Biomedical subjects
Publications and source records attributed to M Yacoub.
We present the case of a child who developed the syndrome of cerebrospinal fluid (CSF) overdrainage with slit-like ventricles on CT in the setting of a disconnected distal shunt valve. Upgrading the shunt alleviated his symptoms. It is suggested that the presence of a patent fibrous tract allowed the overdrainage of CSF.
Datura stramonium is a hallucinogenic plant which causes serious poisoning. Clinical symptoms are those of atropinic intoxication with psychiatric manifestations of dryness of mouth, mydriasis, tachycardia and hallucinations. Diagnosis is essentially clinical. Treatment is symptomatic and suppurative; prognosis is usually favorable.
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The early hemodynamic benefits of stentless aortic valves have been well documented. The issue of long-term functional integrity remains unanswered. We report the clinical results of a multicenter registry with prospective data on 621 patients monitored for 7.1 years. Patient data were collected and analyzed at St Jude Medical Inc, St Paul, Minnesota. In all, 66% of patients were male; the average age was 65.9 years +/-11.0 years, with 39% older than 70 years. Native aortic valves were bicuspid in 40.6%, 91.5% were calcified and 65.7% stenotic. Most valves implanted (83.1%) were sizes 25, 27, or 29 mm. Concomitant coronary bypass was performed in 42% of patients. Total follow-up time for the 621 patients was 1,944.5 valve years (mean 3.1 years per patient). At 5 years, 86.1% (n = 137) and at 6 years 80.4% (n = 51) were in New York Heart Association class I, and 78% had no or trivial atrial insufficiency. The average mean systolic gradient for all valves at 6 years was 4.0 mm Hg, and the peak gradient was 8.6 mm Hg. The effective orifice area varied from 1.4 cm2 (23-mm valve) to 2.7 cm2 (29-mm valve). The decrease in left ventricular mass index was significant and sustained. Actuarial survival at 6 years was 84.2%, and freedom from cardiac-related deaths was 90.1%. Freedom from valve-related deaths was 95.7%, and freedom from prosthetic endocarditis was 98.6%. There were no instances of primary tissue valve failure during follow-up, with 97.2% freedom from reoperation. The early hemodynamic benefits of the TSPV are well maintained during more than 6 years of follow-up, without evident valvular dysfunction. Longer follow-up time is required to validate durability, but there is increasing evidence for well-maintained structural and functional integrity.
Hemophagocytosis has already been in cases of visceral leishmaniasis and thus may complicate search for diagnosis. We report a case of hemophagocytosis in a 20 month-old boy presenting with fever, hepatosplenomegaly, pancytopenia and coagulopathy. An initial diagnosis of kala-azar was refuted because of absence of biological inflammatory syndrome and negativity of bone-marrow aspiration. Specific serology for visceral leishmaniasis become positive. The boy was given stibogluconate for 21 days; he improves gradually with complete remission.
Stentless tissue valves may provide more favorable hemodynamics than conventional stented valves. Hemodynamic findings from a large multicenter trial have not been previously reported. The present report describes the hemodynamic findings from a multinational, multicenter study after implantation of the Toronto SPV valve. A total of 577 patients underwent aortic valve replacement with the Toronto SPV valve at 12 sites in 3 countries. Echocardiograms were recorded in the early postoperative period, 3 to 6 months after surgery, 1 year after surgery, and yearly thereafter, with follow-up to 3 years. Gradients decreased and effective orifice area increased in the months after surgery. One year after surgery, mean gradient for valve sizes 20 to 22, 23, 25, 27, and 29 mm was 7.3 +/- 4.4, 7.4 +/- 4.5, 6.1 +/- 3.3, 4.9 +/- 2.4, and 4.0 +/- 2.1 mm Hg, respectively; effective orifice area was 1.3 +/- 0.7, 1.5 +/- 0.5, 1.7 +/- 0.4, 2.0 +/- 0.4, and 2.4 +/- 0.6 cm2, respectively. There was a very low prevalence of significant aortic regurgitation at all time periods. There was significant left ventricular (LV) mass regression between the early and 3- to 6-month periods and between the 3- to 6-month and 1-year postoperative periods. The Toronto SPV valve has an excellent hemodynamic profile supported by significant regression of LV hypertrophy in the year after implantation. Data through 3 years demonstrates maintenance of low gradients and freedom from significant aortic regurgitation.
