Reversal of the anticoagulant and anti-hemostatic effect of low molecular weight heparin by direct prothrombin activation

Lopap, found in the bristles of Lonomia obliqua caterpillar, is the first exogenous prothrombin activator that shows serine protease-like activity, independent of prothrombinase components and unique lipocalin reported to interfere with hemostasis mechanisms. To assess the action of an exogenous prothrombin activator reversing the anticoagulant and antihemostatic effect induced by low molecular weight heparin (LMWH), male New Zealand rabbits (N = 20, weighing 3.8-4.0 kg) allocated to 4 groups were anticoagulated with 1800 IU/kg LMWH (iv) over 2 min, followed by iv administration of saline (SG) or recombinant Lopap (rLopap) at 1 µg/kg (LG1) or 10 µg/kg (LG10), 10 min after the injection of LMWH, in a blind manner. Control animals (CG) were treated only with saline. The action of rLopap was assessed in terms of activated partial thromboplastin time (aPTT), prothrombin fragment F1+2, fibrinogen, and ear puncture bleeding time (BT) at 5, 10, 15, 17, 20, 30, 40, 60, and 90 min after initiation of LMWH infusion. LG10 animals showed a decrease of aPTT in more than 50% and BT near to normal baseline. The level of prothrombin fragment F1+2 measured by ELISA had a 6-fold increase with rLopap treatment (10 µg/kg) and was inversely proportional to BT in LMWH-treated animals. Thus, Lopap, obtained in recombinant form using E. coli expression system, was useful in antagonizing the effect of LMWH through direct prothrombin activation, which can be a possible strategy for the reversal of bleeding and anticoagulant events.

Proprioceptive Neuromuscular Facilitation of the Wrist Flexors

The present study examined a wrist extension-to-flexion contraction pattern that was theorized to result in proprioceptive neuromuscular facilitation. However, the “reversal of antagonists” contraction pattern may have, alternatively, interfered with motor learning-related increases in strength. Participants (N=24) were matched on predicted strength and randomly assigned to either the control or experimental group. Training occurred during three test sessions within a one-week period. Retention and transfer (crossed-condition) tests were administered during a fourth test session two- weeks later. Both groups exhibited comparable increases in strength (20.2%) and decreases in muscle coactivation (35.2%), which were retained and transferred. Decreases in error and variability of the torque traces were associated with parallel decreases in variability of muscle activity. The reversal of antagonists technique did not interfere with motor learning-related increases in strength and decreases in variability. However, the more complex contraction pattern failed to result in proprioceptive neuromuscular facilitation of strength.

Formation of triple helical nanofibers using self-assembling chiral benzene-1,3,5-tricarboxamides and reversal of the nanostructure's handedness using mirror image building blocks

Intertwining triple helical nanofibers with an overall handedness have been formed from self-assembling chiral benzene-1,3,5-tricarboxamides 1, 2 and 3, whereas the achiralbenzene-1,3,5-tricarboxamide 4 upon self-association gives rise to straight nanofibers without any twist and transmission electron microscopy images of chiral compounds clearly demonstrate that the handedness of the triple helical nanofibers can be reversed by using the enantiomeric benzene-1,3,5-tricarboxamide building blocks.

Allosteric effects of antagonists on signalling by the chemokine receptor CCR5

Antagonists of the chemokine receptor, CCRS, may provide important new drugs for the treatment of HIV-1. In this study we have examined the mechanism of action of two functional antagonists of the chemokine receptor CCRS (UK-396,794, UK-438,235) in signalling and internalisation assays using CHO cells expressing CCR5. Both compounds were potent inverse agonists versus agonist-independent [S-3]GTP gamma S binding to membranes of CHO cells expressing CCR5. Both compounds also acted as allosteric inhibitors of CCL5 (RANTES) and CCL8 (MCP-2) -stimulated [S-35]GTP gamma S binding to CHO-CCR5 membranes, reducing the potency and maximal effects of the two chemokines. The data are consistent with effects of the allosteric inhibitors on both the binding and signalling of the chemokines. Both compounds inhibited CCR5 internalisation triggered by chemokines. When CHO-CCR5 cells were treated with either of the two compounds for prolonged periods of time (24 h) an increase (similar to 15%) in cell surface CCRS was detected. (C) 2007 Elsevier Inc. All rights reserved

Asymmetric synthesis using catalysts containing multiple stereogenic centres and a trans-1,2-diaminocyclohexane core; reversal of predominant enantioselectivity upon N-alkylation

N-Methylation of ligands containing a trans-1,2-diaminocyclohexane core and multiple stereogenic centres is shown to provide the product of the opposite configuration in significant enantiomeric excess, in the addition of diethylzinc to aldehydes. Some of the ligands were effective in an asymmetric Michael addition. (C) 2004 Elsevier Ltd. All rights reserved.

