Monoamine oxidase-B inhibition: a comparison of in vivo and ex vivo measures of reversible effects

Summary A behavioural test involving potentiation of the effects of an acute injection of rh6v77j5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-phenylethylamine (10 mg kg^–1 i.p.) was used to assess the time-course of type-B MAO inhibition after administration of (–)deprenyl (5 mg kg^–1 i.p.) and of MD 240928 (20 mg kg^–1 i.p.) respectively. Potentiation of the effects of rh6v77j5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-phenylethylamine was observed 1 h after injection of (–)deprenyl or MD 240928. This effect was still evident 120 h after administration of (–)deprenyl but not 24 h after administration of MD 240928. Comparisons of ex vivo estimates of MAO activity yielded a corresponding time-course for the recovery of this enzyme. The extent of MAO inhibition required for potentiation of the effects of rh6v77j5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-phenylethylamine was inferred from a comparison of the behavioural test results and the ex vivo MAO activity observed after (–)deprenyl administration. These comparisons indicate a significant underestimation of MD 240928-induced MAO inhibition using ex vivo measures. This underestimation is interpreted as evidence fordilution effects in the ex vivo assay of MAO inhibition. The potentiation of effects of rh6v77j5/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-phenylethylamine under the present conditions is proposed as a useful and simple test for effects of reversible type-B MAO inhibitors.     

Topical recombinant human acidic fibroblast growth factor: An effective therapeutic agent for facemask wearing‐induced pressure sores

Protecting health care workers is crucial during coronavirus disease 2019 pandemic and facemask wearing is considered an effective measure to prevent severe acute respiratory syndrome coronavirus 2 infection. However, long‐time use of a facemask can cause pressure sores on the ears and nose bridge and increase the risk of infection. The topical recombinant human acidic fibroblast growth factor (rh‐aFGF) was used to cure pressure sores for health care workers at Zhongfaxincheng campus of Tongji Hospital. The results from a small sample size survey conducted in Zhongfaxincheng campuses of Tongji Hospital showed that treatment with topical rh‐aFGF could significantly inhibit the progression of pressure sores and accelerate the wound healing with no apparent ill‐effects. Therefore, we propose that topical rh‐aFGF is an effective therapeutic agent for facemask wearing‐induced pressure sores and worth of popularizing and applying.     

Macrophage migration inhibitory factor promotes intestinal tumorigenesis

BACKGROUND & AIMS: The cytokine macrophage migration inhibitory factor (MIF) is expressed throughout the human gastrointestinal tract. Recently, protumorigenic activity of MIF has been described in several cancer models. Therefore, we investigated the expression and function of MIF during the early stages of intestinal tumorigenesis. METHODS: MIF messenger RNA, protein, and tautomerase activity were measured in normal intestinal mucosa and adenomas from patients with sporadic colorectal adenomas and in the adenomatous polyposis coli (Apc)Min/+ mouse model of intestinal tumorigenesis. MIF function was investigated by using VACO-235 human colorectal adenoma cells in vitro and by testing the effect of genetic deletion of Mif on ApcMin/+ mouse intestinal tumorigenesis. RESULTS: MIF expression and tautomerase activity were increased in human and ApcMin/+ mouse intestinal adenomas compared with adjacent normal mucosa. Up-regulation of MIF occurred mainly in epithelial cells (associated with an increasing grade of dysplasia), but also in stromal plasma cells. Exogenous MIF inhibited apoptosis and promoted anchorage-independent growth of VACO-235 cells (maximal at 100 ng/mL). Homozygous deletion of Mif was associated with a reduction in the number and size of ApcMin/+ mouse adenomas (P = .025 for the difference in large [>7-mm] tumors) and decreased angiogenesis (43% decrease in mean tumor microvessel density), but there was no alteration in epithelial cell apoptosis or proliferation. CONCLUSIONS: MIF expression is increased in sporadic human colorectal adenomas, and exogenous MIF drives tumorigenic behavior of epithelial cells in vitro. Mif also promotes intestinal tumorigenesis (predominantly via angiogenesis) in the ApcMin/+ mouse. Therefore, MIF is a potential colorectal cancer chemoprevention target.     

Induction of interleukin 8 release from the HMC-1 mast cell line: synergy between stem cell factor and activators of the adenosine A(2b) receptor

The HMC-1 mast cell line has both adenosine A(3) and A(2b) receptors on its surface, but only agonists of the A(2b) receptor are effective at releasing interleukin 8. Object of this study was to look for co-factors for adenosine A(2b) receptor activation. There was a powerful and statistically significant synergy for release of IL-8, both at the mRNA level (measured after 4 hr) and protein level (measured after 24 hr), between adenosine A(2b) receptor agonists and stem cell factor (SCF). Suitable concentrations for showing synergy were 100 ng/mL SCF and 3 microM 5'-N-ethylcarboxamidoadenosine (NECA). At these concentrations, the IL-8 released into the culture medium after SCF and NECA together was typically 3-5-fold greater in amount than the sum of the amounts of IL-8 released after exposure to the same concentrations of NECA and SCF separately. Since mast cells may be exposed to both adenosine and stem cell factor in the diseased lung, the synergy observed in this model system may have implications for asthma.     

Inorganic arsenite alters macrophage generation from human peripheral blood monocytes

Inorganic arsenite has caused severe inflammatory chronic poisoning in humans through the consumption of contaminated well water. In this study, we examined the effects of arsenite at nanomolar concentrations on the in vitro differentiation of human macrophages from peripheral blood monocytes. While arsenite was found to induce cell death in a culture system containing macrophage colony stimulating factor (M-CSF), macrophages induced by granulocyte-macrophage CSF (GM-CSF) survived the treatment, but were morphologically, phenotypically, and functionally altered. In particular, arsenite-induced cells expressed higher levels of a major histocompatibility complex (MHC) class II antigen, HLA-DR, and CD14. They were more effective at inducing allogeneic or autologous T cell responses and responded more strongly to bacterial lipopolysaccharide (LPS) by inflammatory cytokine release as compared to cells induced by GM-CSF alone. On the other hand, arsenite-induced cells expressed lower levels of CD11b and CD54 and phagocytosed latex beads or zymosan particles less efficiently. We also demonstrated that the optimum amount of cellular reactive oxygen species (ROS) induced by nM arsenite might play an important role in this abnormal monocyte differentiation. This work may have implications in chronic arsenic poisoning because the total peripheral blood arsenic concentrations of these patients are at nM levels.     

Effects of β-Adrenergic Antagonists on the QT Measurements from Exercise Stress Tests in Pediatric Patients with Long QT Syndrome

It has been proposed that rh6ane0a427ga/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-adrenergic antagonist protection against cardiac events in patients with long QT syndrome (LQTS) may be related to a decrease in baseline QTc dispersion. To determine the effects of rh6ane0a427ga/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-blocker therapy on QT measurements, we evaluated the exercise tests of 25 pediatric patients with LQTS. Measurements were made of the maximum QTc interval and QTc dispersion during the various segments of the exercise test. There was no statistically significant difference between the pre-rh6ane0a427ga/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-blocker and post-rh6ane0a427ga/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-blocker maximum QTc interval during the supine (0.473 ± 0.039 vs 0.470 ± 0.038 sec), exercise (0.488 ± 0.044 vs 0.500 ± 0.026 sec), or recovery (0.490 ± 0.031 vs 0.493 ± 0.029 sec) phases of the exercise stress test. There was also no statistically significant difference between the pre-rh6ane0a427ga/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-blocker and post-rh6ane0a427ga/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-blocker QTc dispersion during the supine (0.047 ± 0.021 vs 0.058 ± 0.033 sec), exercise (0.063 ± 0.036 vs 0.063 ± 0.028 sec), or recovery (0.045 ± 0.023 vs 0.052 ± 0.026 sec) phases of the exercise stress test. Therefore, the protection that rh6ane0a427ga/xxlarge946.gif" alt="beta" align="MIDDLE" BORDER="0">-blockers offer appears not to be related to a reduction of the baseline QTc interval or a decrease of QTc dispersion. Paper presented at the Third Annual World Congress of Pediatric Cardiology and Cardiac Surgery, Toronto, Canada, May 2001     

Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes—the EURODIAB Prospective Complications Study

Aims/hypothesis The pathogenesis of vascular complications in type 1 diabetes is poorly understood, but may involve chronic, low-grade inflammation. We investigated the association of markers of inflammation with vascular complications in type 1 diabetes.Methods A cross-sectional nested case-control study of the follow-up data of the EURODIAB Prospective Complications Study. This study included 543 individuals (278 men) with type 1 diabetes diagnosed at <36 years of age. Cases (n=348) had complications of diabetes, controls (n=195) had no complications.Results C-reactive protein, interleukin-6 and tumour necrosis factor-rh8h1v3q940532/xxlarge945.gif" alt="agr" align="BASELINE" BORDER="0"> levels, which were combined in an inflammatory marker Z-score, were associated with albuminuria, retinopathy and cardiovascular disease. Calculated means (95% confidence intervals) of the marker Z-score were –0.15 (–0.22 to –0.07), 0.10 (–0.05 to 0.25), and 0.28 (0.15 to 0.41), p for trend <0.0001, in individuals with normo-, micro- and macroalbuminuria; –0.23 (–0.33 to –0.13), 0.14 (0.02 to 0.25) and 0.20 (0.07 to 0.32), p for trend <0.0001, in individuals with no, non-proliferative and proliferative retinopathy; and –0.28 (–0.39 to –0.18) and 0.06 (–0.08 to 0.20), p<0.001, in individuals without and with cardiovascular disease. Per 1 SD increase of the inflammatory marker Z-score, GFR decreased by –4.6 (–6.6 to –2.6) ml per min per 1.73 m² (p<0.001).Conclusions/interpretation We have shown that markers of inflammation are strongly and independently associated with microvascular complications and cardiovascular disease in type 1 diabetes. These data suggest that strategies to decrease inflammatory activity may help to prevent the development of vascular complications in type 1 diabetes.     

Porcine regulatory T cells: mechanisms and T-cell targets of suppression

Tregs are known for their suppressive capacity on various immune reactions. In swine, existence as well as suppressive activity of Foxp3⁺ Tregs could be demonstrated but detailed functional investigations are lacking. Therefore, we analysed the functional properties of porcine Tregs. We observed that besides TCR stimulation Tregs require IL-2 for activation. Furthermore, we investigated the following mechanisms of suppression: (i) cell–cell contact dependency, (ii) production of soluble suppressive factors and (iii) competition for growth factors. Our experiments revealed that suppression by porcine Tregs is abrogated by blocking cell–cell contact or by supplementing excessive amounts of IL-2. Additionally it could be shown that porcine Tregs produce immunosuppressive IL-10. Thereby, we demonstrated that porcine Tregs can use all main mechanisms of suppression mentioned above. Further investigations on the suppressive activity of Tregs using CFSE proliferation assays demonstrated that suppression affects T-helper cells as well as cytotoxic T lymphocytes and TCR-γδ T cells.