The action profile of lispro is not blunted by mixing in the syringe with NPH insulin

OBJECTIVE: To assess the effect of mixing the insulin analog lispro (Humalog) with NPH (Humulin I) before injection on lispro's fast, short action profile. RESEARCH DESIGN AND METHODS: A total of 12 healthy volunteers received subcutaneous abdominal injections of 0.1 U/kg regular insulin and 0.2 U/kg NPH insulin as follows: lispro and NPH injected separately (treatment group A), lispro and NPH mixed in the syringe up to 2 min before single injection (treatment group B), and human regular insulin and NPH mixed and injected as in group B (treatment group C), on separate occasions, in random order. Plasma glucose was maintained for 12 h by intravenous 20% glucose. Pharmacokinetic and pharmacodynamic parameters were compared by analysis of variance for repeated measures. RESULTS: Peak plasma insulin levels (2.6 +/- 0.8 vs. 2.2 +/- 0.6 vs. 1.9 +/- 0.6 ng/ml, P = 0.075), total glucose infused (121.5 +/- 32.8 vs. 135.0 +/- 49.0 vs. 117.3 +/- 39.9 mg.kg-1.min-1, P = 0.53), and maximum glucose infusion rate (GIRmax) (8.3 +/- 0.9 vs. 8.0 +/- 1.7 vs. 7.1 +/- 2.4 mg.kg-1.min-1, P = 0.65) were not significantly different between treatments. The times until peak insulin concentrations were similar in treatment groups A and B, but significantly shorter than in treatment group C (0.9 +/- 0.3 and 1.2 +/- 0.2 vs. 2.0 +/- 0.4 h, respectively, P = 0.042). The times until GIRmax were also not different (113.9 +/- 41 and 122.0 +/- 45 vs. 209.0 +/- 51.3 min, respectively, P = 0.002). The glucose infusion rate (GIR) then fell to 50% GIRmax more quickly in treatment groups A and B than in treatment group C (239.9 +/- 40.5 vs. 292.4 +/- 133.3 vs. 399.5 +/- 78.3, respectively, P = 0.005). CONCLUSIONS: The action profile of lispro is not attenuated by mixing lispro with NPH in the syringe immediately before injection. The advantages are available to those individuals who need to combine types of insulin before injection to achieve optimal diabetes control.     

Engagement of ICAM-3 activates polymorphonuclear leukocytes: aggregation without degranulation or beta 2 integrin recruitment

ICAM-3 is a preferred counterreceptor for the leukocyte alpha(L)beta2 integrin. It activates T cells through outside-in signaling, but polymorphonuclear leukocytes (PMN) are reported to be refractory to ICAM-3 stimulation. We found that engagement of ICAM-3 by a mAb (CAL3.10), which binds in the region where alpha(L)beta2 integrin binds, activates PMN homotypic aggregation and adhesion to surfaces. These functional changes were due to ICAM-3 outside-in signaling because aggregation and adhesion were beta2 integrin-dependent, tyrosine kinase and protein kinase C activities were activated, and there was a reorganization of the cytoskeleton. This reorganization and kinase activity was required for ICAM-3-, but not FMLP-, induced aggregation. This is not an Fc-mediated event as an appropriate anti-ICAM-3 F(ab')2 fragment still induced aggregation. Another anti-ICAM-3 Ab (HP2/19), which activates T cells, did not activate PMN. Strikingly, anti-ICAM-3 did not induce degranulation or cause an increase in surface beta2 integrin expression, so adhesion and aggregation were due solely to the activation of the constitutively expressed beta2 integrins. Aggregation in response to ICAM-3, but not FMLP, was compromised at lower cell densities, showing that beta2 integrin recruitment enhances aggregation under suboptimal conditions. We conclude that engagement of ICAM-3 stimulates PMN as well as T cells, but that the appropriate epitope varies between these two cells. ICAM-3 outside-in signaling reorganizes the cytoskeleton without causing degranulation, induces serine and tyrosine kinase activation, and activates existing surface beta2 integrins to a proadhesive state.     

