layers of neocortex in vivo.

Perfluorocarbons: new tool for islets preservation in vitro.

Pancreatic islet transplantations to treat type 1 diabetes often fail to function because of hypoxia. Perfluorocarbons (PFCs) exhibit a high oxygen solubility coefficient and maintain high oxygen partial pressure for extended times. They also serve as oxygen "reservoirs" for harvested organs in pancreas organ transplantation. Previous studies have shown the PFCs display antiadhesive effects on beta cells. The aim of this study was to evaluate the effects of PFC on islet viability and functionality and on extracellular matrix (ECM) disruption of islets via inhibition of adhesion. Primary cultures of rat islets were incubated for 24 hours in the presence or absence of 3.5% (weight/volume) PFCs in culture media. We studied viability (FDA/PI), stimulation index linked to insulin secretion (ELISA), and expression of insulin and laminin messenger RNAs (mRNAs). Immunostaining was performed on insulin and laminin. Islet viability was similar in the presence or absence of PFCs (about 80%). Stimulation index showed preservation of islet functionality in the presence of PFC (4.9 +/- 0.7) as compared with controls (2.8 +/- 0.5). Moreover, laminin mRNA expression was lower compared with controls (55% of PFC incubated vs control islets). Immunohistochemistry studies showed preservation of ECM inside the islets in the presence of PFCs versus controls at 24 hours after islet isolation. In conclusion, PFCs preserved islet viability and functionality and prevented ECM disruption. PFCs may represent a new tool for islet preservation in vitro.

In vivo evaluation of a reverse water-in-fluorocarbon emulsion stabilized with a semifluorinated amphiphile as a drug delivery system through the pulmonary route.

The potential of a reverse water-in-fluorocarbon (w-in-FC) emulsion stabilized with a semifluorinated amphiphile, namely C8F17(CH2)11OP(O)[N(CH2CH2)2O]2 (F8H11DMP) for drug delivery through intrapulmonary administration was investigated in the mouse. This study involved assessment of the effect of single or repeated intranasal instillations of a plain emulsion on lung tissue integrity, and evaluation of blood glucose levels in mice treated with an insulin-loaded emulsion. When instilled intranasally to mice, the plain emulsion did not alter lung tissue integrity, as demonstrated by histological staining, and did not induce any airway inflammatory reaction. Treated mice exhibited decreased body weight within the 3-4 days that followed the first emulsion administration, but this decrease was reversible within few days. Mice instilled intranasally with the insulin-loaded emulsion displayed decreased blood glucose levels within the 20 min that followed the administration, thus demonstrating the potential of the reverse w-in-FC emulsion stabilized with F8H11DMP to systemically deliver drugs, including peptides, upon lung administration.

Evaluation of cytotoxicity of new semi-fluorinated amphiphiles derived from dimorpholinophosphate.

