Towards a minimal example of quantum nonlocality without inputs

The network scenario offers interesting new perspectives on the phenomenon of quantum nonlocality. Notably, when considering networks with independent sources, it is possible to demonstrate quantum nonlocality without the need for measurements inputs, i.e. with all parties performing a fixed quantum measurement. Here we aim to find minimal examples of this effect. Focusing on the minimal case of the triangle network, we present examples involving output cardinalities of $3-3-3$ and $3-3-2$. Finally, we discuss the prospects of finding an example of quantum nonlocality in the triangle network with binary outputs, and point out a connection to the Lovasz local lemma

Inhibition of soluble epoxide hydrolase as a novel approach to high dose diazepam induced hypotension.

ContextHypotension is one of the dose limiting side effects of benzodiazepines (BZDs), in particular of diazepam (DZP) which is still widely used in the clinic. Currently, only one FDA approved antidote exists for BZD overdose and novel approaches are needed to improve management of DZP overdose, dependency and withdrawal.ObjectiveHere, we hypothesized that increasing bioactive lipid mediators termed epoxy fatty acids (EpFAs) will prevent hypotension, as was shown previously in a murine model of LPS-induced hypotension. Therefore, we first characterized the time and dose dependent profile of DZP induced hypotension in mice, and then investigated the reversal of the hypotensive effect by inhibiting the soluble epoxide hydrolase (sEH), an enzyme that regulates the levels of EpFAs.Materials and methodsFollowing baseline systolic BP recording using tail cuffs, mice were administered a sEH inhibitor (TPPU) before DZP and BP was monitored. Blood and brain levels of DZP and TPPU were quantified to examine distribution and metabolism. Plasma EpFAs levels were quantified to determine TPPU target engagement.ResultsIn this murine model, DZP induced dose dependent hypotension which was more severe than midazolam. The temporal profile was consistent with the reported pharmacokinetics/pharmacodynamics of DZP. Treatment with TPPU reversed the hypotension resulting from high doses of DZP and decreased the sEH metabolites of EpFAs in the plasma demonstrating target engagement.Discussion and conclusionOverall, these findings demonstrate the similarity of a murine model of DZP induced hypotension to clinical observations in humans. Furthermore, we demonstrate that stabilization of EpFAs by inhibiting sEH is a novel approach to overcome DZP-induced hypotension and this beneficial effect can be enhanced by an omega three diet probably acting through epoxide metabolites of the fatty acids

Inhibition of soluble epoxide hydrolase as a novel approach to high dose diazepam induced hypotension.

ContextHypotension is one of the dose limiting side effects of benzodiazepines (BZDs), in particular of diazepam (DZP) which is still widely used in the clinic. Currently, only one FDA approved antidote exists for BZD overdose and novel approaches are needed to improve management of DZP overdose, dependency and withdrawal.ObjectiveHere, we hypothesized that increasing bioactive lipid mediators termed epoxy fatty acids (EpFAs) will prevent hypotension, as was shown previously in a murine model of LPS-induced hypotension. Therefore, we first characterized the time and dose dependent profile of DZP induced hypotension in mice, and then investigated the reversal of the hypotensive effect by inhibiting the soluble epoxide hydrolase (sEH), an enzyme that regulates the levels of EpFAs.Materials and methodsFollowing baseline systolic BP recording using tail cuffs, mice were administered a sEH inhibitor (TPPU) before DZP and BP was monitored. Blood and brain levels of DZP and TPPU were quantified to examine distribution and metabolism. Plasma EpFAs levels were quantified to determine TPPU target engagement.ResultsIn this murine model, DZP induced dose dependent hypotension which was more severe than midazolam. The temporal profile was consistent with the reported pharmacokinetics/pharmacodynamics of DZP. Treatment with TPPU reversed the hypotension resulting from high doses of DZP and decreased the sEH metabolites of EpFAs in the plasma demonstrating target engagement.Discussion and conclusionOverall, these findings demonstrate the similarity of a murine model of DZP induced hypotension to clinical observations in humans. Furthermore, we demonstrate that stabilization of EpFAs by inhibiting sEH is a novel approach to overcome DZP-induced hypotension and this beneficial effect can be enhanced by an omega three diet probably acting through epoxide metabolites of the fatty acids

