Clinical importance of the presence of giant cells in temporal arteritis.

BACKGROUND: The clinical significance of giant cells seen on temporal artery biopsy in temporal arteritis is unknown. AIM: To help define the prognostic value of the presence of giant cells in temporal arteritis. METHODS: The clinical course of all patients with biopsy proven temporal arteritis from 1994 to 2004 was reviewed. The 92 patients were divided into those with giant cells (GC) (n = 76) seen on biopsy and those with no giant cells (NGC) (n = 16). Clinical findings were compared between groups. An additional analysis combined results with a previous study at the same institution to compare occurrence of blindness. RESULTS: The GC group had a higher proportion of polymyalgia rheumatica (PMR) (36.8%) compared to the NGC group (12.5%) (p = 0.059). There was no significant difference in patient age, sex, sedimentation rate, or presenting symptoms. The length of time treated with corticosteroids and relapse rate was nearly identical for both groups. When combining data with the previous study, in the GC group 21/109 (19%) developed blindness, while only 2/34 (6%) became blind in the NGC group (p = 0.11). CONCLUSION: The presence of giant cells is not a significant factor in determining treatment or clinical progression of temporal arteritis. However, results showed the GC group to have three times the occurrence of blindness and PMR compared to the NGC group. Although the differences were not significant, this analysis suggests an association with giant cells and more aggressive disease.

Histologic compaison of allograft myocardium between short- and long-term survivors of human cardiac transplantation.

Myocardial histology of cardiac allografts differed between short-term (<5 years) and long-term (>5 years) survivors after transplantation. These differences may partially be attributable to a higher prevalence of systemic hypertension and allograft rejection in the short-term survivors, affecting hemodynamics and allograft function.

Quantitative investigation of cardiomyocyte hypertrophy and myocardial fibrosis over 6 years after cardiac transplantation.

OBJECTIVES: This study was performed to determine the degree and time course over 6 years of cardiomyocyte hypertrophy and myocardial fibrosis of the cardiac allograft in transplanted patients. BACKGROUND: Diastolic dysfunction and to a certain extent systolic dysfunction are common cardiac findings after heart transplantation. The development of posttransplant cardiomyocyte hypertrophy and myocardial fibrosis likely contributes to these derangements. METHODS: Cardiomyocyte diameter and percent fibrosis were determined in serial endomyocardial biopsy specimens obtained from 1 month up to 6 years following heart transplantation in 50 patients. Endomyocardial biopsy specimens from 40 patients with primary dilated cardiomyopathy and 11 normal subjects were similarly analyzed for control data. Analyses were performed in a blinded format using a validated computerized image analysis system (Optimas 5.2). RESULTS: Early (1 month) cardiomyocyte enlargement decreased to the smallest diameter 6 months posttransplant, but thereafter progressively increased by 10% to 20% over the subsequent 5- to 6-year period. Although not statistically established, principal stimuli may include a discrepancy in body size (recipient > donor), coronary allograft vasculopathy and posttransplant systemic hypertension. Percent myocardial fibrosis rose early (1 to 2 months) posttransplant and thereafter remained at the same modest level of severity. CONCLUSIONS: Cardiomyocyte diameter of the transplanted heart gradually increases over time, while percent myocardial fibrosis rises early and remains in a modestly elevated plateau after 2 months posttransplant. These histostructural changes likely contribute to the hemodynamic and cardiac functional alterations commonly observed posttransplant.

Morphometric analysis of neointimal formation in murine cardiac grafts: III. Dissociation of intestitial fibrosis from neointimal formation.

BACKGROUND: This study examined the relationship between transplant vascular sclerosis (TVS) and tissue fibrosis, features of chronic rejection that can develop rapidly in accepted heterotopic murine cardiac allografts. METHODS: The rate of development of interstitial fibrosis or TVS development was determined by computerized analysis of tissue sections from DBA/2-->C57BL/6 heterotopic cardiac allografts after immunosuppression with gallium nitrate. RESULTS: In accepted cardiac allografts, neointimal fibrosis developed by 30 days after transplant, whereas TVS was minimal by day 30, and maximal by day 60. Variable levels of fibrosis were found throughout the allografts. DBA/2-->DBA/2 cardiac isografts never displayed TVS in this time period, but displayed allograft-like fibrosis within 60 days of transplantation. CONCLUSIONS: Interstitial fibrosis can be dissociated from the TVS development in this experimental model of chronic cardiac allograft rejection. Apparently, it is caused, at least in part, by alloantigen-independent factors other than TVS-related tissue ischemia.

Morphometric analysis of neointimal formation in murine cardiac allografts: II. Rate and location of lesion development.

