Biomedical subjects

J B Atkinson

Publications and source records attributed to J B Atkinson.

At least 55 records · Page 3Linked to original sources

PubMed1997

Accelerated arteriosclerosis after transplantation: the possible role of calcium channel blockers.

The major factor limiting the long-term success of cardiac transplantation is the development of accelerated arteriosclerosis that occurs in the coronary arteries of the cardiac allograft. Transplant arteriosclerosis is characterized by diffuse, uniform, concentric narrowing of the artery by a proliferative, fibrocellular intima. The etiology of transplant arteriosclerosis is thought to be immune-mediated, and endothelial cells, smooth muscle cells, and inflammatory cells participate in the progression. Based on data derived from studies of conventional atherosclerosis, in which calcium channel blockers (CCBs) have demonstrated beneficial effects, preliminary studies designed to determine if CCBs might affect transplant arteriosclerosis similarly have been performed in animal models as well as in a limited number of cardiac transplant patients. Amlodipine suppressed transplant arteriosclerosis in one animal study, while diltiazem preserved vasodilatory responses in another animal study. Small prospective trials and retrospective studies in humans have shown that CCBs have a favorable effect on the development of transplant arteriosclerosis. While no work has been directed specifically at determining the mechanisms by which CCBs might prevent transplant arteriosclerosis, there are several likely candidates. These include preservation of endothelial function, suppression of smooth muscle cell migration and proliferation, production of extracellular matrix, and regulation of lipid metabolism and certain components of the immune system.

Amlodipine↗

PubMed1997

Histopathology of restenosis after stenting of narrowed coronary arteries after cardiac transplantation during the teenage years.

This study describes the detailed histopathologic appearance of human coronary arteries at 3 weeks, and 3 and 7 months after stent implantation in a cardiac transplant recipient. There was modest arterial injury associated with stent implantation, and immunocytochemistry staining provided evidence that a proliferative response from the adventitia contributes to neointimal hyperplasia.

Adolescent↗

PubMed1997

Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages.

Macrophage-derived foam cells express apolipoprotein E (apoE) abundantly in atherosclerotic lesions. To examine the physiologic role of apoE secretion by the macrophage in atherogenesis, bone marrow transplantation was used to reconstitute C57BL/6 mice with macrophages that were either null or wild type for the apoE gene. After 13 weeks on an atherogenic diet, C57BL/6 mice reconstituted with apoE null marrow developed 10-fold more atherosclerosis than controls in the absence of significant differences in serum cholesterol levels or lipoprotein profiles. ApoE expression was absent in the macrophage-derived foam cells of C57BL/6 mice reconstituted with apoE null marrow. Thus, lack of apoE expression by the macrophage promotes foam cell formation. These data support a protective role for apoE expression by the macrophage in early atherogenesis.

Animals↗

PubMed1997

Contractile failure in chronic doxorubicin-induced cardiomyopathy.

The mechanisms for the progression of the anthracycline-induced cardiomyopathy to contractile failure has not been defined. In vitro, doxorubicin (DOX) appears to modify calcium-mediated excitation-contraction coupling, which depresses cardiac contractility. This study characterizes the onset of contractile failure associated with the development of DOX-induced cardiomyopathy. Rabbits were treated with DOX (1 mg/kg i.v. twice weekly, 12-18 doses; DOX-treated group) and compared with a pair-fed Control group infuse with saline vehicle. The severity of the cardiomyopathy was determined by numerically-scored histopathology. Myocardial contractility was determined in thin fiber bundles from right ventricular (RV) papillary muscles and left atria that were removed and mounted on a force transducer in oxygenated Krebs-bicarbonate buffer (pH=7.4 at 30 degrees C) to record the amplitude (DT) and maximum rate (+dT/dt ) of isometric tension. Myofibrillar and calcium loading properties were determined by the calcium and caffeine-activated tension responses respectively in chemically-permeabilized fibers. With the onset of the cardiomyopathy (score <2) DT at low frequency (0.5 Hz) was depressed (0.61+/-0.01 mN/mg; n=14) compared to Control (0.93+/-0.09 mN/mg; n=15). Contractility at higher rates (1 Hz) was not different in this DOX-treated and Control groups. Maximum calcium and caffeine-activated force and the pCa to half-maximum force of permeabilized fibers were comparable in DOX-treated and Control groups. The loss of contractility of the DOX-treated group was related to reduction in sarcoplasmic reticulum calcium release channel density, as determined by Bmax for 3H-ryanodine binding in cardiac microsomal membrane fraction. Post-rest potentiation of contractility, as well as frequency-dependent (0.25-1.5 Hz) and post-extrasystolic potentiation of contractility were preserved in the DOX-treated group. In vitro, DOX depressed post-rest potentiation of contractility. Thus, the onset of contractile failure of the DOX-induced cardiomyopathy is characterized by effects consistent with disordered calcium-mediated excitation-contraction coupling and these effects are qualitatively different than in vitro effects of DOX.

Animals↗

PubMed1997

Length of transplanted small bowel required for adequate weight gain in rats.

Progress has been made toward developing a clinically successful small-bowel transplant procedure, but there has been little research concerning the functional aspects of the transplanted small bowel. Using a rat model, our study examined the length of transplanted small bowel required to provide adequate weight gain. The rats were divided into six groups; groups 1 and 2 were considered controls. Group 1 (n = 6) underwent a gastrostomy. Group 2 (n = 3) underwent a jejunoile-ectomy followed by re-establishment of intestinal continuity and anastomosis of the native proximal small bowel to an abdominal stoma and the distal portion to the ascending colon. Groups 3 (n = 5), 4 (n = 4), 5 (n = 5), and 6 (n = 4) underwent small-bowel transplantation, receiving 100%, 50%, 25%, and 15% transplants, respectively. The donor small-bowel anastomoses were the same as the native small-bowel anastomoses in group 2. All of the rats began to produce stool within 4 days of becoming dependent upon the transplanted small bowel. By the end of postoperative week 4, there was no significant difference between the percentages of preoperative body weight in groups 1-4 (range 125.7%-130.0%). Although the weight gain in group 5 was significantly less than that in groups 1-4 (P < 0.05), it was adequate (111.8%); group 6 animals lost weight (94.7%). It is concluded that a 50% or more small-bowel transplant with or without an ileocecal valve provides ample weight gain; minimally adequate weight gain is achieved by a 25% transplant without an ileocecal valve; and the graft begins to function soon after transplantation.

Animals↗

PubMed1997

Reduction of myocardial infarct size in rabbits and inhibition of activation of rabbit and human neutrophils by lidocaine.

Myocardial reperfusion is associated with increased influx of activated neutrophils and intracellular accumulation of sodium in the ischemic zone. Lidocaine is a sodium channel blocker that also inhibits several neutrophil functions. We investigated the effect of lidocaine on infarct size in rabbits undergoing 30 minutes of ischemia and 48 hours of reperfusion. Animals randomly received lidocaine (10 mg/kg, n = 11) or saline (n = 11) during occlusion. The area of necrosis (AN) was measured histologically and expressed as a percentage of the area at risk (AR). Myocardial oxygen consumption and the perfusion bed at risk were similar in the two groups. Lidocaine reduced infarct size compared with control (AN/AR = 30% +/- 4% vs 61% +/- 5%, respectively; p = 0.0001). This reduction was associated with a significant decrease in neutrophil infiltration and in the degree of hemorrhage in the reperfused myocardium. Lidocaine also significantly inhibited superoxide anion production by rabbit and human neutrophils in whole blood. Therefore, lidocaine treatment results in a significant reduction in infarct size in the rabbit model, partly through reduction of neutrophil-mediated injury to viable cells, suggesting that lidocaine may be useful to enhance myocardial salvage in patients undergoing pharmacologic or mechanical reperfusion.

Animals↗

PubMed1997

Prospective, randomized evaluation of the efficacy of fibrin sealant as a topical hemostatic agent at the cannulation site in neonates undergoing extracorporeal membrane oxygenation.

BACKGROUND: The topical hemostatic effect of fibrin sealant that has been solvent/detergent treated and plasminogen depleted was evaluated in a multicenter prospective, randomized controlled study at the cannulation site wound of infants undergoing extracorporeal membrane oxygenation (ECMO). METHODS: The test group received standard cauterization and Fibrin sealant, while the control group was given cauterization alone to control hemostasis at this site. Efficacy data were available on 173 randomized study subjects of whom 149 met study entry criteria. All were managed according to standard ECMO practice. RESULTS: Fibrin sealant reduced the risk of bleeding, was associated with less shed blood, and was associated with shorter duration of hemorrhage. Further, control infants showed an increased bleeding risk with less depressed fibrinogen levels and prothrombin time elevations >18 seconds prior to ECMO. CONCLUSION: Fibrin sealant is useful as a topical hemostatic agent in patients with coagulopathy not responding to standard surgical techniques.

Blood Loss, Surgical↗

PubMed1997

Nitric oxide dose response during moderate and severe hypoxia in swine.

BACKGROUND: Elucidation of factors that influence the dose response to inhaled nitric oxide is crucial to optimizing its therapeutic benefit. We investigated whether severity of hypoxia is one such factor. METHODS: Seven Yorkshire swine underwent 14 triphasic experiments: (1) control period of mechanical ventilation (fractional concentration of oxygen = 0.3); (2) induction of hypoxic pulmonary hypertension (fractional concentration of oxygen = 0.1 to 0.15); and (3) inhaled nitric oxide at 5, 10, 20, 40, and 80 parts per million (ppm). Hemodynamics and arterial blood gases were measured by pulmonary and systemic arterial catheters. RESULTS: Experiments were divided into two groups of seven based on hypoxia severity: severe (arterial oxygen tension, 25 to 40 mm Hg) and moderate (arterial oxygen tension, 41 to 60 mm Hg). The percent changes in mean pulmonary artery pressure after each dose were compared within each group by repeated measure analysis of variance and each dose was compared between the two groups by Student's t test. A statistically significant dose response existed in both groups (p < 0.02). Low doses resulted in significantly less vasodilation in the severe versus the moderate hypoxia group (5 ppm, 59% +/- 6% versus 94% +/- 7%, p = 0.003; 10 ppm, 69% +/- 8% versus 99% +/- 8%, p = 0.017). CONCLUSIONS: Lower doses are significantly less effective in achieving maximal pulmonary vasodilation during severe hypoxia. Therefore, the degree of hypoxia is a determinant of the inhaled nitric oxide dose response.

Animals↗

PubMed1997

Neuroblastoma.

Explore the source record for details and available documents.

Algorithms↗

PubMed1996

Pathology of fatal perioperative myocardial infarction: implications regarding pathophysiology and prevention.

The aim of this study was to determine the pathology of fatal postoperative myocardial infarction (MI) and compare it with that of non-operative myocardial infarction. Histopathological analyses of coronary arteries and myocardium were performed on autopsy heart specimens (n = 67), and clinical attributes were studied. Findings of perioperative MI (n = 42) were compared to those of non-perioperative MI (n = 25). Significant atherosclerotic obstruction (> 50% cross-sectional narrowing) was observed in the majority of patients (93%). Left main (> 50% cross-sectional narrowing) and/or three-vessel coronary artery disease were especially common (44%) in this group. Evidence of unstable plaques with disruption was noted in 55% of perioperative MI patients (n = 23); plaque hemorrhage was found in 45% (n = 19). Predicting the site of infarction based on severity of underlying stenosis would have been unsuccessful in more than half the patients in both perioperative and nonoperative MI groups. Clinical profiles of the patients in the two groups were similar in terms of prior cardiac history, gender and age. Fatal perioperative MI occurs predominantly in patients with multivessel coronary disease, especially left main and three-vessel disease. The severity of preexisting underlying stenosis did not predict the resulting infarct territory. Evidence of acute plaque disruption in the infarct-related artery is common. Perioperative MIs have similar coronary artery pathology to non-operative MIs with regard to coronary plaque hemorrhage, rupture, and thrombus formation and probably occur by a similar mechanism.

Aged↗

PubMed1996

Role of endothelin in a rabbit model of acute myocardial infarction: effects of receptor antagonists.

