The Role of Myocardial KATP‐Channel Blockade in the Protective Effects of Glibenclamide against Ischaemia in the Rat Heart

Abstract: Glibenclamide preserves postischaemic myocardial function in the isolated, erythrocyte perfused, working rat heart model. This study addresses the possible involvement of K_ATP channels in this beneficial action of glibenclamide. We hypothesized that if glibenclamide improved postischaemic cardiac function by blocking of K_ATP channels, opening of these K_ATP channels should result in the opposite, namely detrimental effects on postischaemic heart function. Postischaemic functional loss and coronary blood flow were recorded during treatment with glibenclamide (4 μmol.l^?1; n=5), the K_ATP channel openers pinacidil (1 μmol.l^?1; n=5) and diazoxide (30 μmol.l^?1; n=5), the combination of glibenclamide with pinacidil (n=5) and glibenclamide with diazoxide (n=5), and vehicle (n=8). Both pinacidil and diazoxide significantly increased coronary blood flow 2–3 times, which was abolished by glibenclamide pre‐ and postischaemically. This confirms that under both flow conditions glibenclamide significantly blocks K_ATP channels in the coronary vasculature. The 12 min. global ischaemic incident resulted in a cardiac functional loss of 22.2±2.9% during vehicle. Glibenclamide reduced the cardiac functional loss to 4.3±1.2% (P<0.01). Interestingly, both pinacidil and diazoxide reduced the cardiac functional loss to 4.0±1.5% (P<0.01) and 2.9±1.4% (P<0.001), respectively. The combination pinacidil+glibenclamide resulted in additional protection compared with the individual components (0.6±0.1 versus 4.0±1.5%, P<0.05). Thus, in contrast to its effect on coronary vascular tone, the glibenclamide‐induced improvement of postischaemic cardiac function may not be mediated through blockade of the K_ATP channel. Alternative mechanisms may be operative, such as uncoupling of the mitochondrial respiratory chain, thereby preconditioning the hearts against stunning.     

Attachment Measures for Research and Practice

Strategies and specific measures for assessing attachment in infancy and childhood are reviewed. The review highlights that, although the evidence base for a number of measures is now strong, the incorporation of these measures into clinical practice has been slow. Some of the practical barriers to include attachment measures in clinical practice are considered, and ideas for overcoming these barriers are proposed.     

Mortality related to diagnostic cardiac catherization

Background. The mortality of diagnostic catheterization is very low but still exists. Large series have documented left main disease as the most important anatomical risk factor but have not clarified the mechanism. Objectives. (1) To determine the mortality of diagnostic catheterization in a single high volume centre over a 9 year period and assess any change during this period. (2) To compare this experience with that of larger multicentre surveys (3) To identify the clinical and anatomical risk factors. (4) To investigate the mechanism of the event (5) To develope quidelines for prevention. Methods. Cardiac catheterization records were reviewed over a 9 year period and patients dying during or within 24 hours were identified. The clinical and anatomical profile of the patients who died were compared with the overall group to search for independent risk factors. The angiograms of the deaths were reviewed for a mechanism. Results. There were 30 deaths in 42,345 procedures (0.071%). There was no change in the incidence over the 9 years. Left main coronary disease was an overwhelming risk factor (incidence 0.7%, p<.002 compared to all other subgroups) and no other anatomical subgroup including triple vessel disease was at greater risk than the overall group. Dissection of the left main coronary artery by the diagnostic catheter was the mechanism of death in 20 cases (67%). Conclusions. Left main disease and catheter induced trauma are the most important risk factor for and mechanism of death during diagnostic catheterization and may account for the unchanging incidence. Technical guidelines are described which may reduce this risk.     

Anatomy of the human patellofemoral joint articular cartilage: Surface curvature analysis

Articular cartilage surfaces of 49 human patellae and 24 distal femora were characterized by identifying distinctive features with surface curvature analysis. Paired specimens from the same donor generally exhibited natural symmetry, so only results from nonpaired specimens were considered (39 patellae and 19 femora). In 23 of 39 patellae, proximal median and lateral transverse ridges extended to form an oblique ridge resembling a skewed lambda (λ). Most of the unpaired patellae (37 of 39) exhibited only a single lateral transverse ridge, and most (32 of 39) had an odd facet. All but one patella exhibited a concave depression in the lateral and medial facets and a sellar area in the proximal region. All distal femoral surfaces exhibited a sellar trochlea. The concavity of the trochlea was greatest in the posterioraspect, near the intercondylar notch.     

Pointwise assessment of three-dimensional computer reconstruction of mitral leaflet surfaces from rotationally scanned echocardiograms in vitro.