Induction of the ferritin gene (ftnA) of Escherichia coli by Fe2+–Fur is mediated by reversal of H-NS silencing and is RyhB independent

FtnA is the major iron-storage protein of Escherichia coli accounting for < or = 50% of total cellular iron. The FtnA gene (ftnA) is induced by iron in an Fe(2+)-Fur-dependent fashion. This effect is reportedly mediated by RyhB, the Fe(2+)-Fur-repressed, small, regulatory RNA. However, results presented here show that ftnA iron induction is independent of RyhB and instead involves direct interaction of Fe(2+)-Fur with an 'extended' Fur binding site (containing five tandem Fur boxes) located upstream (-83) of the ftnA promoter. In addition, H-NS acts as a direct repressor of ftnA transcription by binding at multiple sites (I-VI) within, and upstream of, the ftnA promoter. Fur directly competes with H-NS binding at upstream sites (II-IV) and consequently displaces H-NS from the ftnA promoter (sites V-VI) which in turn leads to derepression of ftnA transcription. It is proposed that H-NS binding within the ftnA promoter is facilitated by H-NS occupation of the upstream sites through H-NS oligomerization-induced DNA looping. Consequently, Fur displacement of H-NS from the upstream sites prevents cooperative H-NS binding at the downstream sites within the promoter, thus allowing access to RNA polymerase. This direct activation of ftnA transcription by Fe(2+)-Fur through H-NS antisilencing represents a new mechanism for iron-induced gene expression.

Response of the Atlantic meridional overturning circulation to a reversal of greenhouse gas increases

The reversibility of the Atlantic meridional overturning circulation (AMOC) is investigated in multi-model experiments using global climate models (GCMs) where CO2 concentrations are increased by 1 or 2 % per annum to 2× or 4× preindustrial conditions. After a period of stabilisation the CO2 is decreased back to preindustrial conditions. In most experiments when the CO2 decreases, the AMOC recovers before becoming anomalously strong. This "overshoot" is up to an extra 18.2Sv or 104 % of its preindustrial strength, and the period with an anomalously strong AMOC can last for several hundred years. The magnitude of this overshoot is shown to be related to the build up of salinity in the subtropical Atlantic during the previous period of high CO2 levels. The magnitude of this build up is partly related to anthropogenic changes in the hydrological cycle. The mechanisms linking the subtropical salinity increase to the subsequent overshoot are analysed, supporting the relationship found. This understanding is used to explain differences seen in some models and scenarios. In one experiment there is no overshoot because there is little salinity build up, partly as a result of model differences in the hydrological cycle response to increased CO2 levels and partly because of a less aggressive scenario. Another experiment has a delayed overshoot, possibly as a result of a very weak AMOC in that GCM when CO2 is high. This study identifies aspects of overshoot behaviour that are robust across a multi-model and multi-scenario ensemble, and those that differ between experiments. These results could inform an assessment of the real-world AMOC response to decreasing CO2.

Reversal of a single base pair step controls guanine photo-oxidation by an intercalating Ru(II) dipyridophenazine complex

Small changes in DNA sequence can often have major biological effects. Here the rates and yields of guanine photo-oxidation by Λ [Ru(TAP)2(dppz)]2+ have been compared in 5′-{CCGGATCCGG}2 and 5′-{CCGGTACCGG}2 using ps/ns transient visible and time-resolved IR (TRIR) spectroscopy. The inefficiency of electron transfer in the TA sequence is consistent with the 5′-TA-3′ vs. 5′-AT-3′ binding preference predicted by X-ray crystallography. The TRIR spectra also reveal the differences in binding sites in the two oligonucleotides.

A reversal of climatic trends in the North Atlantic since 2005

In the mid-1990s the North Atlantic subpolar gyre warmed rapidly, which had important climate impacts, such as increased hurricane numbers, and changes to rainfall over Africa, Europe and North America. Evidence suggests that the warming was largely due to a strengthening of the ocean circulation, particularly the Atlantic Meridional Overturning Circulation (AMOC). Since the mid-1990s direct and indirect measurements have suggested a decline in the strength of the ocean circulation, which is expected to lead to a reduction in northward heat transport. Here we show that since 2005 a large volume of the upper North Atlantic Ocean has cooled significantly by approximately -0.45C or 1.5x10^22 J, reversing the previous warming trend. By analysing observations and a state-of-the-art climate model, we show that this cooling is consistent with a reduction in the strength of the ocean circulation and heat transport, linked to record low densities in the deep Labrador Sea. The low density in the deep Labrador Sea is primarily due to deep ocean warming since 1995, but a long-term freshening also played a role. The observed upper ocean cooling since 2005 is not consistent with the hypothesis that anthropogenic aerosols directly drive Atlantic temperatures.