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BACKGROUND: Leukotrienes are a class of biologically active lipids that have potent effects on the heart. To assess their role in coronary artery disease, we compared the contractile responses of leukotriene C4 (LTC4) and leukotriene D4 (LTD4) and their binding activity in both atherosclerotic and nonatherosclerotic human coronary arteries. We also studied expression of the enzymes that control their formation to understand how the 5-lipoxygenase (5-LO) pathway is activated in the coronary arteries. METHODS AND RESULTS: The capacity of leukotrienes to affect coronary vessel tone and the influence of atherosclerosis was tested in organ baths. Leukotriene receptors were examined by autoradiography, and antibody binding to the various enzymes responsible for their formation was assessed by use of immunocytochemistry. Nonatherosclerotic coronary artery ring segments were unresponsive to LTC4 and LTD4. In contrast, LTC4 and LTD4 induced concentration-dependent contractions in atherosclerotic coronary arteries. Specific [3H]-LTC4 but not LTD4 binding to atherosclerotic coronary artery was evident, with no evidence of specific binding of [3H]-leukotrienes to nonatherosclerotic coronary artery. High-resolution autoradiography identified specific [3H]-LTC4 binding sites to smooth muscle cell and to regions of intimal proliferation and plaque. Cells showing positive antibody binding to 5-LO, FLAP (5-lipoxygenase activating protein), and leukotriene A4 hydrolase were also present in the coronary arteries and had a similar distribution to macrophages. CONCLUSIONS: Atherosclerosis is associated with a specific leukotriene receptor(s) capable of inducing hyperreactivity of human epicardial coronary arteries in response to LTC4 and LTD4.
Low density lipoprotein (LDL) interactions with the endothelium are thought to play a major role in the development of atherosclerosis. The mechanism(s) involved are not fully understood, although several lines of evidence support the idea that oxidation of LDL increases its atherogenicity. In this study we report for the first time that native LDL (n-LDL) binding to the LDL receptor (100-700 mug/ml) triggers a rise in intracellular calcium which acts as a second messenger to induce vascular cell adhesion molecule-1 (VCAM-1) expression in human coronary artery (HCAEC) and pig aortic endothelial cells (PAEC) and VCAM-1 and E-selectin expression in human aortic (HAEC) endothelial cells. Preincubation of HCAEC with a monoclonal antibody (IgGC7) to the classical LDL receptor or pretreatment with pertussis toxin blocked the n-LDL-induced calcium transients. Preincubation of each of the endothelial cell lines with the calcium chelator 1,-2-bis(o-aminophenoxy)ethane-N,N,N', N'-tetraacetic acetomethyl ester (BAPTA/AM) prevented the expression of VCAM-1 and E-selectin. The increase in VCAM-1 by n-LDL results in increased monocyte binding to HCAEC which can be attenuated by inhibiting the intracellular calcium rise or by blocking the VCAM-1 binding sites. These studies in human and pig endothelial cells link calcium signaling conferred by n-LDL to mechanisms controlling the expression of endothelial cell adhesion molecules involved in atherogenesis.
