Inhibition of NO-synthase and degranulation of rat omental mast cells in vitro

Mast cell amines, platelet-activating factor (PAF), thromboxanes and leukotrienes have been shown to be released during nitric oxide-synthase inhibition in the rat intestine. Mast cells in rat isolated omentum (OMCs) or isolated from the rat peritoneal cavity (PMCs) have been used here to investigate the relationship(s) between these agents. N-nitro-L-arginine methyl ester (L-NAME, 100 μM) caused some degranulation of OMCs, but no enhancement of histamine release from PMCs. PAF (5 μM) and U46619 (1 μM) degranulated OMCs and enhanced histamine release from PMCs. Pre-treatment of the omentum with BN52021 (10 μM) inhibited degranulation of OMCs in response to L-NAME, PAF or U46619. Pretreatment with 1-benzylimidazole (5 or 50 μM) inhibited the effect of L-NAME but not that of PAF. Indomethacin (1 μM) or sodium nitroprusside (10 μM) also inhibited the effects of L-NAME, but nordihydroguaiaretic acid (30 μM) did not. In PMCs BN52021 inhibited PAF-induced, but not U46619-induced, release of histamine. These results suggest that inhibition of nitric oxidesynthase in the omentum by L-NAME allows thromboxanes to release PAF, which in turn degranulates and releases histamine from OMCs

Rate of perfusion modulates colloidal carbon leakage from rat intestinal microvessels in vitro

In order to investigate the effects of varying the rate of flow on endothelial integrity the rat isolated small intestinal vasculature was perfused at 1, 5, 10 or 20 ml/min with a gelatin-containing physiological salt solution (GPSS), followed by an injection of colloidal carbon suspension (CC). Significantly greater microvascular CC leakage occurred at 1 or 5 ml/min than at 10 or 20 ml/ mitt. CC leakage at the two slower rates of flow was reduced by adding red blood cells to the GPSS, suggesting that the microvascular endothelium became hypoxic when perfused with GPSS at 1 or 5 ml/min. After perfusion at 20 ml/min with GPSS containing resiniferatoxin (1 μM) or 5-hydroxytryptamine (100 μM), CC leakage was significantly lower than after similar perfusion at 10 ml/min. Two nitric oxide (NO) synthesis blockers, N-nitro-L-arginine methyl ester (L-NAME, 100 μM) and methylene blue (20 μM), and an NO scavenger CPTIO (100 μM) each increased CC leakage. This suggests that NO was being produced at perfusion rates of 10 or 20 ml/min. Sodium nitroprusside (10 μM), 8-bromo-cGMP (100 μM) and BN52021 (10 μM) each significantly reduced CC leakage in the presence of L-NAME

Possible bi-directional link between ETA receptors and protein kinase C in rat blood vessels

Possible links have been investigated between activation of protein kinase C (PKC) and endothelin (ET) production by small blood vessels. Perfusion pressures were recorded from rat isolated mesenteric artery, with or without the small intestine attached, before and after addition to the perfusate of either ET-1, ET-3 or the PKC activator 12-deoxyphorbol 13-phenylacetate (DOPPA). Rises in perfusion pressure in response to ET-1 (10−8 M)or DOPPA (10−6 M) were reduced significantly by pre-treatment with either the ETA receptor antagonist PD151242 (10−6 M) or the PKC inhibitor Ro 31-8220 (10−6 M). ET-3 (10−8 M) had a significant, albeit small, effect only when the gut was still attached to the mesentery. Inthis latter preparation ET-1 and DOPPA increased the permeability of villi microvessels to colloidal carbon in the perfusate. This effect of DOPPA was reduced by pre-treatment with either PD151242 or Ro 31-8220, but the effects of ET-1 were reduced significantly only by Ro 31-8220. ET-3 (10−8 M) was without effect. The results suggest a possible bi-directional link between ETA receptors and PKC in the intestinal vasculature

Rat intestinal mast cell amines are released during nitric oxide synthase inhibition in vitro