Reversal of Postprandial Endothelial Dysfunction by Cyclooxygenase Inhibition in Healthy Volunteers

The aim of this study was to evaluate the role of cyclooxygenase (COX) in venous vascular reactivity changes after an oral lipid overload (OLO). Venous endothelial function (dorsal hand vein technique) was evaluated in fasting, 30 minutes after COX inhibition (aspirin-fasting), 2 to 4 hours after an OLO (1000 kcal, 58% fat), and again after COX inhibition (aspirin-OLO, 600 mg/200 mL water) in 10 healthy adults (age, 28.1 +/- 1.3 years; body mass index, 22.3 +/- 0.6 kg/m(2)). Fasting, 2- to 4-hour post-OLO, and 60-minute postaspirin plasma glucose, insulin, and lipids were also evaluated. The OLO increased triglycerides and insulin, reduced low-density lipoprotein and high-density lipoprotein, but glycemia and total cholesterol remained unchanged. There were no metabolic differences between OLO and aspirin-OLO. In fasting, aspirin reduced acetylcholine-induced venodilation (107.0% +/- 14% versus 57.3% +/- 11%; P < 0.001). Vascular reactivity was blunted after the OLO (phenylephrine dose: 0.3 +/- 0.2 fasting versus 1.9 +/- 0.8 nmol/min after OLO; P < 0.001) and was partially corrected by aspirin (0.4 +/- 0.2; P < 0.001). Similar changes were observed in maximum venodilation after acetylcholine (107.0% +/- 14% fasting versus 60.4% +/- 9% after OLO, P < 0.001; aspirin-OLO: 95.9% +/- 6%; P < 0.001). The responses to sodium nitroprusside remained unchanged during the study. We conclude that the OLO reduction in the endothelium-dependent venoconstruction and venodilation is partially the result of the action of COX.

Reversal of the anticoagulant and anti-hemostatic effect of low molecular weight heparin by direct prothrombin activation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Comparative study between atropine and hyoscine-N-butylbromide for reversal of detomidine induced bradycardia in horses

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Actions of oestradiol and progesterone on the prostate in female gerbils: reversal of the histological effects of castration

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Use of Sugammadex after Neostigmine Incomplete Reversal of Rocuronium-Induced Neuromuscular Blockade

Menezes CC, Peceguini LAM, Silva ED, Simoes CM Use of Sugammadex after Neostigmine Incomplete Reversal of Rocuronium-Induced Neuromuscular Blockade. Background and objectives: Neuromuscular blockers (NMB) have been used for more than half of a century in anesthesia and have always been a challenge for anesthesiologists. Until recently, the reversal of nondepolarizing neuromuscular blockers had only one option: the use of anticholinesterase agents. However, in some situations, such as deep neuromuscular blockade after high doses of relaxant, the use of anticholinesterase agents does not allow adequate reversal of neuromuscular blockade: Recently, sugammadex, a gamma-cyclodextrin, proved to be highly effective for reversal of NMB induced by steroidal agents. Case report: A female patient who underwent an emergency exploratory laparotomy after rapid sequence intubation with rocuronium 1.2 mg.kg(-1). At the end of surgery, the pat ent received neostigmine reversal of NMB. However, neuromuscular junction monitoring did not show the expected recovery, presenting residual paralysis. Sugammadex 2 mg.kg(-1) was used and the patient had complete reversal of NMB in just 2 minutes time. Conclusion: Adequate recovery of residual neuromuscular blockade is required for full control of the pharynx and respiratory functions in order to prevent complications. Adequate recovery can only be obtained by neuromuscular junction monitoring with TOF ratio greater than 0.9. Often, the reversal of NMB with anticholinesterase drugs may not be completely reversed. However, in the absence of objective monitoring this diagnosis is not possible. The case illustrates the diagnosis of residual NMB even after reversal with anticholinesterase agents, resolved with the administration of sugammadex, a safe alternative to reverse the NMB induced by steroidal non-depolarizing agents.

Reversal of established lupus nephritis and prolonged survival of New Zealand black x New Zealand white mice treated with the topoisomerase I inhibitor irinotecan

Systemic lupus erythematosus is a chronic autoimmune disorder that predominantly affects women of childbearing age. Lupus-associated glomerulonephritis is a major cause of mortality in these patients. Current treatment protocols for systemic lupus erythematosus include cyclophosphamide, prednisolone, azathioprine, and mycophenolate mofetil. However, in mice none of these agents alone or in combination were shown to reverse established proteinuria. Using New Zealand Black x New Zealand White F1 mice, we report that administration of the topoisomerase I inhibitor irinotecan from week 13 completely prevented the onset of proteinuria and prolonged survival up to at least 90 wk without detectable side effects. Furthermore, application of irinotecan to mice with established lupus nephritis, as indicated by grade 3+ (> or =300 mg/dl) and grade 4+ (> or =2000 mg/dl) proteinuria and, according to a median age of 35 wk, resulted in remission rates of 75% and 55%, respectively. Survival was significantly prolonged with 73 wk (grade 3+ and 4+ combined) versus 40 wk for control animals. Although total IgG and anti-dsDNA Abs in the serum and mesangial IgG deposits in the kidneys were not reduced in irinotecan-treated mice, subendothelial immune deposits were considerably diminished, suggesting a prevention of glomerular basement membrane disruption. This effect was accompanied by increased rates of ssDNA breaks and inhibition of renal cell apoptosis being different to what is known about irinotecan in anticancer therapy. In conclusion, our data provide evidence that irinotecan might represent an entirely new strategy for the treatment of systemic lupus erythematosus.