Three-dimensional transesophageal echocardiography offers promise for improved understanding of mitral leaflet pathology, but it has not been validated quantitatively, nor has the minimum number of imaging planes for satisfactory reconstruction been determined with a rotational scanning geometry. This study assessed its accuracy in vitro by comparing, on a 1 x 1-mm grid, the surfaces of mitral leaflets derived from 5-degree rotational ultrasonic scans with those derived from laser scans of casts of the atrial side of the leaflets. Overall, the ultrasonically derived surface had a mean absolute deviation of 0.65 +/- 0.12 mm from the laser-derived surface. Using only alternate imaging planes (10-degree increments) made no significant difference in the overall distribution of deviations (P =.56), although the distributions on some individual specimens differed markedly. We conclude that 5-degree rotational scanning in vitro can reconstruct the mitral valve leaflets with sufficient accuracy and detail to render clinically important features.     

Variation in the TNF gene promoter and risk of osteolysis after total hip arthroplasty.

Genetic factors may influence implant failure caused by osteolysis after THA. In an association study of 481 subjects after THA, we found that carriage of the TNF-238A allele was associated with an increased incidence of osteolysis versus noncarriage (odds ratio, 1.7) and was independent of other risk factors. Genetic and environmental factors influence implant survival after THA. INTRODUCTION: Tumor necrosis factor (TNF) is thought to play a role in osteolysis, the major cause of implant failure after total hip arthroplasty (THA). Natural sequence variations at -238 and -308 in the TNF gene promoter are associated with differences in susceptibility to several TNF-mediated diseases. We tested whether these polymorphisms are associated with osteolysis after THA. MATERIALS AND METHODS: A total of 481 whites (214 with failed versus 267 with intact implants) were recruited 11.7 +/- 4 years after cemented THA. Genomic DNA was extracted from peripheral blood and genotyped for the -238 and -308 polymorphisms using the Taqman 5' nuclease method. Healthy controls (n = 500) from the background population were also genotyped to establish the local prevalence of these alleles. RESULTS: The carriage of -238A was 8.8% in the background population and 10.9% in the THA controls (p > 0.05). Carriage of -238A in the osteolysis group was 17.3% (odds ratio, 1.7; 95% CI, 1.0-2.9). Carriage was highest (20.5%) in patients with more widespread osteolysis (OR, 2.1; 1.2-3.8). The association of -238A with osteolysis was independent of other risk factors for osteolysis (logistic regression analysis: OR, 1.8; 1.0-3.2). Carriage of -308A was not associated with osteolysis. CONCLUSION: Genetic, as well as environmental factors, influence implant failure after THA. Whether the TNF-238 polymorphism causes a biological change that predisposes to loosening or is in linkage disequilibrium with such a locus is not yet known.     

Quantitative 89Zr immuno-PET for in vivo scouting of 90Y-labeled monoclonal antibodies in xenograft-bearing nude mice.

Immuno-PET as a scouting procedure before radioimmunotherapy (RIT) aims at the confirmation of tumor targeting and the accurate estimation of radiation dose delivery to both tumor and normal tissues. Immuno-PET with (89)Zr-labeled monoclonal antibodies (mAbs) and (90)Y-mAb RIT might form such a valuable combination. In this study, the biodistribution of (89)Zr-labeled and (88)Y-labeled mAb ((88)Y as substitute for (90)Y) was compared and the quantitative imaging performance of (89)Zr immuno-PET was evaluated. METHODS: Chimeric mAb (cmAb) U36, directed against an antigen preferentially expressed in head and neck cancer, was labeled with (89)Zr using the bifunctional chelate N-succinyldesferrioxamine B (N-sucDf) and with (88)Y using the bifunctional chelate p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bz-DOTA). The radioimmunoconjugates were coinjected in xenograft-bearing nude mice, and biodistribution was determined at 3, 24, 48, 72, and 144 h after injection. (89)Zr was evaluated and compared with (18)F in phantom studies to determine linearity, resolution, and recovery coefficients, using a high-resolution research tomograph PET scanner. The potential of PET to quantify cmAb U36-N-sucDf-(89)Zr was evaluated by relating image-derived tumor uptake data (noninvasive method) to (89)Zr uptake data derived from excised tumors (invasive method). RESULTS: (89)Zr-N-sucDf-labeled and (88)Y-p-SCN-Bz-DOTA-labeled cmAb U36 showed a highly similar biodistribution, except for sternum and thigh bone at later time points (72 and 144 h after injection). Small differences were found in kidney and liver. Imaging performance of (89)Zr approximates that of (18)F, whereas millimeter-sized (19-154 mg) tumors were visualized in xenograft-bearing mice after injection of cmAb U36-N-sucDf-(89)Zr. After correction for partial-volume effects, an excellent correlation was found between image-derived (89)Zr tumor radioactivity and gamma-counter (89)Zr values of excised tumors (R(2) = 0.79). CONCLUSION: The similar biodistribution and the favorable imaging characteristics make (89)Zr a promising candidate for use as a positron-emitting surrogate for (90)Y.