One- and two-compartment minimal models detect similar alterations of glucose metabolism indexes in hypertension

A standard intravenous glucose tolerance test (IVGTT) was performed in 10 nondiabetic patients with essential hypertension (H group) and 9 normotensive control subjects (N group). A 2-compartment minimal model (2CMM) of glucose kinetics was applied to estimate indexes of glucose effectiveness, S2G and insulin sensitivity, S2I, by means of a maximum a posteriori (MAP) bayesian estimation technique. These estimates were contrasted to the S1G and S1I indexes provided by the classic minimal model (1CMM). In both the N group and the H group, the 2CMM underestimated the glucose effectiveness and overestimated the insulin sensitivity. In the H group, S2G was, on average, 63% of S1G (P > .05) and S2I was 137% of S1I (P > .05). In the N group S2G was 67% of S1G (P > .05) and S2I was 134% of S1I (P > .05). The 2CMM detected a reduction of approximately 40% (P > .05) and approximately 48% (P > .05) in S2G and S2I estimates, respectively, from the N group to the H group. Despite its reduced complexity, the 1CMM also detected a reduction of approximately 35% (P < .05) and approximately 49% (P < .05) in the S1G and in S1I indexes, respectively. Thus, the 1CMM and 2CMM showed a substantial equivalence in detecting a severe reduction in insulin sensitivity and impaired glucose effectiveness in hypertensive patients compared with normal.     

High Ascitic Fluid Leptin Levels in Patients with Decompensated Liver Cirrhosis and Sterile Ascites: Relationship with TNF-α Levels

Leptin is an adipocyte-derived hormone involved in the homeostasis of body composition. An imbalance in leptin regulation has been observed in patients with liver cirrhosis. We aimed to assess serum and ascitic leptin levels in a group of patients with decompensated liver cirrhosis and to evaluate the relationship of these levels with tumor necrosis factor alpha (TNF-alpha). We assessed both serum and ascitic fluid leptin levels in a series of 16 consecutive patients with liver cirrhosis. We calculated the body mass index (BMI) and assessed body fat (BF) of all patients by means of bioelectric impedence analysis. Leptin levels were analyzed in relationship to biochemical indexes, TNF-alpha levels, and body composition. None of the patients had spontaneous bacterial peritonitis. Both serum and ascites leptin levels were correlated with BMI and BF. On average, ascitic fluid leptin levels (13.1 +/- 10.9 ng/ml) were twice as high as serum levels (7.0 +/- 6.4 ng/ml), and the ascitic fluid/serum ratio of leptin was > 1 in all patients. Serum and ascites leptin levels were positively correlated (rS = 0.675, P = 0.009), while no correlation was observed between leptin and TNF-alpha levels, both in serum and in ascites. Serum and ascites TNF-alpha were not correlated. The ascitic fluid leptin levels of cirrhotic patients with sterile ascites are on average two times higher than circulating levels of this hormone. Noteworthily, they correlate significantly with body composition. These findings seem to suggest that in patients with decompensated liver cirrhosis, intraabdominal production of leptin may contribute to the metabolic picture.     

Mitochondria of human adrenal cortex have tubular cristae with bulbous tips

By taking advantage of a modified osmium maceration technique, we have been able to examine by high resolution scanning electron microscopy (HRSEM) the interior of human adrenocortical mitochondria from which all soluble material has been extracted. The so-called vesicles apparent in thin sections examined by transmission electron microscopy actually are finger-like cristae as determined by HRSEM. These digitiform cristae have a segmented appearance and a bulbous tip. The segmented form of the cristae may have important metabolic implications.     

A study on the action of vitamin E supplementation on plasminogen activator inhibitor type 1 and platelet nitric oxide production in type 2 diabetic patients

Background and aimType 2 diabetic (T2DM) patients show decreased fibrinolysis, mainly linked to high plasminogen activator inhibitor type 1 (PAI-1) production, together with a reduced bioavailability of nitric oxide and an impairment in Na⁺/K⁺-ATPase activity possibly involved in increased cardiovascular risk. Vitamin E is the major natural lipid-soluble antioxidant in human plasma. The present work was conducted in order to measure PAI-1, ICAM and VCAM-1 plasma levels, platelet nitric oxide production and membrane Na⁺/K⁺-ATPase activity in type 2 diabetic subjects treated with vitamin E (500 IU/day) for 10 weeks and then followed for other 20 weeks.Methods and resultsThirty-seven T2DM patients (24 males and 13 females) were studied. None of them were affected by any other disease or diabetic complications. Significant differences were detected for PAI-1 antigen (p < 0.001), PAI-1 activity (p < 0.001), nitric oxide (NO) production (p < 0.001), and Na⁺/K⁺-ATPase activity (p < 0.001) among the 4 phases of the study. A significant decrease both in ICAM and VCAM-1 plasma levels was also found at the 10th week compared with baseline (respectively p < 0.001 and p < 0.05).ConclusionOur data suggest that vitamin E counteracts endothelial activation in T2DM patients possibly representing a new tool for endothelial protection.     