C allele in transforming growth factor-beta 1 rs1800471 gene polymorphisms might indicate a protective feature in encapsulating peritoneal sclerosis development

Introduction: Peritoneal fibrosis may progress in peritoneal dialysis (PD) patients to a fatal clinical condition called encapsulating peritoneal sclerosis (EPS). Transforming growth factor (TGF)-beta plays a pivotal role in the pathogenesis of peritoneal fibrosis. We aimed to investigate the association among polymorphisms in the gene encoding TGF-beta 1, which were -509C/T (rs1800469), + 869T/C (rs1982073), and + 915G/C (rs1800471) in EPS patients

Soluble Epoxide Hydrolase Inhibition Is Antinociceptive in a Mouse Model of Diabetic Neuropathy

Neuropathic pain is currently an insufficiently treated clinical condition. There remains a critical need for efficacious therapies without severe side effects to treat the uniquely persistent and tonic pain of neuropathy. Inhibitors of the soluble epoxide hydrolase (sEH) enzyme which stabilize endogenous epoxy fatty acids have demonstrated antihyperalgesia in clinical chronic inflammatory pain and modeled neuropathic pain. Recently, the conditioned place preference (CPP) assay has been used to evaluate the tonic nature of neuropathy in several animal models. The current experiments use the CPP assay alongside withdrawal thresholds to investigate the antihyperalgesic efficacy of sEH inhibitors in a murine model of diabetic neuropathy. Here, the sEH inhibitor t-TUCB at 10 mg/kg induced a robust place preference in diabetic neuropathic mice representative of pain relief. Importantly, this effect was absent both in control mice and in sEH knockout mice at the same dose indicating t-TUCB is not positively reinforcing or rewarding. When compared to gabapentin, t-TUCB elicited a similar degree of withdrawal threshold improvement without the same degree of spontaneous locomotion decline in neuropathic mice. Overall, these experiments show that inhibiting the sEH attenuates chronic pain and offers an alternative to current side-effect limited therapies to meet this clinical need

Omeprazole increases the efficacy of a soluble epoxide hydrolase inhibitor in a PGE2 induced pain model

Epoxyeicosatrienoic acids (EETs) are potent endogenous analgesic metabolites produced from arachidonic acid by cytochrome P450s (P450s). Metabolism of EETs by soluble epoxide hydrolase (sEH) reduces their activity, while their stabilization by sEH inhibition decreases both inflammatory and neuropathic pain. Here, we tested the complementary hypothesis that increasing the level of EETs through induction of P450s by omeprazole (OME), can influence pain related signaling by itself, and potentiate the anti-hyperalgesic effect of sEH inhibitor. Rats were treated with OME (100 mg/kg/day, p.o., 7 days), sEH inhibitor TPPU (3 mg/kg/day, p.o.) and OME (100 mg/kg/day, p.o., 7 days) + TPPU (3 mg/kg/day, p.o., last 3 days of OME dose) dissolved in vehicle PEG400, and their effect on hyperalgesia (increased sensitivity to pain) induced by PGE(2) was monitored. While OME treatment by itself exhibited variable effects on PGE(2) induced hyperalgesia, it strongly potentiated the effect of TPPU in the same assay. The significant decrease in pain with OME + TPPU treatment correlated with the increased levels of EETs in plasma and increased activities of P450 1A1 and P450 1A2 in liver microsomes. The results show that reducing catabolism of EETs with a sEH inhibitor yielded a stronger analgesic effect than increasing generation of EETs by OME, and combination of both yielded the strongest pain reducing effect under the condition of this study