Effect of Rb+ on cromakalim-induced relaxation and ion fluxes in guinea pig trachea.

The effects of cromakalim, verapamil and salbutamol have been examined in guinea pig trachealis smooth muscle in both Krebs physiological salt solution and Krebs solution where K+ has been replaced by Rb+. Cromakalim-induced relaxation in the presence of Rb+ was reduced in extent and became transient, whilst the relaxation response to verapamil was enhanced and that to salbutamol unaffected. The transient relaxation occurring in Rb+ was blocked by quinidine and glibenclamide. The presence of extracellular Rb+ also prevented cromakalim-stimulated efflux of both 86Rb+ and 42/43K+. There was, however, no effect on cromakalim-stimulated 86Rb+ uptake. It is proposed that cromakalim is opening two populations of potassium channel in guinea pig tracheal smooth muscle, one of which is susceptible to blockade by Rb+ and one of which is not. The latter channel appears to play the dominant role in cromakalim-stimulated uptake, and is responsible for the transient relaxation response in the presence of rubidium, whilst the former is responsible for the maintained relaxation.     

The effect of monoclonal antibodies to calcitonin gene-related peptide (CGRP) on CGRP-induced vasodilatation in pig coronary artery rings.

1. The modification of the vasodilator effect of calcitonin gene-related peptide (CGRP) by a panel of monoclonal antibodies (MAbs), which map to discrete epitopes on the CGRP molecule, was investigated in pig coronary artery rings (PCA). The preparations were pre-constricted with acetylcholine (3 x 10(-7) M) and concentration-response curves to CGRP (2 x 10(-10)-2.56 x 10(-8) M) were obtained in the presence or absence of each MAb. 2. CGRP caused a concentration-dependent relaxation of PCAs which reached a maximum (98.2 +/- 4.8%, n = 25) at 1.28 x 10(-8) M and gave an EC50 of 3.8 +/- 0.8 x 10(-9) M. 3. Two MAbs which map to the N-terminal, CN1 and CRA3, did not affect the CGRP response whilst a third, CRA5, significantly inhibited its effect. 4. The C-terminal MAb, CRA2, did not modify the CGRP response whilst, in contrast, CB3 (C-terminal) potentiated its effect. A similar augmentation of the CGRP-induced vasodilatation was seen in the presence of the middle-region MAb, CRA8. 5. These results suggest that regional specific MAbs can modify the vasodilator effect of CGRP causing either inhibition (CRA5, N-terminal) or potentiation (CB3, C-terminal; CRA8, middle region).     

Do discrepancies in interpersonal perception predict relapse?: A comparison of remitted depressed patients and collaterals

In an effort to examine whether disturbed interpersonal relationships are associated with relapse in depression, discrepancies in self-ratings provided by formerly depressed patients and their collateral informants were compared. Thirty-eight remitted depressed patients and their collateral informants were asked to monitor moods, life events, and stress levels on a bimonthly basis for a 1-year period. It was hypothesized that patient/collateral dyads displaying a greater discrepancy in interpersonal perception would have a higher risk of relapse than dyads who showed more agreement in their ratings. Results indicated that while discrepancies in the perceptions of patients' life events were associated with the duration of a relapse once it occurred, discrepancies were generally not related to the emergence of new episodes of depressive disorder. The implications of these findings for models seeking to integrate cognitive and interpersonal models of depression, through the study of environmentally determined and personally appraised adversity, is discussed.This research was supported by grants to the first and third authors from the Canadian Psychiatric Research Foundation and the Laidlaw Foundation.     

Bremsstrahlung imaging using the gamma camera: factors affecting attenuation.

Quantitative imaging of bremsstrahlung from pure beta emitters is proposed as a means for in vivo management of antibody therapy. The method involves the use of high-energy collimation, an empirically selected broad photon energy window to enhance detector sensitivity, and a Wiener restoration filter to compensate for system blur. The measured and filtered data were obtained for an idealized scattering medium and isolated spherical sources. An effective linear attenuation coefficient of about 0.13 cm-1 was determined from the raw image data of 32P. A coefficient of 0.14 cm-1 was determined after the images were restored using the Wiener filter. The measured attenuation was not significantly dependent on the size of the region of interest or the size of the source. Its variation was within the experimental error of measurement (+/- 5%). The measured sensitivity (6 x 10(-6) cps/Bq) was sufficient for imaging therapy doses of 32P or 90Y.     

Comparison of risk stratification with pharmacologic and exercise stress myocardial perfusion imaging: A meta-analysis

BACKGROUND: Although pharmacologic stress myocardial perfusion imaging (MPI) and exercise stress MPI have comparable diagnostic accuracy, their comparative value for risk stratification of patients with known or suspected coronary disease is not known. METHODS AND RESULTS: The data of 14,918 patients were combined from 24 studies evaluating prognosis in patients undergoing either pharmacologic stress or exercise stress MPI. Studies were included if a 2 x 2 table for hard cardiac events (cardiac death and myocardial infarction [MI]) could be constructed from the data available. Excluded were studies performed for post-MI, post-revascularization, or preoperative risk stratification. A weighted t test was used to compare the cardiac events, and a random effects model was used to calculate summary odds ratios. Summary odds ratios for hard cardiac events were similar for pharmacologic stress and exercise stress MPI. Summary receiver operating characteristic curves also showed no difference in discriminatory power between the stressors. The cardiac event rates were significantly higher with normal and abnormal test results with pharmacologic stress MPI than with exercise stress MPI (1.78% vs 0.65% [P < .001] for normal results and 9.98% vs 4.3% [P < .001] for abnormal results). Subgroup analysis revealed that both cardiac death and nonfatal MI were significantly higher with pharmacologic stress MPI. Patients undergoing pharmacologic stress MPI had a significantly higher prevalence of poor prognostic factors, and meta-regression revealed that exercise capacity was the single most important predictor of cardiac events. CONCLUSIONS: This meta-analysis shows that exercise stress MPI and pharmacologic stress MPI are comparable in their ability to risk-stratify patients. However, patients undergoing pharmacologic stress studies are at a higher risk for subsequent cardiac events. This is true even for those with normal perfusion imaging results.     