Water-in-fluorocarbon reverse emulsions and microemulsions stabilized by semi-fluorinated amphiphiles derived from the dimorpholinophosphate polar head group, C(n)F(2n+1)(CH(2))(m)OP(O)[N(CH(2)CH(2))(2)O](2) (FnHmDMP), are being investigated as new delivery systems for drugs or genetic materials into the lung. Since information related to the toxicity of fluorinated surfactants is still very limited, we evaluated herein the cytotoxicity of a series of FnHmDMP (n=4, 6, 8 and 10 and m=2, 5, and 11). Both solutions of FnHmDMP in fluorocarbons, and reverse water-in-fluorocarbon emulsions stabilized by FnHmDMP were assessed in order to determine the relation between surfactant structure and cell toxicity, and select the most innocuous emulsifier. A first short-term evaluation on mouse fibroblasts using a viability/cytotoxicity assay indicated that amphiphiles (in solution) with a chain length longer than C12 exhibit less toxicity than amphiphiles with shorter chain. Moreover cytotoxicity decreased also with length of the fluorinated segment. The protective effect of the fluorinated chain was strongly supported by the fact that the hydrogenated analog, C(15)H(31)OP(O)[N(CH(2)CH(2))(2)O](2) (H15DMP), was highly toxic. Qualitative evaluation on human lung epithelial cells (HLEC) using a colorimetric method (Mayer's hematoxylin) confirmed that amphiphiles (in solution) with longer chain were the least cytotoxic. The protective effect of the fluorinated chain appeared, however, to be significant only at low amphiphile concentrations (0.1% w/v). In contrast, at higher concentrations (1% and 5% w/v), the total chain length was the determining factor. Quantitative evaluation of the least cytotoxic amphiphiles using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method then showed that F10H11DMP (in solution) was harmless until its solubility limit (1% w/v); cell growth was even enhanced due to improved oxygenation provided by the fluorocarbon phase. F8H11DMP exhibited some cytotoxicity at both 1% and 5% w/v, but the toxicity appeared to level off with concentration. Reverse water-in-perfluorooctyl bromide (PFOB) emulsions stabilized by either F10H11DMP or F8H11DMP were found to be non-cytotoxic. In conclusion, the present evaluation indicates that the cytotoxicity of FnHmDMP depends on both total and fluorinated amphiphile chain length, and leads us to select F8H11DMP and F10H11DMP as the less cytotoxic amphiphiles among a series of FnHmDMP compounds. Furthermore, water-in-fluorocarbon emulsions stabilized with F8H11DMP and F10H11DMP appeared to be non-cytotoxic towards HLEC in culture.

Reverse water-in-fluorocarbon emulsions for use in pressurized metered-dose inhalers containing hydrofluoroalkane propellants.

Pulmonary administration of drugs has demonstrated numerous advantages in the treatment of pulmonary diseases due to direct targeting to the respiratory tract. It enables avoiding the first pass effect, reduces the amount of drugs administered, targets drugs to specific sites and reduces their side effects. Reverse water-in-fluorocarbon (FC) emulsions are potential drug delivery systems for pulmonary administration using pressurized metered-dose inhalers (pMDI). The external phase of these emulsions consists of perfluorooctyl bromide (PFOB, perflubron), whereas their internal phase contains the drugs solubilized or dispersed in water. These emulsions are stabilized by a perfluoroalkylated dimorpholinophosphate (F8H11DMP), i.e. a fluorinated surfactant. This study demonstrates the possibility of delivering a reverse fluorocarbon emulsion via the pulmonary route using a CFC-free pMDI. Two hydrofluoroalkanes (HFAs) (Solkane(R) 134a and Solkane(R) 227) were used as propellants, and various solution (or emulsion)/propellant ratios (1/3, 1/2, 2/3, 1/1, 3/2, 3/1 v/v) were investigated. The insolubility of water (with or without the fluorinated surfactant F8H11DMP) in both HFA 227 and HFA 134a was demonstrated. PFOB and the reverse emulsion were totally soluble or dispersible in all proportions in both propellants. This study demonstrated also that the reverse FC emulsion can be successfully used to deliver caffeine in a homogeneous and reproducible way. The mean diameter of the emulsion water droplets in the pressured canister was investigated immediately after packaging and after 1 week of storage at room temperature. Best results were obtained with emulsion/propellant ratios comprised between 2/3 and 3/2, and with HFA 227 as propellant.

Detection of perfluorocarbons in blood by headspace solid-phase microextraction combined with gas chromatography/mass spectrometry.

A new method of detection of perfluorocarbon molecules (PFCs) in blood sample has been established. After an extraction and pre-concentration step performed by headspace solid-phase microextraction (HS-SPME), the PFCs are detected by gas chromatography-mass spectrometry (GC/MS) with an ion trap mass spectrometer in MS and MS/MS modes. The influence of different parameters on the SPME process is discussed. The limit of detection and the linearity of the procedure have been determined for two PFCs.

Total synthesis of (+/-)-asteriscanolide.

The total synthesis of asteriscanolide (1) has been achieved by taking advantage on an intermolecular Pauson-Khand cycloaddition and a ring-closing metathesis as key bond-forming transformations. The approach incorporates the cyclooctane stereogenic center prior to ring formation. Interestingly, the ring-closing metathesis generates a new eight-membered ring with an "in-out" intrabridgehead relationship.