BACKGROUND: During open cardiac operations using cardiopulmonary bypass, there is activation of coagulation and fibrinolysis. We assessed the separate contributions of the surgical procedure itself and cardiopulmonary bypass to this, by studying sequential samples from patients undergoing routine open cardiac operations or thoracic operations without cardiopulmonary bypass. METHODS: Activation of coagulation and the extent of fibrinolysis were measured from sequential samples obtained before the operation to 48 hours after the operation for 7 thoracic patients and 8 cardiac patients. RESULTS: In the thoracic group operation length was shorter (p = 0.002), and there was no significant increase in thrombin-antithrombin III complexes or D-dimers until 24 hours postoperatively. In contrast, there was a highly significant increase in thrombin-antithrombin III complexes (p = 0.0043) and D-dimer levels (p = 0.009) during cardiopulmonary bypass. The increase in fibrinolytic activity was caused by an increase in tissue plasminogen activator (p = 0.013). At 48 hours postoperatively, the cardiac patients had a more hypercoagulable state than thoracic patients with significantly higher levels of thrombin-antithrombin III complexes (p = 0.041) and plasminogen activator inhibitor-1 activity (p = 0.0033). CONCLUSIONS: This study suggests the major activation of coagulation and fibrinolysis seen during cardiac operations is caused by the use of cardiopulmonary bypass.
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OBJECTIVE: To assess the in vivo contribution to complement activation of an extracorporeal circuit and the use of high-dose aprotinin during major surgery. DESIGN: Sequential samples were obtained from 8 patients undergoing thoracic surgery, 20 patients undergoing orthotopic liver transplantation (OLT) using venovenous bypass, and 19 patients undergoing cardiac surgery using cardiopulmonary bypass (CPB). INTERVENTION: The latter two groups were part of a randomized controlled trial of high-dose aprotinin. MEASUREMENTS: Total complement activation was measured with the hemolytic complement activity and the C3 activation-specific marker, C3d antigen. MAIN RESULTS: Complement activation did not occur during thoracic surgery. During OLT, C3d antigen levels, expressed as mean +/- standard deviation (SD), were elevated from baseline at skin closure (8.6 +/- 2.5 v 13.0 +/- 5.2 mg/L; p = 0.0082). During cardiac surgery, C3d antigen levels increased 10 minutes after the start of CPB (pre-CPB, 8.0 +/- 1.9 v 14.2 +/- 3.1 mg/L; p = 0.0001) and remained at greater than baseline values postoperatively (8.0 +/- 1.9 v 11.8 +/- 2.3 mg/L; p = 0.002). There was no difference in complement activation in those receiving high-dose aprotinin during OLT or cardiac surgery. Complement activation during cardiac surgery using extracorporeal circulation occurred to a greater extent than during OLT and thoracic surgery. Complement activation during cardiac surgery or OLT was not attenuated by the use of high-dose aprotinin.
1. It is now accepted that uncontrolled proliferation of human airway smooth muscle (HASM) cells contributes, in many cases, to the chronic stages of asthma. However, the physiological and pathophysiological processes regulating cell growth and division in the airway are not clear. We have recently shown that the immediate early gene, cyclo-oxygenase-2, is induced by cytokines in HASM cells. Since cyclo-oxygenase metabolites, such as prostaglandin (PG) E2 have been shown to modulate HASM cell growth, we have investigated any autocrine action of endogenously released cyclo-oxygenase-1/2 products on the proliferative responses in these cells. 2. HASM cells were cultured from healthy tissue obtained at lung or heart/lung transplantation. HASM cell proliferation was measured by [3H]-methyl thymidine uptake by cells and by cell counts. Cyclo-oxygenase-2 expression was measured by Western blot analysis and activity measured by the release of PGE2, by radioimmunoasay. 3. HASM cells proliferated in response to foetal calf serum, a response that was greatly inhibited when cyclo-oxygenase-2 was induced with either interleukin-1beta plus tumour necrosis factor-alpha or interleukin-1beta, tumour necrosis factor alpha plus interferon gamma (each at 10 ng ml(-1)). The inhibitory effect of cytokines on HASM cell proliferation was reversed in a concentration dependent manner by either the mixed cyclo-oxygenase-1/-2 inhibitor, indomethacin or the selective cyclo-oxygenase-2 inhibitor, L-745,337 (each at 10 microM). 4. PGE2 or the stable analogue of prostacyclin, cicaprost concentration-dependently (0.1 pmol to 1 microM) inhibited serum induced proliferation of HASM cells. By contrast, the TP receptor agonist, U46619 stimulated proliferation of HASM cells when cells were cultured without but not with serum. Other cyclo-oxygenase products, PGD2, PGF2alpha had no effect on cellular proliferation at concentrations up to 1 microM. 5. These observations illustrate a profound inhibitory effect of cyclo-oxygenase-2 induction on HASM cell proliferation, possibly via IP or EP receptor activation. Cyclo-oxygenase-2 induction has, thus far, been associated with the pro-inflammatory responses of plasma exudation and oedema formation and is assumed to be an enzyme worthy of selective inhibition in many disease states. However, our observations suggest that cyclo-oxygenase-2 can have an anti-inflammatory, anti-proliferative function in the airways. These observations may have importance in the use and development of therapies for airway disease such as asthma.