Mechanism of suppression of cell-mediated immunity by measles virus

The mechanisms underlying the profound suppression of cell-mediated immunity (CMI) accompanying measles are unclear. Interleukin-12 (IL-12), derived principally from monocytes and macrophages, is critical for the generation of CMI. Measles virus (MV) infection of primary human monocytes specifically down-regulated IL-12 production. Cross-linking of CD46, a complement regulatory protein that is the cellular receptor for MV, with antibody or with the complement activation product C3b similarly inhibited monocyte IL-12 production, providing a plausible mechanism for MV-induced immunosuppression. CD46 provides a regulatory link between the complement system and cellular immune responses.     

Analogues of the thrombin receptor tethered-ligand enhance mesangial cell proliferation

Thrombin stimulates cytosolic calcium mobilization and tritiated thymidine incorporation in rat glomerular mesangial cells. This effect may be mediated by a thrombin receptor similar to the receptor found in human platelets. In order to test this possibility, a series of analogues of the thrombin receptor peptide, SFLL-RNPNDKYEPF, was evaluated for their effects on mesangial cells. Analogues of the thrombin receptor peptide containing five, six, seven and 14 amino acids were as efficacious as thrombin with respect to calcium mobilization and thymidine incorporation, although they were significantly less potent. The dissimilarity in potency between thrombin and the thrombin receptor peptides is consistent with the kinetics of the proposed mechanism of action of the enzyme, since the cleavage by thrombin of its receptor results in a tethered ligand which is at a relatively high concentration compared to the free peptides in solution. Those thrombin receptor peptide analogues which showed decreased activity in platelets were tested in mesangial cells. Removal of serine at position one, N-acetylation, or replacement of the phenylalanine at position two with alanine resulted in analogues which were inactive in stimulating mesangial cell proliferation or calcium mobilization. In addition, those analogues which had no stimulatory effects in mesangial cells were not antagonists of SFLLRN-mediated calcium mobilization and thymidine incorporation in mesangial cells.     

Anemia increases gastric blood flow in noncirrhotic and cirrhotic patients

BACKGROUND: Previous studies in rats have demonstrated that anemia induces a significant increment in gastric mucosal blood flow. In the present study, we investigated whether chronic anemia induces similar changes in gastric blood perfusion in humans, and if this effect is also present in cirrhotic patients in whom gastric blood flow is usually increased in basal conditions. METHODS: Gastric mucosal blood perfusion was assessed by means of laser-Doppler flowmetry and reflectance spectrophotometry applied through the endoscope. RESULTS: Anemia significantly increases laser-Doppler signal in cirrhotic (2.3 +/- 0.11 vs 2.9 +/- 0.22 volts, p < 0.05) and noncirrhotic patients (1.71 +/- 0.15 vs 2.24 +/- 0.17, p < 0.05). In anemic patients the index of hemoglobin concentration of the gastric mucosa, assessed by reflectance spectrophotometry, was significantly decreased in cirrhotic patients (107.6 +/- 4.7 vs 95.5 +/- 3.3, p < 0.05) and noncirrhotic patients (93.9 +/- 4.1 vs 76.1 +/- 4.2, p < 0.01), whereas the index of oxygen saturation was increased (36.7 +/- 0.7 vs 40.4 +/- 1.4, p = 0.05; and 36.4 +/- 1.1 vs 43.2 +/- 1.9, p < 0.01, respectively). CONCLUSIONS: In conclusion, chronic anemia is associated with an enhanced gastric blood perfusion reflected by an increased laser-doppler signal and gastric mucosal oxygen index despite a decrease in gastric hemoglobin concentration. In cirrhotic patients, anemia promotes a further increment in its basal gastric hyperemia.     

Stress and the immune response in rats

The in vitro response of sensitized splenic lymphocytes to antigen (thyroglobulin) was increased by crowding and decreased by isolation in female rats. Both isolated and crowded male rats responded by a decrease in the in vitro reactivity of lymphocytes to antigen. The response of the lymphocytes to PHA was not altered in any consistent manner. Similar animals, both control and those immunized with thyroglobulin, were tested for an effect of in vivo injections of epinephrine on the in vitro reactivity of lymphocytes; epinephrine was given intraperitoneally 30 min before the rats were killed for removal of spleens. Incorporation of 3H-thymidine by lymphocytes was greater in control cultures (neither PHA nor antigen present) but there was a decreased response to either PHA or antigen when epinephrine had been injected.