Search PubMed⌕ Search

Biomedical subjects

M E Billingham

Publications and source records attributed to M E Billingham.

At least 37 records · Page 2Linked to original sources
PubMed1996

Induction of nitric oxide synthase in the human cardiac allograft is associated with contractile dysfunction of the left ventricle.

BACKGROUND: The mechanisms underlying cardiac contractile dysfunction after transplantation remain poorly defined. Previous work has revealed that inducible nitric oxide synthase (iNOS) is expressed in the rat heterotopic cardiac allograft during rejection; resultant overproduction of nitric oxide (NO) might cause cardiac contractile dysfunction via the negative inotropic and cytotoxic actions of NO. In this investigation, we tested the hypothesis that induction of iNOS may occur and be associated with cardiac allograft contractile dysfunction in humans. METHODS AND RESULTS: We prospectively studied 16 patients in the first year after cardiac transplantation at the time of serial surveillance endomyocardial biopsy. Clinical data, the results of biopsy histology, and echocardiographic and Doppler evaluation of left ventricular systolic and diastolic function were recorded. Total RNA was extracted from biopsy specimens, and mRNA for beta-actin, detected by reverse transcription-polymerase chain reaction (RT-PCR) using human specific primers, was used as a constitutive gene control; iNOS mRNA was similarly detected by RT-PCR using human specific primers. iNOS protein was detected in biopsy frozen sections by immunofluorescence. Myocardial cGMP was measured by radioimmunoassay, and serum nitrogen oxide levels (NOx = NO2 + NO3) were measured by chemiluminescence. iNOS mRNA was detected in allograft myocardium at some point in each patient and in 59 of 123 biopsies (48%) overall. In individual patients, iNOS mRNA expression was episodic and time dependent; the frequency of expression was highest during the first 180 days after transplant (P = .0006). iNOS protein associated with iNOS mRNA was detected by immunofluorescence in cardiac myocytes. iNOS mRNA expression was not related to the ISHLT histological grade of rejection or to serum levels of NOx but was associated with increased levels of myocardial cGMP (P = .01) and with both systolic (P = .024) and diastolic (P = .006) left ventricular contractile dysfunction measured by echocardiography and Doppler. CONCLUSIONS: These data support a relation between iNOS mRNA expression and contractile dysfunction in the human cardiac allograft.

Adolescent↗
PubMed1996

Local disruption of the insulin-like growth factor system in the arthritic joint.

OBJECTIVE: To identify differences in levels of insulin-like growth factor (IGF) and IGF binding proteins (IG-FBPs) between 30 patients with arthritis (14 with rheumatoid arthritis [RA], 16 with osteoarthritis [OA]) and 11 normal control subjects. IGF and IGFBP levels were correlated to the disease activity marker C-reactive protein (CRP) to determine whether they were disease related. We also examined the degree of proteolytic modification of the IGFBPs. METHODS: Radioimmunoassays were used for measuring IGF and IGFBP-3 levels; CRP was measured by enzyme-linked immunosorbent assay. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by Western blotting, chemiluminescence, and autoradiography were used for visualizing binding proteins. RESULTS: There was a significant increase in synovial fluid levels of both IGF-1 and IGFBP-3 in both RA and OA. This resulted in an elevated IGFBP-3 to IGF molar ratio of 1.49 in the OA group and 1.47 in the RA group, compared with 0.86 in the normal control group (P = 0.0002 for both). A significantly lower degree of IGFBP-3 proteolysis was also seen in the synovial fluids from the patients compared with the controls. There were significant correlations between the CRP level and levels of IGF-1, IGF-2, and IGFBP-3 in the RA patients (r = 0.62-0.898, P = 0.04-0.0007). CONCLUSION: There was significant local disruption of the IGF system in patients with arthritis. This may result in a lower amount of IGF that is able to bind to IGF receptors in the arthritic joint. Levels of IGF-1 IGF-2, and IGFBP-3 all correlated with the CRP level in patients with RA, which indicates the possibility that the IGF system is involved in the disease process.

Aged↗
PubMed1996

Accuracy of biplane and multiplane transesophageal echocardiography in diagnosis of typical acute aortic dissection and intramural hematoma.