Lp(a) is a major inherited risk factor for premature atherosclerosis. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to interfere with plasminogen activation and its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that Lp(a) stimulates production of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin in cultured human coronary artery endothelial cells (HCAEC). This effect resulted from a rise in intracellular free calcium induced by Lp(a) and could be inhibited by the intracellular calcium chelator, BAPTA/AM. The involvement of the LDL and VLDL receptors in Lp(a) activation of HCAEC were ruled out since Lp(a) induction of adhesion molecules was not prevented by an antibody (IgGC7) to the LDL receptor or by receptor-activating protein, an antagonist of ligand binding to the VLDL receptor. Addition of alpha2-macroglobulin as well as treatment with heparinase, chondroitinase ABC, and sodium chlorate did not decrease levels of VCAM-1 and E-selectin stimulated by Lp(a), suggesting that neither the low density lipoprotein receptor-related protein nor cell-surface proteoglycans are involved in Lp(a)-induced adhesion molecule production. Neither does the binding site on HCAEC responsible for adhesion molecule production by Lp(a) appear to involve plasminogen receptors, as levels of VCAM-1 and E-selectin were not significantly decreased by the addition of glu-plasminogen, the lysine analog epsilon-aminocaproic acid, or by trans-4-(aminomethyl)-cyclohexanecarboxymethylic acid (tranexamic acid), which acts by binding to the lysine binding sites carried on the kringle structures in plasminogen. In contrast, recombinant apolipoprotein (a) [r-apo(a)] competed with Lp(a) and attenuated the expression of VCAM-1 and E-selectin. In summary, we have identified a calcium-dependent interaction of Lp(a) with HCAEC capable of inducing potent surface expression of VCAM-1 and E-selectin that does not appear to involve any of the known potential Lp(a) binding sites. Because leukocyte recruitment to the vessel wall appears to represent one of the important early events in atherogenesis, this newly described endothelial cell-activating effect of Lp(a) places it at a crucial juncture in the initiation of atherogenic disease and may lead to a better understanding of the role of Lp(a) in the vascular biology of atherosclerosis.
BACKGROUND: Lung transplantation is an accepted therapeutic option for patients with end stage pulmonary sarcoidosis. However, the medium term outcome of transplantation in this patient group is unknown. METHODS: This study was performed to evaluate our experience with lung transplantation for end stage pulmonary sarcoidosis. Between July 1988 and July 1997 12 patients (nine men) underwent lung transplantation for sarcoidosis at our institution. Ten underwent single lung transplantation and two double lung transplantation. RESULTS: Survival at three and five years was 70% and 56%, respectively. Three patients developed obliterative bronchiolitis at six, 18, and 45 months. One died at the time of retransplantation. Sarcoid granulomas have recurred in the donor organ in three patients. In one the development of granulomas has been associated with clinical deterioration, necessitating retransplantation. Mean (SD) forced expiratory volumes in one second at three and five years were 1.37 (0.67) 1 and 1.34 (0.13) 1, respectively. CONCLUSIONS: Lung transplantation is a viable option for patients with end stage pulmonary sarcoidosis. The medium term results are comparable with patients undergoing lung transplantation for other indications. Despite histological recurrence of sarcoidosis, the risk of clinically important recurrence is low.