Inhibition of nitric oxide synthase increases microvascular permeability in rat small intestinal villi. To determine the mechanism(s) whereby this occurs we have perfused the vasculature of rat isolated small intestines with a gelatin-containing physiological salt solution. Inclusion of N-nitro-L-argintne methyl ester (L-NAME, 100 μM) or indomethacin (1 μM) in the perfusate increased leakage of injected colloidal carbon into microvessel walls. Pre-treatment with sodium nitroprusside (10 μM) significantly reduced the effects of both L-NAME and indomethacin, whereas carbacyclin (1 μM) only reduced the effects of indomethacin. PD151242 (1 μM) showed some antagonism towards the effects of L-NAME, but nordihydroguaiaretic acid (3 μM) was inactive. Pre-tment with cyproheptadine (10 μM) reduced the effects of both L-NAME and indomethacin, and also significantly reduced background (control) colloidal carbon leakage. Small intestines from polymixin B-treated rats showed significantly reduced colloidal carbon leakage in response to L-NAME. This suggests that the leakage-enhancing effects of both L-NAME and indomethacin in this preparation may be mediated by mast cell-derived amines

Does observability affect prosociality?

The observation of behaviour is a key theoretical parameter underlying a number of models of prosociality. However, the empirical findings showing the effect of observability on prosociality are mixed. In this meta-analysis, we explore the boundary conditions that may account for this variability, by exploring key theoretical and methodological moderators of this link. We identified 117 papers yielding 134 study level effects (Total N = 788, 164) and found a small but statistically significant, positive association between observability and prosociality (r = .141, 95% CI = .106, .175). Moderator analysis showed that observability produced stronger effects on prosociality (1) in the presence of passive observers (i.e., people whose role was to only observe participants) vs perceptions of being watched, (2) when participants decisions were consequential (vs non-consequential), (3) when the studies were performed in the laboratory (as opposed to in the field/online), (4) when studies used repeated measures (instead of single games) and (5) when studies involved social dilemmas (instead of bargaining games). These effects show the conditions under which observability effects on prosociality will be maximally observed. We describe the theoretical and practical significance of 14 these results

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1α (HIF-1α) and HIF-2α protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n=90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1α and HIF-2α expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1α and HIF-2α, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR)=8.7, P<0.005) and decreased disease-free survival (HR=4.7, P<0.005). hypoxia-inducible factor-1α and -2α were expressed in >50% of rectal cancers (HIF-1α, 54%, 48/90; HIF-2α, 64%, 58/90). HIF-1α positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were shown between HIF-2α expression and any pathological features, and HIF-1α positivity had no effect on outcome. The study showed an independent association between HIF-1α expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1α, but not HIF-2α, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management

An EBSD Study of the Deformation of Service-Aged 316 Austenitic Steel

Electron backscatter diffraction (EBSD) has been used to examine the plastic deformation of an ex-service 316 austenitic stainless steel at 297K and 823K (24 °C and 550 °C)at strain rates 3.5x10-3 to 4 x 10-7 s-1. The distribution of local misorientations was found to depend on the imposed plastic strain following a lognormal distribution at true strains 0.1. At 823 K (550 °C), the distribution of misorientations depended on the applied strain rate. The evolution of lattice misorientations with increasing plastic strain up to 0.23 was quantified using the metrics kernel average misorientation, average intragrain misorientation, and low angle misorientation fraction. For strain rate down to 10-5 s-1 all metrics were insensitive to deformation temperature, mode (tension vs. compression) and orientation of the measurement plane. The strain sensitivity of the different metrics was found to depend on the misorientation ranges considered in their calculation. A simple new metric, proportion of undeformed grains, is proposed for assessing strain in both aged and unaged material. Lattice misorientations build up with strain faster in aged steel than in un-aged material and most of the metrics were sensitive to the effects of thermal aging. Ignoring aging effects leads to significant overestimation of the strains around welds. The EBSD results were compared with nanohardness measurements and good agreement established between the two techniques of assessing plastic strain in aged 316 steel