John Boland

Cyclosporine-associated central nervous system toxicity after allogeneic bone marrow transplantation

Five of 64 recipients of HLA-identical sibling marrow allografts who were given cyclosporin (CSP) to minimize graft-versus-host disease posttransplant had a serious neurological illness thought to be due to CSP. Characteristic clinical features included a motor spinal cord syndrome, a cerebellar-like syndrome, and mental confusion. All five recovered when the CSP dose was reduced or the drug was stopped.

Tissue distribution and toxicity of cyclosporin a in the mouse

Summary Groups of mice were given cyclosporin A (CyA) subcutaneously for 6 wk at a dose of 12.5, 50 or 200 mg/kg/d. After 7, 21 and 42 days of CyA administration the CyA content of serum, thymus, mesenteric lymph nodes, spleen, kidney, liver, lung, small and large intestine and brain was measured, each organ was examined histologically, and the total viable nucleated cell content of thymus, mesenteric lymph nodes, spleen and femoral marrow was analysed. CyA was detected in every organ assayed at each concentration of CyA administered. The mean concentration of CyA per organ was consistently highest in organs of mice given CyA 200 mg/kg/d and lowest in those given 12.5 mg/kg/d at each time point, but there was pronounced variability in the concentration of CyA between individual mice. Repeated administration of CyA after the first week did not further elevate CyA tissue concentrations. At doses of 50 or 200 mg/kg/d CyA caused weight loss, diarrhea, intussusception and fatal neurotoxicity. In addition, the spleen, thymus and mesenteric lymph nodes of mice given CyA 50 or 200 mg/kg/d were hypocellular and disorganized, and all lymphoid organs contained numerous pyknotic lymphocytes. The liver showed fatty change and the kidney degeneration of proximal tubules. Femoral marrow showed enlarged and congested sinuses. No abnormalities were noted in mice given CyA 12.5 mg/kg/d.

Effects of antiplatelet therapy on platelet extracellular vesicle release and procoagulant activity in health and in cardiovascular disease

Abstract Dual antiplatelet therapy with aspirin and clopidogrel is commonly used to prevent recurrent ischemic events in patients with cardiovascular disease. Whilst their effects on platelet reactivity are well documented, it is unclear, however, whether antiplatelet therapy inhibits platelet extracellular vesicle (EV) release. The aim of this study was to investigate the effects of antiplatelet therapy on platelet EV formation and procoagulant activity. Blood samples from 10 healthy controls not receiving antiplatelet therapy were incubated in vitro with aspirin or a P2Y12 inhibitor (MeSAMP). Blood samples from 50 patients receiving long-term dual antiplatelet therapy and undergoing coronary angiography were also studied. Platelet reactivity was assessed by Multiplate™ impedance aggregometry. Platelet EV formation and procoagulant activity of pretreated and untreated blood samples in response to arachidonic acid (AA), adenosine diphosphate (ADP), ADP+PGE1, and thrombin receptor-activating peptide (TRAP) stimulation were assessed by flow cytometry and Procoag-PL assays, respectively. Incubation of normal platelets with aspirin significantly inhibited AA-induced platelet reactivity, EV formation, and procoagulant activity, whilst MeSAMP significantly inhibited platelet reactivity and EV formation in response to AA, ADP, and TRAP, but had minimal effect on procoagulant activity. Most patients receiving dual antiplatelet therapy showed an appropriate reduction in platelet reactivity in response to their treatment; however there was not complete inhibition of increased platelet and EV procoagulant activity in response to ADP, AA, or TRAP. In addition, we could not find any correlation between platelet reactivity and procoagulant activity in patients receiving dual antiplatelet therapy.

Impact of New-generation Hybrid Imaging Technology on Radiation Dose during Percutaneous Coronary Interventions and Trans-femoral Aortic Valve Implantations: A comparison with conventional flat-plate angiography

BACKGROUND Technological advancements in newer-generation catheterisation laboratories may reduce patient and occupational radiation exposure. METHODS We compared fluoroscopy time and dose-area product (DAP) between a Philips Allura X-PER FD20 and Siemens Artis Zeego Hybrid systems for 47 single-vessel percutaneous coronary interventions (PCI) and 35 transcatheter aortic valve implantations (21 Corevalve, 14 Edwards Sapien TAVI) using the FD20, versus 30 PCI and 28 TAVI (15 Corevalve, 13 Sapien) with the Zeego over a 24-month period. RESULTS Multivariate analysis revealed that, adjusting for patient weight and fluoroscopy time, DAP (median, interquartile range) was 26% lower for PCI with the Zeego than the FD20 [55.6 (27.0-91.5) vs 77.6 (51.2-129.1) Gy.cm(2), P=0.03)] and using tomographic imaging with the Zeego did not increase DAP for TAVI procedures [98.1 (65.9-136.6) vs 112.4 (64.9-156.2) Gy.cm(2) (P=NS). Although fluoroscopy times were longer for TAVI procedures than PCI with both systems (23.5-24.4 vs 7.3-9.2mins, p<0.0001), there was a significant difference in DAP between PCI and combined TAVI with the Zeego (55.6 vs 112.4Gy.cm(2), P<0.006) but not with the FD20 (77.6 vs 98.1Gy.cm(2), P=NS). CONCLUSION Specific dose-reducing features of the new-generation system reduced DAP more for PCI than TAVI, as valve replacement procedures use additional cine-acquisition not necessary for PCI.

Radiation Dose During Percutaneous Treatment of Structural Heart Disease

BACKGROUND With the increased application of structural heart intervention techniques, there is concern over increasing radiation dose, especially during lengthy procedures. METHODS We compared data from 91 consecutive single-vessel percutaneous coronary interventions, 69 patent foramen ovale closures, 25 atrial septal defect closures, 49 percutaneous transluminal mitral valvuloplasties, 57 balloon aortic valvuloplasties, 53 trans-catheter aortic valve implantations (TAVI), 21 left atrial appendage occlusions and 7 MitraClip procedures. RESULTS The following fluoroscopy times and dose-area product (median, interquartile range) were recorded: patent foramen ovale closure (7.8, 5.3-10.9 minutes; 16.9, 7.5-30.6 Gycm(2)), atrial septal defect closure (10.1, 7.3-13 minutes; 15.5, 11.6-30.5 Gycm(2)), percutaneous transluminal mitral valvuloplasty (14.3, 11.4-24.2 minutes; 37.4, 19.8-87.0 Gycm(2)), balloon aortic valvuloplasty (8.4, 5.2-13.2 minutes; 19.8, 10.2-30.0 Gycm(2)), Edwards Sapien TAVI (24.0, 19.3-34.4 minutes; 86.4, 64.0-111.4 Gycm(2)), Medtronic CoreValve TAVI (19.4, 15.0-26.0 minutes; 101.9, 52.6-143.2 Gycm(2)), left atrial appendage occlusion (18.5, 15.7-29.1 minutes; 84.1, 36.4-140.0 Gycm(2)), Mitraclip procedures (37.2, 14.2-59.9 minutes; 89.1, 26.2-118.7 Gycm(2)), coronary angiography and single vessel percutaneous coronary intervention (6.6, 5.1-11.0 minutes; 62.5, 37.0-95.8 Gycm(2)). CONCLUSION For structural heart interventions, dose-area product was not significantly greater than for coronary angiography with single-vessel percutaneous coronary artery intervention. This should be reassuring to patients and staff attending prolonged structural heart interventions.