The role of endothelin (ET) in acute myocardial infarction and proarrhythmic potential was investigated in a rabbit model. One group of rabbits underwent 30 min of circumflex occlusion and 3 h of reperfusion with measurements of myocardial blood flow and myocardial levels of ET-1 messenger RNA (mRNA). In a second group, the systemic and coronary effects of exogenous ET were studied in animals pretreated with either saline, FR139317, an ETA-receptor antagonist, or PD145065, an ETA-and ETB-receptor antagonist. In a third study, animals undergoing 30 min of circumflex occlusion followed by 48 h of reperfusion were treated with exogenous ET-1, FR139317, PD145065, or saline. Arrhythmias were recorded and infarct size measured at 48 h. These studies revealed that ischemia and reperfusion was followed by a progressive microcirculatory failure ("no-reflow phenomenon") in rabbits. This was associated with a 2.6-fold elevation in levels of myocardial ET-1 mRNA in the ischemic zone in comparison to the nonischemic zone (p = 0.04). Exogenous ET-1 caused elevation in coronary and systemic vascular resistance that was significantly blocked by antagonism of the ETA receptor. In rabbits subjected to myocardial ischemia and reperfusion, ET-1 infusion led to a higher incidence of ventricular arrhythmias, whereas ET-receptor antagonism with PD145065 significantly reduced ventricular arrhythmias. Exogenous ET-1 and FR139317 failed to alter infarct size (AN) of the area at risk (AR) compared with control [AN/AR(%) was 46 +/- 8, 55 +/- 9, and 47 +/- 7, respectively]. However, PD145065 significantly decreased AN/AR (22 +/- 7; p < or = 0.02). The increased production of ET-1, resulting from increased levels of mRNA after reperfusion, may contribute to the no-reflow phenomenon. Although the vasoconstrictor effects of ET-1 can be blocked by ETA-receptor antagonism alone, only blockade of both the ETA and ETB receptors significantly reduced infarct size. These data suggest that production of ET increases in the heart during ischemia and is deleterious to the reperfused myocardium.

Animals↗

PubMed1996

Consolidation chemoradiotherapy and autologous bone marrow transplantation versus continued chemotherapy for metastatic neuroblastoma: a report of two concurrent Children's Cancer Group studies.

PURPOSE: To compare event-free survival (EFS) for patients with stage IV neuroblastoma who were treated with induction chemotherapy followed by additional courses of the same chemotherapy or by intensive chemoradiotherapy and autologous bone marrow transplantation (ABMT). METHODS: Two hundred seven children who were diagnosed with stage IV neuroblastoma after 1 year of age were given five to seven courses of induction chemotherapy consisting of cisplatin, etoposide, doxorubicin, and cyclophosphamide (CCC-321-P2). This chemotherapy was continued for 13 total courses for some patients, whereas intensive chemoradiotherapy with ABMT was given to others (CCG-321-P3). The decision to continue chemotherapy versus to consolidate with chemoradiotherapy was not randomized but was made by parents and physicians. Marrow used for ABMT was purged ex vivo and was free of immunocytologically detectable neuroblastoma cells. RESULTS: One hundred fifty-nine of 207 patients (77%) remained event-free during induction therapy. Of these, 67 received chemoradiotherapy/ABMT (CCG-321-P3) and 74 continued chemotherapy (CCG-321-P2). Using Cox regression analysis, the relative risk (RR) of an event after chemoradiotherapy/ABMT was estimated to be 58% of that for patients who continued chemotherapy (P = .01). Similarly, Kaplan-Meier analysis estimated EFS at four years for the chemoradiotherapy/ABMT and chemotherapy groups to be 40% and 19% respectively (P = .019). Subgroups appearing to benefit from chemoradiotherapy/ABMT were those with only a partial tumor response to induction chemotherapy (RR = 0.43; P = .008; EFS, 29% v 6%) and those whose tumors had amplification of the N-myc gene (RR = 0.26; P = .112; EFS, 67% v 0%). CONCLUSION: Consolidation with intensive, myeloablative chemoradiotherapy followed by purged ABMT may be more effective than continuing chemotherapy for patients with stage IV neuroblastoma.

Adolescent↗

PubMed1995

Association of acidic fibroblast growth factor and untreated low grade rejection with cardiac allograft vasculopathy.