OBJECTIVES: The purpose of this study was to evaluate the diagnostic accuracy of biplane and multiplane transesophageal echocardiography in patients with suspected aortic dissection, including intramural hematoma. BACKGROUND: Transesophageal echocardiography is a useful technique for rapid bedside evaluation of patients with suspected acute aortic dissection. The sensitivity of transesophageal echocardiography is high, but the diagnostic accuracy of biplane and multiplane transesophageal echocardiography for dissection and intramural hematoma is less well defined. METHODS: We studied 112 consecutive patients at a major referral center who had undergone biplane or multiplane transesophageal echocardiography to identify aortic dissection. The presence, absence and type of aortic dissection (type A or B, typical dissection or intramural hematoma) were confirmed by operation or autopsy in 60 patients and by other imaging techniques in all. The accuracy of transesophageal echocardiography for ancillary findings of aortic dissection (intimal flap, fenestration and thrombosis) was assessed in the 60 patients with available surgical data. RESULTS: Of the 112 patients, aortic dissection was present in 49 (44%); 10 of these had intramural hematoma (5 with and 5 without involvement of the ascending aorta). Of the remaining 63 patients without dissection, 33 (29%) had aortic aneurysm and 30 (27%) had neither dissection nor aneurysm. The overall sensitivity and specificity of transesophageal echocardiography for the presence of dissection were 98% and 95%, respectively. The specificity for type A and type B dissection was 97% and 99%, respectively. The sensitivity and specificity for intramural hematoma was 90% and 99%, respectively. The accuracy of transesophageal echocardiography for diagnosis of acute significant aortic regurgitation and pericardial tamponade was 100%. CONCLUSIONS: Biplane and multiplane transesophageal echocardiography are highly accurate for prospective identification of the presence and site of aortic dissection, its ancillary findings and major complications in a large series of patients with varied aortic pathology. Intramural hematoma carries a high complication rate and should be treated identically with aortic dissection.

Acute Disease↗
PubMed1996

A 71-kD heat shock protein (hsp) from Mycobacterium tuberculosis has modulatory effects on experimental rat arthritis.

The effects of a mycobacterial 71-kD hsp antigen have been investigated for its ability to modulate arthritis in rats. Subcutaneous injection (base of tail) of increasing amounts of hsp71 from Mycobacterium tuberculosis (MTB) produced dose-dependent differential inhibitory effects on induction of arthritis by MTB and CP20961 in rats. As little as 1 microgram of the hsp71 produced a reduction in MTB arthritis, whereas complete protection was observed when 50 micrograms were administered. When 71-kD-treated rats were challenged with CP20961, all developed reduced symptoms of arthritis compared with control rats, but in this model no complete protection was observed over the dose range studied. The effects of 71-kD pretreatment on collagen II arthritis were not significant, but in general symptoms of arthritis were milder than in the control group. The same pattern of results was observed previously when hsp65 was used in the different models. These results show that the modulatory effects of hsp on adjuvant arthritis are not restricted to the hsp65 series, but are also mediated by a member of the hsp70 family.

Adjuvants, Immunologic↗
PubMed1995

Detection of Epstein-Barr virus in cardiac biopsies of heart transplant patients with lymphoproliferative disorders.

We investigated whether in situ hybridization for EBV RNA on routine cardiac biopsies could be used as a predictive test for the development of posttransplant lymphoproliferative disorder (PTLD) in cardiac transplant recipients. We examined the sensitivity of the test by determining the frequency of EBV-positive cells in cardiac biopsy specimens from patients with a known history of PTLD. Biopsy specimens obtained during routine monitoring for rejection before or shortly after the diagnosis of PTLD from 10 pediatric heart transplant patients were examined. Four of 74 specimens (5.4%) demonstrated EBV-positive lymphocytes in the cardiac biopsy rejection infiltrates. The four positive specimens were obtained from 3 different patients, all before the diagnosis of PTLD. Given the low number of cardiac biopsy specimens with EBV-positive lymphocytes, as well as the low incidence of PTLD in cardiac transplant patients, we conclude that a routine screening of all cardiac biopsy specimens using in situ hybridization for EBV with the intention of predicting PTLD is not warranted. However, in situ hybridization for EBV might be used in selected cases, such as those in which the transplant patient does not respond to immunosuppressive therapy for rejection. In these patients, the presence of EBV-positive lymphocytes in biopsy specimens initially interpreted as showing rejection might instead raise the suspicion of incipient PTLD.

Adolescent↗
PubMed1995

A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators.

BACKGROUND: Myocarditis is a serious disorder, and treatment options are limited. This trial was designed to determine whether immunosuppressive therapy improves left ventricular function in patients with myocarditis and to examine measures of the immune response as predictors of the severity and outcome of disease. METHODS: We randomly assigned 111 patients with a histopathological diagnosis of myocarditis and a left ventricular ejection fraction of less than 0.45 to receive conventional therapy alone or combined with a 24-week regimen of immunosuppressive therapy. Immunosuppressive therapy consisted of prednisone with either cyclosporine or azathioprine. The primary outcome measure was a change in the left ventricular ejection fraction at 28 weeks. RESULTS: In the group as a whole, the mean (+/- SE) left ventricular ejection fraction improved from 0.25 +/- 0.01 at base line to 0.34 +/- 0.02 at 28 weeks (P < 0.001). The mean change in the left ventricular ejection fraction at 28 weeks did not differ significantly between the group of patients who received immunosuppressive therapy (a gain of 0.10; 95 percent confidence interval, 0.07 to 0.12) and the control group (a gain of 0.07; 95 percent confidence interval, 0.03 to 0.12). A higher left ventricular ejection fraction at base line, less intensive conventional drug therapy at base line, and a shorter duration of disease, but not the treatment assignment, were positive independent predictors of the left ventricular ejection fraction at week 28. There was no significant difference in survival between the two groups (P = 0.96). The mortality rate for the entire group was 20 percent at 1 year and 56 percent at 4.3 years. Features suggesting an effective inflammatory response were associated with less severe initial disease. CONCLUSIONS: Our results do not support routine treatment of myocarditis with immunosuppressive drugs. Ventricular function improved regardless of whether patients received immunosuppressive therapy, but long-term mortality was high. Patients with a vigorous inflammatory response had less severe disease.

Adult↗
PubMed1995

Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement.

Rapamycin (RPM) and mycophenolic acid (MPA) inhibit immune responses by antagonizing IL-stimulated lymphocyte activation. These 2 drugs, used alone or preferably in combination, also significantly reduced the response of vascular cells to balloon-catheter arterial injury in rats. When rats were treated for 2 weeks with both drugs starting the day of injury, intimal thickening was significantly reduced (P < 0.001) 14 days after injury; however, by 44 days after injury, intimal thickening had progressed to the extent measured in arteries of untreated control rats. When RPM and MPA were administered for 3 days before and 13 days after injury, arterial intimal thickening was significantly (P = 0.024) reduced and endothelium had regrown in vessels analyzed 44 days after injury. Compared with initiation of treatment on the day of injury, starting the administration of RPM plus MPA before injury appears to limit the activation of cells or actions of factors responsible for the progression of intimal thickening that occurred after the administration of the drugs was terminated. RPM and MPA prevented the development of arterial intimal thickening in a model not dependent upon a rejection response. This direct antiproliferative action on smooth muscle cells by RPM and MPA, in vivo, may prevent the development of arterial intimal thickening associated with chronic rejection.

Animals↗
PubMed1995

Increased proteoglycan synthesis in cartilage in experimental canine osteoarthritis does not reflect a permanent change in chondrocyte phenotype.

OBJECTIVE: To determine whether chondrocytes in early experimental osteoarthritic (OA) cartilage continue to show increased synthesis and turnover of proteoglycans (PGs) during explant culture. A comparison was also made between the responsiveness of experimental OA and control cartilage to interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) after 1 day and 3 days in culture. METHODS: OA was induced in mature animals by sectioning of the anterior cruciate ligament followed by 3 months of normal exercise. PG synthesis in the articular cartilage was determined by measuring 35S-sulfate incorporation during explant culture over 1-3 days. Inhibition of PG synthesis was also determined with various concentrations of IL-1 beta and TNF alpha after 1 and 3 days in culture. PGs extracted from the articular cartilage over 1-3 days in culture were examined by agarose-polyacrylamide gel electrophoresis. RESULTS: Up to 24 hours after excision from the joint, PG synthesis was higher in experimental OA cartilage than in control cartilage. It was also less sensitive to inhibition by TNF alpha. These differences were no longer detected after 48-72 hours in culture. There were no changes in the relative proportions of aggrecan and decorin/biglycan extracted from and synthesized by control and experimental OA cartilage over the 3 days in culture. CONCLUSION: Previous results indicated that PG synthesis and turnover in articular cartilage was increased for many months after induction of experimental OA. Our present results show that the enhanced rate of PG synthesis and turnover were evident in freshly explanted tissue, but the differences were lost over 3 days in culture. A decreased responsiveness to TNF alpha was also lost. The hypermetabolic activity of experimental OA chondrocytes was thus reversible and not a permanent change in chondrocyte phenotype.

Aggrecans↗
PubMed1995

The aortic valve after heart transplantation.