Enhancement of chemotactic factor-stimulated neutrophil oxidative metabolism by leukotriene B4

Leukotriene B4 (LTB4) is a potent primary stimulator of neutrophil chemotaxis, aggregation, and degranulation and induces superoxide production at higher concentrations. In order to determine whether LTB4 modulates neutrophil responses to oxidative stimuli, human neutrophils (PMNs) were incubated with LTB4 prior to stimulation with f-Met-Leu-Phe (fMLP, 10(-7) mol/L), opsonized zymosan (OZ, 250 micrograms/mL), or phorbol myristate acetate (PMA, 32 nmol/L). Superoxide (O2-) production by stimulated PMNs was assessed by the superoxide dismutase-inhibitable reduction of cytochrome c. LTB4 alone did not stimulate O2- production in concentrations below 10(-7) mol/L and had no effect on the O2- assay. In the concentration range of 10(-12) to 10(-8) mol/L, LTB4 did not alter O2- release induced by OZ or PMA. In contrast, LTB4-treated cells demonstrated enhanced O2- production following exposure to fMLP, and in the presence of 10 nmol/LLTB4, generated 180% +/- 41% of O-2 quantities produced by control cells (n = 23). Enhancement was LTB4 dose-dependent, was maximal in the range of 1 to 10 nmol/L LTB4, was not reversed by removal of the lipid from the medium prior to fMLP stimulation, and was not dependent on the presence of Ca++ or Mg++ in the suspending medium. Chemiluminescence of fMLP-stimulated neutrophils was increased to 323% of controls in neutrophils preincubated with 10 nmol/L LTB4. Unlike augmentation of oxidative responses to fMLP seen with other degranulating stimuli, enhancement by LTB4 was not correlated with an increase in 3H-fMLP receptor binding. These results indicate that, in addition to its primary effects on neutrophil function, LTB4 modulates PMN oxidative responses to the chemotactic peptide and, thus, may amplify the release of oxygen metabolites at inflammatory foci.     

Thrombospondin mediates the cytoadherence of Plasmodium falciparum- infected red cells to vascular endothelium in shear flow conditions

Cerebral malaria is thought to involve specific attachment of Plasmodium falciparum-infected knobby red cells to venular endothelium. The nature of surface ligands on host endothelial cells that may mediate cytoadherence is poorly understood. We have investigated the effects of soluble thrombospondin, rabbit antiserum raised against thrombospondin, and human immune serum on cytoadherence of parasitized erythrocytes in ex vivo mesocecum vasculature. Preincubation of infected red cells with soluble thrombospondin or human immune serum inhibits binding of infected red cells to rat venular endothelium. Infusion of the microcirculatory preparation with rabbit antithrombospondin antibodies before perfusion of parasitized erythrocytes also resulted in decreased cytoadherence. In addition, incubation of infected cells with human immune sera obtained from malaria patients significantly inhibited the observed cytoadherence. Our results indicate that thrombospondin mediates binding of infected red cells to venular endothelium and may thus be involved in the pathogenesis of cerebral malaria.     

Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is characterized by moderate thrombocytopenia and thrombotic complications, whereas quinine/quinidine-induced thrombocytopenia usually presents with severe thrombocytopenia and bleeding. Using flow cytometry and assays of procoagulant activity, we investigated whether sera from patients with these immune drug reactions could stimulate normal platelets to generate platelet-derived microparticles with procoagulant activity. Sera or purified IgG from patients with heparin-induced thrombocytopenia stimulated the formation of platelet-derived microparticles in a heparin-dependent fashion. Further studies showed that heparin-induced thrombocytopenia sera also produced a marked increase in procoagulant activity. In contrast, sera from patients with quinine- or quinidine-induced thrombocytopenia did not generate platelet-derived microparticles nor generate increased procoagulant activity. However, quinine/quinidine-induced thrombocytopenia sera produced a significant increase in the binding of IgG to platelets in a drug-dependent fashion, whereas sera from patients with heparin-induced thrombocytopenia demonstrated no drug-dependent binding of IgG to platelets. We also observed increased levels of circulating microparticles in patients with acute heparin-induced thrombocytopenia compared with control patients. Our observations indicate that the generation of procoagulant platelet-derived microparticles in vivo is a plausible explanation for the thrombotic complications observed in some patients with heparin-induced thrombocytopenia.     

Normal synthesis and expression of endothelial IIb/IIIa in Glanzmann's thrombasthenia

Glanzmann's thrombasthenia is a bleeding disorder, inherited in an autosomal recessive way and characterized by an absence or deficiency of the platelet glycoprotein (GP) IIb/IIIa complex. Recently, we and others demonstrated that cultured human umbilical vein endothelial cells synthesized a membrane protein complex similar to the platelet GP IIb/IIIa complex. In this article, we demonstrate that endothelial cells isolated from the umbilical vein of a newborn with Glanzmann's thrombasthenia, as compared with normal endothelial cells, show no difference in their ability to synthesize and express this GP IIb/IIIa complex. Our results indicate that Glanzmann's thrombasthenia is not accompanied by an "endotheliopathy."     

A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo

Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients.