The Myocardial Lesions Produced by the Potassium Channel Opener Aprikalim in Monkeys and Rats Are Prevented by Blockade of Cardiac {beta}-Adrenoceptors

Aprikalim is a potent, specific, and selective opener of ATP-sensitiveK⁺ (K_ATP) channels. By virtue of this pharmacological property,aprikalim affords cardioprotection in experimental models ofischemia/reperfusion injury, and, at higher doses, also causesperipheral or coronary vasodilatation. Direct-acting peripheralvasodilators can cause myocardial lesions, particularly in ratsand dogs. However, unexpectedly, aprikalim produced this effectalso in monkeys. Thus, the primary aim of this investigationwas to assess whether in monkeys these myocardial lesions werethe direct or indirect consequence of the vascular effects ofaprikalim. Cyno-mologus monkeys were given the ß-adrenoceptorantagonist nado-lol (2 mg/kg po, twice daily) for 4 consecutivedays. On the third and fourth day of the experiment, they receivedaprikalim (1 mg/kg po). In another series, two monkeys carryingtelemetry transmitters for blood pressure and heart rate measurementswere also given aprikalim or its vehicle. Finally, aprikalim(1 mg/kg po for 2 days) or its vehicle was administered to ratswhich were concurrently treated with the ß-adrenoceptorantagonist atenolol (5 mg/ kg sc) or its vehicle. In cynomologusmonkeys, aprikalim produced focal and multifocal myocardialnecrosis of minimal to moderate intensity in or near the papillarymuscles of the left ventricle. These effects were abrogatedby nadolol. Similarly, necrotic lesions were caused by aprikalimonly in those rats which had not been pretreated with atenolol.In monkeys, aprikalim produced a marked and long-lasting decreasein aortic blood pressure, accompanied by an even more prolongedtachycardia. These results demonstrate that aprikalim can producemyocardial necrosis not only in rats but also in monkeys. Toour knowledge, this is the first time that such adverse effectsare reported for a vasodilator in monkeys. More importantly,these effects were prevented by blocking cardiac ß-adrenoceptors.Thus, the myocardial lesions produced by aprikalim may be attributedto its profound and prolonged hemodynamic effects.     

Subchronic Inhalation Study with Vinyl Fluoride: Effects on Hepatic Cell Proliferation and Urinary Fluoride Excretion

Subchronic Inhalation Study with Vinyl Fluoride: Effects onHepatic Cell Proliferation and Urinary Fluoride Excretion. BOGDANFFY,M. S., KEE, C. R., KELLY, D. P., CARAKOSTAS, M. C, AND SYKES,G. P. (1990). Fundam Appl Toxicol. 15, 394/406. Vinyl fluorideis used widely in the manufacture of fluoropolymers. Based inpart on the structural similarity of vinyl fluoride to the hepatocarcinogensvinyl chloride and vinyl bromide, a TSCA Section 4 test rulemandated the testing of vinyl fluoride for oncogenicity. Thisreport presents the results of a 90-day inhalation study inrats and mice with vinyl fluoride designed to set test concentrationsfor a subsequent oncogenicity study. Groups of 15 male and femalerats and mice were exposed 6 hr per day, 5 days per week forapproximately 90 days to target concentrations of 0, 200, 2000,or 20,000 ppm vinyl fluoride. Clinical chemical, hematological,and urine analyses were performed on rats after 45 and 90 daysof exposure. A hematological evaluation was performed on micefollowing 45 and 90 days of exposure. A complete gross and microscopicevaluation was conducted at the end of the study. After 93 dayson test, groups of five rats and five mice per sex were implantedwith osmotic minipumps containing [3H]thymidine and were exposedfor an additional 5 days to measure cell proliferation in liver,kidney, lung, and nasal cavity tissues. Results of the histopathological,clinical chemical, and hematological evaluations showed no significanteffects of vinyl fluoride exposure at any concentration followingeither 45 or 90 days of exposure. A concentration-related increasein fluoride ion in urine was observed in rats at 45 and 90 daysof exposure. A plateau in urinary fluoride excretion was observedat approximately 2000 ppm, suggesting saturation of vinyl fluoridemetabolism. Vinyl fluoride-related cell proliferation effectswere largely restricted to liver. Hepatic cell proliferationin male and female rats and mice was elevated at all concentrations.The response was similar at concentrations of either 2000 or20,000 ppm and was consistent with concentration-response relationshipsfor other haloethylenes. Taken together, the urinary fluorideexcretion and hepatic cell proliferation data suggest a mechanisticlink between the two effects. On the basis of these findingsand experience with other haloethylenes, concentrations of vinylfluoride to be tested for oncogenicity should be chosen suchthat the full linear range of the concentration-response curveis evaluated. The present study demonstrates through examplethe value of incorporating cell proliferation studies in standardtesting protocols     

Risk Factors for Implantable Defibrillator Lead Fracture in a Recalled and a Nonrecalled Lead

Risk Factors for ICD Lead Fracture. Introduction: The Medtronic Sprint Fidelis® implantable cardioverter defibrillator (ICD) lead was “recalled” in October 2007 after 268,000 implants worldwide due to increased failure risk. Manufacturer suggested monitoring has not been shown effective at preventing adverse events. Only limited data exist regarding clinical predictors of Fidelis® lead fracture. We sought to identify risk factors for Fidelis® fracture to guide clinical monitoring and compare its performance with a control lead. Methods: Fractured lead cases were retrospectively reviewed for demographic data, implant technique, radiographic appearance and clinical presentation was analyzed. Lead survival was compared using Kaplan‐Meir curves. Results: Study patients (n = 1314) experienced 18 Fidelis® and 6 Quattro? lead fractures. Patients with failed Fidelis® leads were younger than those with surviving leads (49.5 vs 64.6 years, P = 0.0066). Fidelis® lead fractures often occurred around the time of physical activity. No other measured demographic or technique related factors were associated with lead fracture. Fidelis® leads had significantly decreased survival compared with Quattro? leads (89.3 vs 98.9% at 30 months). Patients less than 50 years old had significantly decreased lead survival compared with those older than 50 in both Fidelis® (79.6% vs 96.5% at 24 months) and Quattro? (93.4 vs 99.8%, P < 0.001 at 24 months) leads. Conclusions: Patients under age 50, with either Fidelis® or Quattro? ICD leads, are at increased risk of lead fracture compared with patients over 50, particularly around the time of intense physical activity. Aggressive monitoring and advisory programming appears warranted in patients with Fidelis® leads as well as especially in younger patients. (J Cardiovasc Electrophysiol, Vol. 21, pp. 671‐677, June 2010)     

Review article: Luminex technology for HLA antibody detection in organ transplantation

Since its inception in the early 1960s, the serologically based complement-dependent cytotoxicity (CDC) assay has been the cornerstone technique for the detection of human leucocyte antigen (HLA) antibodies, not only in pre-transplant renal patients, but also in other forms of organ transplantation. Recently, solid phase assays have been developed and introduced for this purpose, and in particular the Flow-based bead assays such as the Luminex system. This latter assay has proved to be far more sensitive than the CDC assay and has revealed pre-sensitization in potential transplant recipients not detected by other methods of HLA antibody detection. However, the clinical implications of this increased sensitivity have not been convincingly demonstrated until recently. This technology for HLA antibody detection permits the evaluation of the clinical importance of antibodies directed at, for example, HLA-DPB1 and HLA-DQA1, which has not been possible to date. There are Luminex issues, however, requiring resolution such as the ability to distinguish between complement fixing and non-complement fixing antibodies and determination of their relative clinical significance. Luminex technology will permit a re-evaluation of the role of HLA antibodies in both early and late antibody-mediated rejection.     

Primary hepatic lymphoma in a patient with chronic hepatitis C

The case is presented of a woman with chronic active hepatitis C who developed primary hepatic lymphoma. The possible roles of viral hepatitis and therapeutic interferon in the pathogenesis and progression of this unusual maligancy are discussed. In addition, the importance of accurate tissue diagnosis to identify potentially treatable hepatic tumours is emphasized.