We studied the aortic root (wall, semilunar cusp, septal myocardium) in 37 patients (29 male and 8 female; mean age; 41 years) who died 2 to 4,380 days (mean, 398 days) after heart (n = 34) and heart-lung (n = 3) transplantation. The aim of the study was to assess tissue viability, graft-host biological interaction, and cusp mineralization with time. Study methods included gross inspection and photos of each specimen, microradiography, histology and immunohistochemistry, scanning and transmission electron microscopy, and atomic absorption spectroscopy. There were no cases of valve dysfunction; in particular, cusp tears or perforations never occurred. Only 1 valve, in place for 12 years, had a pin-point calcification visible to the naked eye. Optimal preservation of the tissue components (endothelium, fibroblasts, collagen and elastic fibers, proteoglycans, intrinsic nervous ganglia) was observed at both short and long term. Concomitant acute rejection of valve leaflets and myocardium was seen in 7, mild valve thickening in 14, myxoid degeneration in 4, and graft aortic atherosclerosis in 26. Mineralization was negligible and was not progressive with time. No linear correlation was found between mineralization and number of acute rejections. In conclusion, we observed optimal cusp viability and integrity even at long term, concomitant valve and myocardium rejection with no valvular sequelae, and negligible, non-progressive cusp calcification. Donor-recipient blood group matching, heart-beating donor, and chronic immunosuppression are the reasonable explanations of the optimal durability of the aortic valve after heart transplantation.

Adult↗
PubMed1995

"Quilty" revisited: a 10-year perspective.

The goals of this study were to better define Quilty lesions, facilitating differentiation from other endocardial infiltrates; to correlate Quilty lesions with clinical parameters; and to assess whether classification into Quilty A (noninvasive lesions) and Quilty B (invasive lesions) had clinical utility. Two hundred seventeen adults who received transplants between 1981 and 1987 and 22 children who received transplants between 1981 and 1989 were studied. Allograft survival for over 1 year was the selection criterion. Clinical, angiographic, and biopsy data were reviewed up to 1992, obtaining a minimum follow up of 5 years for adults and 3 years for children. All 7,439 endomyocardial biopsy cases were allotted an International Society for Heart and Lung Transplantation (ISHLT) grade for rejection, and Quilty was classified as Quilty A or B. Quilty was correlated with transplant recipient age and gender, cytomegalovirus and Epstein-Barr virus (EBV) infection, treatment protocols, allograft rejection, graft vascular disease (GVD), and lymphoma. Immunohistochemistry was performed to determine Quilty cell composition. Quilty incidence was 49.77% in adults and 68.18% in children, and did not appear to be influenced by cyclosporine dosage. Quilty showed no gender variation nor association with cytomegalovirus (CMV) or EBV infection or lymphoma. A total of 74.04% of adults developed Quilty within the first year posttransplant and 81.48% had multiple Quilty-positive biopsies. One hundred eight of 217 Quilty-positive adults had 456 Quilty-positive endomyocardial biopsies, 82.24% of which were associated with an ISHLT grade of 0 or I, and only 12.28% being associated with a grade III rejection. Histological division into Quilty A and Quilty B did not appear to have clinical significance. Graft vascular disease appears to have decreased significantly more in Quilty-positive patients. Although our findings in children were similar to those in the adults, we were unable to draw definite conclusions, the number of children being too small to permit valid statistical correlations.

Adolescent↗
PubMed1995

Spontaneous reversibility of catecholamine-induced cardiotoxicity in rats.

In order to evaluate the chronic in vivo effects of excessive catecholamine levels, and the potential for spontaneous reversibility of these effects, we employed a chronic two-week infusion of epinephrine in rats. Epinephrine infusion resulted in myocyte hypertrophy, left ventricular fibrotic degenerative changes, diminished response to adrenergic stimuli, and enhanced left ventricular papillary contractile responses to calcium. Two weeks after cessation of the epinephrine infusion, left ventricular fibrotic degenerative changes were reduced, and responses to adrenergic stimuli were partially restored. However, myocyte hypertrophy and the enhanced responses to calcium persisted in these animals. This study indicates the potential for spontaneous reversal of some of epinephrine's toxic effects, and further implies that the loss in adrenergic sensitivity in epinephrine-treated animals may be a desensitization phenomenon, while the alterations in calcium response are less readily reversed.

Adenylyl Cyclases↗
PubMed1994

Incidence of myocarditis in peripartum cardiomyopathy.

Peripartum cardiomyopathy (PC), an uncommon cause of peripartum heart failure, is defined as a cardiomyopathy presenting in the last trimester of pregnancy or the first 6 months postpartum, without evidence of preexisting cardiovascular disease. The etiology of PC and idiopathic dilated cardiomyopathy (IDC) remains uncertain. Several reports have addressed possible differences in clinical presentation and prognosis between these groups. A relatively high incidence of myocarditis has been recently reported in patients with PC, raising the possibility that this may represent a distinct difference between this condition and IDC. A retrospective review of endomyocardial biopsy specimens from 34 patients fulfilling the criteria for a diagnosis of PC was therefore performed to further evaluate this finding. Results indicate a lower incidence of myocarditis (8.8%, 3 of 34) than that reported in other studies. This incidence was comparable to that found in an age- and sex-matched control population undergoing transplantation for IDC (9.1%, 2 of 22). Factors that may influence the diverse range in the reported incidence of myocarditis are discussed.

Adult↗