Novel force-displacement control passive finite element models of the spine to simulate intact and pathological conditions; comparisons with traditional passive and detailed musculoskeletal models.

Passive finite element (FE) models of the spine are commonly used to simulate intact and various pre- and postoperative pathological conditions. Being devoid of muscles, these traditional models are driven by simplistic loading scenarios, e.g., a constant moment and compressive follower load (FL) that do not properly mimic the complex in vivo loading condition under muscle exertions. We aim to develop novel passive FE models that are driven by more realistic yet simple loading scenarios, i.e., in vivo vertebral rotations and pathological-condition dependent FLs (estimated based on detailed musculoskeletal finite element (MS-FE) models). In these novel force-displacement control FE models, unlike the traditional passive FE models, FLs vary not only at different spine segments (T12-S1) but between intact, pre- and postoperative conditions. Intact, preoperative degenerated, and postoperative fused conditions at the L4-L5 segment for five static in vivo activities in upright and flexed postures were simulated by the traditional passive FE, novel force-displacement control FE, and gold-standard detailed MS-FE spine models. Our findings indicate that, when compared to the MS-FE models, the force-displacement control passive FE models could accurately predict the magnitude of disc compression force, intradiscal pressure, annulus maximal von Mises stress, and vector sum of all ligament forces at adjacent segments (L3-L4 and L5-S1) but failed to predict disc shear and facet joint forces. In this regard, the force-displacement control passive FE models were much more accurate than the traditional passive FE models. Clinical recommendations made based on traditional passive FE models should, therefore, be interpreted with caution.

Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats.

AIM: The aim of this study was to investigate the hypothesis that the opioid system is involved in the development of hepatic fibrosis. METHODS: The effect of naltrexone (an opioid receptor antagonist) on hepatic fibrosis in bile duct ligated (BDL) or sham rats was assessed by histology and hepatic hydroxyproline levels. Liver matrix metalloproteinase 2 (MMP-2) was measured by zymography, and alpha smooth muscle actin (alpha-SMA) and CD45 (leucocyte common antigen) by immunohistochemistry. The redox state of the liver was assessed by hepatic glutathione (GSH)/oxidised glutathione (GSSG) and S-nitrosothiol levels. Subtypes of opioid receptors in cultured hepatic stellate cells (HSCs) were characterised by reverse transcriptase-polymerase chain reaction, and the effects of selective delta opioid receptor agonists on cellular proliferation, tissue inhibitor of metalloproteinase 1 (TIMP-1), and procollagen I expression in HSCs determined. RESULTS: Naltrexone markedly attenuated the development of hepatic fibrosis as well as MMP-2 activity (p<0.01), and decreased the number of activated HSCs in BDL rats (p<0.05). The development of biliary cirrhosis altered the redox state with a decreased hepatic GSH/GSSG ratio and increased concentrations of hepatic S-nitrosothiols, which were partially or completely normalised by treatment with naltrexone, respectively. Activated rat HSCs exhibited expression of delta1 receptors, with increased procollagen I expression, and increased TIMP-1 expression in response to delta(1) and delta(2) agonists, respectively. CONCLUSIONS: This is the first study to demonstrate that administration of an opioid antagonist prevents the development of hepatic fibrosis in cirrhosis. Opioids can influence liver fibrogenesis directly via the effect on HSCs and regulation of the redox sensitive mechanisms in the liver.

Hydrogen sulphide and the hyperdynamic circulation in cirrhosis: a hypothesis.

Cirrhosis is associated with the development of a hyperdynamic circulation, which is secondary to the presence of systemic vasodilatation. Several mechanisms have been postulated to be involved in the development of systemic vasodilatation, including increased synthesis of nitric oxide, hyperglucagonaemia, increased carbon monoxide synthesis, and activation of K(ATP) channels in vascular smooth muscle cells in the systemic and splanchnic arterial circulation. Hydrogen sulphide (H2S) has recently been identified as a novel gaseous transmitter that induces vasodilatation through activation of K(ATP) channels in vascular smooth muscle cells. In this brief review, we comment on what is known about H2S, vascular and neurological function, and postulate its role in the pathogenesis of the vascular abnormalities in cirrhosis.

Ultra-low dose naltrexone potentiates the anticonvulsant effect of low dose morphine on clonic seizures.

Significant potentiation of analgesic effects of opioids can be achieved through selective blockade of their stimulatory effects on intracellular signaling pathways by ultra-low doses of opioid receptor antagonists. However, the generality and specificity of this interaction is not well understood. The bimodal modulation of pentylenetetrazole-induced seizure threshold by opioids provide a model to assess the potential usefulness of this approach in seizure disorders and to examine the differential mechanisms involved in opioid anti- (morphine at 0.5-3 mg/kg) versus pro-convulsant (20-100 mg/kg) effects. Systemic administration of ultra-low doses of naltrexone (100 fg/kg-10 ng/kg) significantly potentiated the anticonvulsant effect of morphine at 0.5 mg/kg while higher degrees of opioid receptor antagonism blocked this effect. Moreover, inhibition of opioid-induced excitatory signaling by naltrexone (1 ng/kg) unmasked a strong anticonvulsant effect for very low doses of morphine (1 ng/kg-100 microg/kg), suggesting that a presumed inhibitory component of opioid receptor signaling can exert strong seizure-protective effects even at very low levels of opioid receptor activation. However, ultra-low dose naltrexone could not increase the maximal anticonvulsant effect of morphine (1-3 mg/kg), possibly due to a ceiling effect. The proconvulsant effects of morphine on seizure threshold were minimally altered by ultra-low doses of naltrexone while being completely blocked by a higher dose (1 mg/kg) of the antagonist. The present data suggest that ultra-low doses of opioid receptor antagonists may provide a potent strategy to modulate seizure susceptibility, especially in conjunction with very low doses of opioids.