Seventy-two hours hypothermic intestinal preservation study using a new perfluorocarbon emulsion.

We investigated the effect of a perfluorocarbon emulsion (FC) added to the University of Wisconsin (UW) solution on hypothermic (4 degrees C, 12-72h) preservation of rat small bowel grafts. The FC was 90%w/v perfluorooctylbromide, 2%w/v egg yolk phospholipids and 1.4%w/v mixed fluorocarbon-hydrocarbon molecular dowels. Four groups were defined: [1] UW flush and UW storage; [2] UW flush and FC storage; [3] flush with FC diluted 2 times with UW (FU) and FU storage; [4] FU flush and storage in oxygenated FU. Preservation was estimated with a histological score based on villus epithelium adhesion, on villus sloughing and on crypt cell adhesion to the basal membrane. Antioxidant potential was estimated by measurement of total thiol functions (SH) and activities of glutathione-peroxidase (GSH-P), superoxide dismutase (SOD) and catalase. FC in flush improved preservation during the first 24h (p<0.01). Storage in FC appeared superior to UW for the first 24h (p<0.01). Oxygenation (100% O2) of the storage medium yielded superior results at 12h and 24h (p<0.01 and p<0.001 versus group [1] respectively). After 72h, SOD and catalase activities increased in groups [3] and [4], and SOD decreased in group [1] (p<0.05). SH progressively decreased in group [1] (p<0.05) and GSH-P increased at 24 and 48h in groups [3] and [4] (p<0.01). The increase of O2 in the perfusion flush or storage medium ameliorated the preservation status and protected the antioxidant potential of the small bowel.

Fluorocarbons and fluorinated amphiphiles in drug delivery and biomedical research.

The specific properties of fluorocarbons, exceptional chemical and biological inertness, high gas-dissolving capacity, low surface tension, excellent spreading characteristics and high fluidity, have triggered numerous applications of these compounds in oxygen delivery. An injectable emulsion of fluorocarbon-in-water destined to deliver oxygen to tissues at risk of hypoxia has now completed Phase III clinical trials in Europe. A neat fluorocarbon is currently investigated in Phase II for treatment of acute respiratory failure by liquid ventilation. Fluorinated lipids and fluorinated surfactants can be used to elaborate and stabilize various colloidal systems, including different types of emulsions, vesicles and tubules, that also show promise for controlled release drug delivery.

Practical cobalt carbonyl catalysis in the thermal Pauson--Khand reaction: efficiency enhancement using Lewis bases.

In this report we have shown that the commercially available Co(2)(CO)(8) and Co(4)(CO)(12), and enyne--Co(2)(CO)(6) complexes, are sufficiently effective in catalyzing the Pauson--Khand reaction under one atmosphere of CO pressure. It was further demonstrated that the efficiencies of these cyclization protocols could be enhanced by the presence of cyclohexylamine. These procedures have also rendered more practical and highly convenient alternatives for the catalytic Pauson--Khand reaction. Most importantly, we have dispelled the common belief that Co(4)(CO)(12) is inactive in the Pauson--Khand reaction under one atmosphere of carbon monoxide. Of mechanistic importance is that these studies have also shown that the probable formation of Co(4)(CO)(12) is not necessarily a dead end pathway in the Co(2)(CO)(8)-catalyzed Pauson--Khand reaction. It is also of interest that substoichiometric amounts of Co(2)(CO)(8), in DME and in the presence of cyclohexylamine, are sufficient for the cyclocarbonylation of enynes under a nitrogen atmosphere. Our findings have provided more practical protocols for the Pauson-Khand reaction using catalytic amounts of cobalt carbonyl complexes and a better understanding of the influence of Lewis bases on their efficiency. These reports on the activity of Co(4)(CO)(12) are anticipated to develop into a convenient and practical alternative for Co(2)(CO)(8) catalysis.

Determination of perfluorodecalin and perfluoro-N-methylcyclohexylpiperidine in rat blood by gas chromatography-mass spectrometry.