Acidic fibroblast growth factor (aFGF) is a potent growth factor for vascular smooth muscle cells and may mediate vasculopathy in cardiac allografts subjected to chronic immunological injury. Therefore, we examined cardiac expression of aFGF, the number of rejection episodes, and other potential risk factors in 32 heart transplant patients who underwent intravascular ultrasound (IVUS) for detection of cardiac allograft vasculopathy (CAV). As defined by IVUS, CAV was present in 21 patients and absent in 11 patients (follow-up time: 52 +/- 21 vs. 51 +/- 12 months, respectively, P = NS). The level of aFGF in myocardial biopsies obtained at the time of IVUS was measured by semiquantitative reverse transcriptase polymerase chain reaction and expressed as the aFGF:GAPDH ratio. Higher level of aFGF were associated with CAV (mean aFGF:GAPDH ratio was 1.45 +/- 0.99 in patients with vs. 0.18 +/- 0.12 in patients without CAV [P < 0.001]). A strong association was found between high levels of cardiac aFGF and CAV, as 18 of 19 patients (95%) with high levels of aFGF (aFGF:GAPDH > 1) but only 3 of 13 patients with low levels of aFGF had CAV (P < 0.001). The relative risk of high level of aFGF for CAV was 4.1. Untreated low grade rejection (ISHLT I), but not treated high grade rejection (ISHLT > 2), was also associated with CAV (average number of untreated low grade rejection episodes was 3.5 +/- 1.8 in patients with vs. 2.1 +/- 1.0 in patients without CAV [P = 0.04]). Among other risk factors examined (age, sex, serum cholesterol, blood pressure, CMV infection, dose of immunosuppressants, and ischemic time), only triglycerides were higher in patients with than those without CAV (P = 0.003). We conclude that increased cardiac production of aFGF is significantly associated with CAV, which suggests that aFGF may serve as an important mediator in CAV. Untreated low grade rejection also poses an increased risk for CAV.

Adult↗

PubMed1995

Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation.

Apolipoprotein E (apoE) deficiency causes severe hyperlipidemia and atherosclerosis in humans and in gene-targeted mice. Although the majority of apoE in plasma is of hepatic origin, apoE is synthesized by a variety of cell types, including macrophages. Because macrophages derive from hematopoietic cells, bone marrow transplantation was used to examine the potential of apoE synthesized by bone marrow-derived cells to correct the hyperlipidemia and atherosclerosis caused by apoE deficiency. After transplantation of bone marrow from mice with the normal apoE gene into apoE-deficient mice, apoE was detected in serum and promoted clearance of lipoproteins and normalization of serum cholesterol levels. ApoE-deficient mice given transplants of normal bone marrow showed virtually complete protection from diet-induced atherosclerosis.

Animals↗

PubMed1995

The Kasai procedure in the treatment of biliary atresia.

From 1978 to 1992, 62 patients were diagnosed as having extrahepatic biliary atresia (EHBA) at Childrens Hospital Los Angeles. The patients presented with either persistent jaundice, alcoholic stools, and/or hepatomegaly. Hepatobiliary IDA scans were performed in 47 of the patients; 46 had results typical of EHBA. Fifty-nine of the 62 patients underwent a Kasai portoenterostomy; three patients were more than 4 months of age at initial presentation and were referred directly for liver transplantation. The preoperative total bilirubin level for all patients averaged 8.6 mg/dL (range, 4.1 to 18.1). All patients underwent a standardized Kasai procedure using a 40-cm Roux-en-Y intestinal segment performed in the end-to-side fashion. Postoperative management included oral antibiotics and fat-soluble vitamins for at least 9 months. Long-term complications included cholangitis in 20 cases and portal hypertension in 25, which led to variceal hemorrhage in 12 cases. Growth rates were at or above the 50th percentile for age in 59% of the Kasai patients. Forty-one of the 59 Kasai patients survived (69.5%); six deaths occurred within 2 years after the Kasai procedure. Twelve patients were lost to follow-up within 2 years after surgery, and for calculation of mortality were presumed dead. Seventeen patients had follow-up for 5 or more years, 13 had follow-up for 2 to 5 years, and 29 had follow-up for less than 2 years. The average total bilirubin level for the patients with less than 2 years of follow-up was 7.9 mg/dL (0.3 to 20.8), and that for the patients with more than 2 years of follow-up was 1.6 mg/dL (0.3 to 18.1). Orthotopic liver transplantation was performed in 11 Kasai patients, in whom chronic liver failure eventually developed. Rejection occurred in one of these patients, which required retransplantation. Based on these results, the Kasai portoenterostomy procedure continues to offer palliation, if not long-term success, in a large percentage of patients with EHBA.

