Enhanced nitric oxide release during cortical spreading depression following infusion of glyceryl trinitrate in the anaesthetized cat

Intravenous infusion of glyceryl trinitrate (GTN) into migraineurs induces an immediate headache followed by migraine. We studied the effect of GTN 10.25 g kg¹ min ¹) on local cerebrovascular laser Doppler flux (rCBF_LDF), artery diameter and NO concentration (selective NO microelectrode) in the pial middle cerebral artery perfusion territory of the anaesthetized cat, at rest and during cortical spreading depression (SD). GTN infusion induced a significant increase in pial artery diameter, rCBF_LDF, and NO concentration. Following termination of infusion, NO concentrations remained significantly elevated above controls for 60 min, other parameters returned to baseliae within 10 min ( p 0.05, ANOVA, post hoc Dunnett's multiple comparison procedure). Two hours after termination of infusion KCl-evoked SD was initiated. GTN-treated animals exhibited significantly ( p 0.05, Kruskal-Wallis) elevated SD-induced NO release compared to controls. All other parameters remained unaffected. Our results demonstrate that GTN induces a prolonged increase in local NO concentrations and enhances SD-induced NO release.     

The differentiation of delayed hemolytic and delayed serologic transfusion reactions: incidence and predictors of hemolysis

BACKGROUND: After differentiation of the entities of clinically detectable delayed hemolytic (DHTR) and delayed serologic transfusion reactions (DSTR), previous investigators calculated a DHTR:DSTR incidence ratio of 18:72 from a retrospective review of patients with serologic evidence of DHTR or DSTR. There are no published data on factors that may influence the occurrence of DHTR versus DSTR in a given patient. STUDY DESIGN AND METHODS: Retrospective review was conducted of 292 patients at the Mayo Clinic who, between 1980 and 1992, received a clinical diagnosis of DHTR or DSTR concurrently with a serologic diagnosis. Red cell alloantibody specificity, the activity of the patient's reticuloendothelial system, and concurrent immunosuppression were evaluated as potential predictors of the occurrence of DHTR versus DSTR in different patients. RESULTS: The incidence of DHTR or DSTR was 1 in 1899 allogeneic red cell units transfused, with a DHTR:DSTR ratio of 36:64. Alloantibody specificity was the only variable that affected the occurrence of DHTR versus DSTR at the clinical level, with the anti-Jka and anti-Fya specificities, as well as multiple coexisting specificities, significantly associated with detectable hemolysis (p < 0.05). CONCLUSION: Clinically detectable DHTRs are found to occur more commonly than previously believed when the clinical and serologic diagnoses are made concurrently and appropriate work-ups for hemolysis are ordered. The association of certain alloantibody specificities with detectable DHTRs may have implications for clinical transfusion practice.     

Furosemide inhibits regenerative cortical spreading depression in anaesthetized cats

Ionic perturbations occur during cortical spreading depression (SD), a phenomenon implicated in migraine pathophysiology. We studied the effect of 0.2,2 and 20 mg kg⁻¹ iv ( n =4) furosemide on cortical direct current (d.c.) potential, cerebrovascular laser Doppler flux (rCBF_LDF), artery diameter and NO concentration in the parietal cortex of the anaesthetized cat during repetitive SD. In vehicle treated animals ( n =4), SD activity was sustained for 50 1.8 min. However, duration of SD activity was significantly reduced when compared to vehicle to 39 6.6 ( n =4), 3.1 8.3 ( n =4) and 27.3 11.3 min ( n =4), at 0.2, 2 and 20 mg kg⁻¹ iv furosemide respectively. It is hypothesized that the mechanism of inhibition of SD d.c. activity by furosemide may be through alterations in cortica ion buffering capacity or inhibition of cell swelling in neurones or glia. These mechanisms may represent potential novel drug targets in future migraine therapy.     

Recombinant immunoblot assay reaction patterns and hepatitis C virus RNA in blood donors and non-A, non-B hepatitis patients

To establish the value of the second-generation recombinant immunoblot assay (RIBA-2) and cDNA polymerase chain reaction (cDNA PCR) for confirmation of hepatitis C virus (HCV) infection, anti-HCV reaction patterns and the presence of HCV RNA were examined in 610 blood donors and 255 non-A, non-B hepatitis patients who were positive or indeterminate in RIBA-2. Of RIBA-2-positive donors (n = 191) and patients (n = 224), 75.4 and 89.7 percent, respectively, were HCV RNA positive. The most frequently observed anti-HCV recognition patterns in HCV RNA-positive donors and patients were c22, c33c, and c100 and/or 5- 1-1 (67.3%, 57.7%) and c22, c33c (24.8%, 29.3%). Among subjects with a RIBA-2-indeterminate result, HCV RNA was detected more often in patients (n = 31) than in donors (n = 419): 67.7 and 2.1 percent, respectively. In viremic persons with single-band reactivity in RIBA-2, this reactivity was always directed against either c22 or c33c. HCV RNA was detected by cDNA PCR in none of 162 persons with only anti-c100 and/or anti-5-1-1 reactivity. Therefore, RIBA-2 reactivity against c100 in combination with 5-1-1 should not be considered positive but indeterminate. In RIBA-2-indeterminate persons, HCV RNA detection is necessary for reliable confirmation of HCV infection.     

Discovery and evaluation of biphenyl derivatives of 2-iminobenzimidazoles as prototype dual PTP1B inhibitors and AMPK activators with in vivo antidiabetic activity

This work describes the synthesis of series hydrobromides of N-(4-biphenyl)methyl–N′-dialkylaminoethyl-2-iminobenzimidazoles, which, due to the presence of two privileged structural fragments (benzimidazole and biphenyl moieties), can be considered as bi-privileged structures. Compound 7a proved to activate AMP-activated kinase (AMPK) and simultaneously inhibit protein tyrosine phosphatase 1B (PTP1B) with similar potency. This renders it an interesting prototype of potential antidiabetic agents with a dual-target mechanism of action. Using prove of concept in vivo study, we show that dual-targeting compound 7a has a disease-modifying effect in a rat model of type 2 diabetes mellitus via improving insulin sensitivity and lipid metabolism.