A gas chromatography-mass spectrometry method (SIM mode) was developed for the determination of perfluorodecalin (cis and trans isomers, 50% each) (FDC), and perfluoromethylcyclohexylpiperidine (3 isomers) (FMCP) in rat blood. The chromatographic separation was performed by injection in the split mode using a CP-select 624 CB capillary column. Analysis was performed by electronic impact ionization. The ions m/z 293 and m/z 181 were selected to quantify FDC and FMCP due to their abundance and to their specificity, respectively. The ion m/z 295 was selected to monitor internal standard. Before extraction, blood samples were stored at -30 degrees C for at least 24 h in order to break the emulsion. The sample preparation procedure involved sample clean-up by liquid-liquid extraction. The bis(F-butyl)ethene was used as the internal standard. For each perfluorochemical compound multiple peaks were observed. The observed retention times were 1.78 and 1.87 min for FDC, and 2.28, 2.34, 2.48 and 2.56 min for FMCP. For each compound, two calibration curves were used; assays showed good linearity in the range 0.0195-0.78 and 0.78-7.8 mg/ml for FDC, and 0.00975-0.39 and 0.39-3.9 mg/ml for FMCP. Recoveries were 90 and 82% for the two compounds, respectively with a coefficient of variation <8%. Precision ranged from 0.07 to 15.6%, and accuracy was between 89.5 and 111.4%. The limits of quantification were 13 and 9 microg/ml for FDC and FMCP, respectively. This method has been used to determine the pharmacokinetic profile of these two perfluorochemical compounds in blood following administration of 1.3 g of FDC and 0.65 g of FMCP per kg body weight, in emulsion form, in rat.

How crash severity in rear impacts influences short- and long-term consequences to the neck.

The main public-health problem concerning WAD are injuries leading to long-term consequences. Yet epidemiological studies mostly concentrate on data based on the injury outcome occurring shortly after the crash. The purpose of this article is to study the influence of crash severity in rear impacts leading to short and long-term consequences to the neck (WAD 1-3), lasting less than or more than 1 year. The influence of change of velocity as well as the car acceleration were investigated by using data from crash pulse recorders (CPR) installed in vehicles, involved in rear impacts. The influence of the car acceleration were also investigated by studying the frequency of occurrence of a tow-bar (hinge) on the struck car. Apart from real-life data, full-scale car-to-car crashes were performed to evaluate the influence of a tow-bar on the struck car. The crash tests showed that a tow-bar may significantly affect the acceleration of the car as well as that of the occupant. According to real-life crashes, a tow-bar on the struck car increased the risk of long-term consequences by 22% but did not affect the risk of short-term consequences. Out of the 28 crash recorder-equipped struck cars involving 38 occupants, 15 sustained no injury where the peak acceleration was 6g or less, 20 sustained short-term consequences where the peak acceleration was 10g or less. Three occupants from two different crashes sustained long-term consequences. The two crashes which resulted in long-term disabling neck injuries had the highest peak acceleration (15 and 13 x g), but not the highest change of velocity.

Neck injuries in frontal impacts: influence of crash pulse characteristics on injury risk.

AIS1 neck injuries are the most frequent disabling injuries among car occupants in road traffic accidents. Although neck injury is mostly regarded as resulting from rear end collisions, almost one third of all neck injuries occur in frontal impacts. The injury mechanisms in both rear-end and frontal impacts are still not known, although different hypotheses exist. Since 1992, approx. 100,000 vehicles on the Swedish market have been equipped with crash recorders to measuring frontal impacts. This paper analyses the influence of different characteristics derived from the acceleration time history on the risk of short- and long-term disability to the neck in frontal impacts. The study includes injury outcomes from 187 restrained front seat occupants in 143 frontal collisions with an overlap exceeding 25%, where the crash pulses have been recorded using crash pulse recorders. The results show that the shape of the crash pulse influences the risk of long-term disability to the neck. The vehicle accelerations in the mid and last third of the crash pulse seem to be important. It is also shown how change of velocity and mean and peak accelerations influence the neck-injury risk. It is suggested that the risk of sustaining an AIS1 neck injury in frontal impacts could be reduced by using more effective pretensioners and more advanced belt-load limiters. These results may also have implications for neck injury mechanisms in rear-end impacts.