Anastomosis, Roux-en-Y↗

PubMed1995

Surgical management and outcome of locoregional neuroblastoma: comparison of the Childrens Cancer Group and the international staging systems.

Although precise anatomic staging is prognostically important in neuroblastoma, most widely employed staging systems remain incompatible. The International Neuroblastoma Staging System (INSS) was formulated to incorporate the basic elements of several systems to and define the significance of tumor resectability, anatomic "midline," and lymph node involvement. The authors sought to determine the applicability and value of the INSS compared with the classic Evans system. Between 1980 and 1992, 424 children with the diagnosis of local or regional neuroblastoma were entered in Childrens Cancer Group (CCG) clinical trials. The patients were assigned to Evans stage I, II, or III, by clinical and surgicopathologic assessment, and were treated uniformly by Group-wide therapy protocols. INSS stage 1, 2A, 2B, or 3, was applied, by retrospective analysis, to the children in the earlier studies, and by prospective evaluation of recent patients in the current studies. Survival and relapse-free survival (RFS) rates were determined and compared, based on age at diagnosis, extent of resection, and staging reassignment. All 87 Evans stage I patients were classified as INSS stage 1 and had a 92% 3-year RFS rate. Of the 144 Evans stage II patients, 65 also qualified as INSS stage 1 patients, with an 82% RFS rate. The other 79 stage II children remained in INSS stage 2A or 2B and had a 70% RFS rate (P = .10). Of the 193 Evans stage III patients, 24 were reassigned to INSS stage 1 (85% RFS rate) and 33 to stage 2A or 2B (65% survival rate; 61% RFS rate).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1995

Role of myeloablative therapy in improved outcome for high risk neuroblastoma: review of recent Children's Cancer Group results.

The use of new strategies for dose intensification using peripheral blood stem cell or autologous purged bone marrow rescue has raised expectations for cure in advanced neuroblastoma, although conflicting reports exist regarding the efficacy of these approaches. Using risk groups based on both biological and clinical staging, the Children's Cancer Group (CCG) has conducted a series of pilot studies to test new induction, consolidation and myeloablative regimens to attempt to improve outcome. We summarise below the outcome and prognostic factor analysis for the pilot chemotherapy trial, CCG-(CCG-321P2), and the use of high dose myeloablative chemoradiotherapy with allogeneic (CCG-321P1) or autologous purged bone marrow rescue (CCG-321P3) for high risk neuroblastoma patients who were progression-free at the end of induction chemotherapy. After autologous bone marrow transplantation (ABMT), progression-free survival (PFS) at 4 years was 38% (median follow-up 4 years). Prognostic factors for relapse after ABMT included pre-BMT disease status, bone marrow tumour content at harvest, extent of primary resection at diagnosis, and time to ABMT. MYCN amplification, age, stage, and pre-BMT myeloablative regimen were not significant. Allogeneic BMT did not have a better outcome than ABMT. In a retrospective, non-randomised comparison of ABMT and chemotherapy, there was a significant difference in PFS for stage IV patients. High risk subgroups possibly benefiting from ABMT could be identified, including those with tumour MYCN amplification, over 2 years at diagnosis, and those not in complete remission at the end of induction. A randomised prospective trial comparing myeloablative therapy with ABMT to continuous infusion consolidation chemotherapy is currently underway in CCG to determine the relative benefit.

Adolescent↗

PubMed1995

Successful use of transesophageal echocardiography during extracorporeal membrane oxygenation in infants after cardiac operations.

We report the use of transesophageal echocardiography in infants after cardiac operations while supported on extracorporeal membrane oxygenation. In all patients transesophageal echocardiography provided valuable information when standard transthoracic echocardiographic evaluation was limited by poor acoustic windows. This report describes the application of transesophageal echocardiography during extracorporeal membrane oxygenation after cardiac operations.

Cardiac Surgical Procedures↗