Mortality risk associated with ejection fraction differs across resting nuclear perfusion findings.

BACKGROUND: Left ventricular ejection fraction (LVEF) is a significant predictor of morbidity and death. The nuclear summed rest score (SRS) measures myocardial perfusion defects and provides prognostic information, but its effects on long-term outcomes are not fully established. Moreover, information regarding the potential interaction between these 2 covariates is limited. The purpose of this study was to determine whether the mortality risk associated with LVEF is the same across all values of SRS in a population undergoing evaluation for ischemic heart disease. METHODS AND RESULTS: We examined 3,187 patients who underwent cardiac catheterization and perfusion single photon emission computed tomography imaging with a maximum follow-up of 8.1 years and median follow-up of 3.1 years. Cox proportional hazards modeling showed that increasing nuclear SRS and decreasing LVEF were independently associated with a higher long-term mortality rate, with a clinically significant interaction between them (P = .032). Patients with a normal LVEF and a high SRS (greater perfusion abnormality) have a prognosis similar to those with a reduced LVEF. CONCLUSIONS: Resting perfusion studies provide prognostic information for long-term survival and significantly impact the interpretation of mortality risk associated with changes in LVEF. Patient prognostication, risk stratification, and future research using these variables should take this interaction into account.     

Mortality risk associated with ejection fraction differs across resting nuclear perfusion findings

Background  Left ventricular ejection fraction (LVEF) is a significant predictor of morbidity and death. The nuclear summed rest score (SRS) measures myocardial perfusion defects and provides prognostic information, but its effects on long-term outcomes are not fully established. Moreover, information regarding the potential interaction between these 2 covariates is limited. The purpose of this study was to determine whether the mortality risk associated with LVEF is the same across all values of SRS in a population undergoing evaluation for ischemic heart disease. Methods and Results  We examined 3,187 patients who underwent cardiac catheterization and perfusion single photon emission computed tomography imaging with a maximum follow-up of 8.1 years and median follow-up of 3.1 years. Cox proportional hazards modeling showed that increasing nuclear SRS and decreasing LVEF were independently associated with a higher long-term mortality rate, with a clinically significant interaction between them (P=.032). Patients with a normal LVEF and a high SRS (greater perfusion abnormality) have a prognosis similar to those with a reduced LVEF. Conclusions  Resting perfusion studies provide prognostic information for long-term survival and significantly impact the interpretition of mortality risk associated with changes in LVEF. Patient prognostication, risk stratification, and future research using these variables should take this interaction into account. Supported by a grant from the Tom & Lynn Royster Foundation. Durham, NC, and a National Institutes of Health Research Fellowship Grant (T5 GM08679-04), Bethesda, Md.     

A randomized pilot study in Type 1 diabetes complicated by severe hypoglycaemia, comparing rigorous hypoglycaemia avoidance with insulin analogue therapy, CSII or education alone.

AIM: To determine potential for amelioration of recurrent severe hypoglycaemia without worsening in overall control in individuals with long-standing Type 1 diabetes (T1DM). METHODS: Twenty-one people with T1DM characterized by altered hypoglycaemia awareness and debilitating severe hypoglycaemia were randomized in a pilot 24-week prospective study to optimized analogue therapy (ANALOGUE; lispro/glargine); continuous subcutaneous insulin infusion therapy (CSII; lispro); or re-education with relaxation of blood glucose targets on existing conventional insulin regimen (EDUCATION). Glycaemic profiles and duration of biochemical hypoglycaemia were measured by continuous subcutaneous glucose monitoring and self-monitored blood glucose. RESULTS: Further severe hypoglycaemia was prevented in five participants (71%) in each group (P = 0.06). Incidence of severe hypoglycaemia was: 0.6 (ANALOGUE), 0.9 (CSII), and 3.7 (EDUCATION) episodes per patient year. Restoration of hypoglycaemia awareness was confirmed by validated questionnaire in three (43%) ANALOGUE, four (57%) CSII and five (71%) EDUCATION patients. Glycated haemoglobin (HbA1c) was significantly improved in the ANALOGUE group between weeks 0 and 24 (8.6 +/- 1.1 vs. 7.6 +/- 0.8%; P = 0.04 for change). Non-significant improvement was seen in the CSII group (8.5 +/- 1.9 vs. 7.4 +/- 1.0%; P = 0.06). No change in HbA1c was seen in the EDUCATION group (8.5 +/- 1.1 vs. 8.3 +/- 1.0%; P = 0.54). There were no episodes of diabetic ketoacidosis or any other adverse events in any group. CONCLUSIONS: In this pilot randomized trial comparing optimized ANALOGUE, CSII or EDUCATION alone in unselected individuals with recurrent severe hypoglycaemia, we show potential for restoring hypoglycaemia awareness and preventing further severe hypoglycaemia with concomitant improvement in glycaemic control in ANALOGUE and CSII groups.