BACKGROUND: Transplant vascular sclerosis (TVS) is manifested in transplanted human and murine hearts as a concentric, intimal lesion. The purpose of this study was to characterize the rate, location, and intensity of developing TVS lesions in murine cardiac allografts using quantitative morphometric analysis. METHODS: Murine cardiac allografts, treated with the immunosuppressant gallium nitrate, were explanted at 30, 60, and 90 days after transplant. The grafts were histologically stained and evaluated for intimal thickening by deriving a neointimal index (NI) using a computerized image-analysis system. RESULTS: In cardiac allografts, mild vascular lesions of varying NI were detectable by day 30 and lesion severity increased significantly by day 60. Thereafter, average lesion severity stabilized, although the percentage of affected vessels continued to increase from day 30 to day 90. In contrast, day-90 cardiac isografts showed little to no TVS development. Vascular lesions developed randomly without regard for vessel location or size. TVS developed more regularly in vessels of the interventricular septum than in the right or left ventricular walls. The degree of TVS development fluctuated along the length of individual vessels, even as late as 90 days after transplant. The smaller vessels (<85 microm in diameter) appeared to occlude more quickly than the larger vessels. CONCLUSIONS: TVS developed reproducibly in a random pattern throughout cardiac allografts over a 1-month to 3-month period after transplant. This development can be quantitatively monitored by computerized morphometric analysis. In general, under these experimental conditions, 30-day cardiac allografts seem to provide a useful experimental model for studying early aspects of TVS, whereas 60-day allografts may be better suited for analysis of advanced TVS.

Morphometric analysis of neointimal formation in murine cardiac allografts.

BACKGROUND: Transplant vascular sclerosis is expressed in transplanted human and murine hearts as a concentric intimal thickening. The purpose of this study was to characterize the location, distribution, and intensity of transplant vascular sclerosis in murine cardiac allografts using computerized morphometric analysis. METHODS: Murine cardiac allograft recipients were treated with the immunosuppressant gallium nitrate to promote graft survival. The grafts were removed at 60 days after transplantation and histologically stained. The coronary arteries were analyzed for intimal thickening using a neointimal index (NI) derived with a computer imaging system. RESULTS: A cross-section taken from the middle of a cardiac allograft showed four major coronary arteries, each with widely different NI values (65, 0, 92, and 0). The same four vessels in two other grafts also showed highly variable NI values, but different patterns of vessel involvement. Next, NI values were determined along the length of a single vessel from aorta to apex. This revealed variable, fluctuating intimal thickening along the length of the vessel. In general, arteries from the aortic versus apical regions of the grafted hearts expressed similar amounts of intimal thickening (analysis of variance, P=0.4826). Finally, a method was devised to quantitate intimal thickening from a sampling of three tissue cross-sections taken from the middle of each cardiac allograft. This value was statistically indistinguishable from values obtained by analysis of intimal thickening in multiple sections covering the entire heart (P=0.6734, 0.9021, and 0.1474). CONCLUSIONS: Intimal thickening in the coronary arteries of murine cardiac allografts appears to be variable in terms of location, distribution, and intensity. This is true for different regions of the same vessel, different vessels in the same heart region, and the same vessels in different cardiac allografts.

Morphometric and immunocytochemical analysis of coronary arterioles in human transplanted hearts.

BACKGROUND: Heart transplant vascular sclerosis has been characterized in epicardial coronaries of human transplanted hearts. The purpose of this study was to analyze coronary arterioles (< 100 microns in diameter) within endomyocardial biopsy specimens from heart transplant recipients for the presence of disease. METHODS: The morphologic compartments of trichrome-stained vessels were quantified by means of computer imaging to measure the percentage of stenosis of 164 arterioles from 30 transplant recipients over time. The arterioles were divided into three groups based on their biopsy date after transplantation: early (0 to 6 months), middle (6 to 18 months), and late (18 to 36 months). The percentage of stenosis of arterioles from a control group of nondiseased hearts was compared with the grafts. Also, arterioles from heart transplant recipients were immunohistochemically labeled with an antibody, PC10, specific for proliferating cell nuclear antigen. The arterioles were immunocytochemically labeled with an antibody specific for vascular smooth muscle alpha-actin and the fluorescent signal was analyzed. RESULTS: The percentage of stenosis was not significantly different among the early, middle, late, and control groups. Vessels from the early, middle, and late groups did not show binding of the PCNA antibody. The antibody signal intensity and amount of alpha-actin within each vessel was significantly higher in the late groups as compared with the early and middle groups. CONCLUSIONS: The coronary microvasculature of human transplanted hearts does not exhibit intimal thickening or cellular proliferation within 3 years after transplantation. However, as shown by an increase of smooth muscle alpha-actin over time, vascular remodeling may occur in response to cytokines released as a result of injury.

Toxicological investigation of liquid petroleum gas explosion: human model for propane/ethyl mercaptan exposures.

Four individuals died as the result of a propane explosion. As with many propane explosions, the question was raised as to the adequacy of the product's odorization after the autopsy studies had been conducted. In most cases, this question leads to litigation. Ethyl mercaptan is a widely used odorant for propane and was used in this instance. Three of the four victims had blood available at autopsy for study. Quantitative analyses of the victims' blood, obtained during autopsy, were performed using gas chromatography/mass spectrometry, without subjecting the samples to hydrolysis. These analyses determined the relative amounts of propane and ethyl mercaptan in the blood to be 90, 63, and 175 mL/m3 headspace, and 0.36, 0.34, and 0.77 microgram/L blood, respectively. Since mercaptans have been reported in human blood as products of metabolism, modeling studies were conducted to establish the validity of the autopsy data and to develop an autopsy toxicology protocol for investigating explosion deaths. When subjects were not exposed to an atmosphere containing ethyl mercaptan, dimethylsulfide was the only mercaptan detectable in their blood without severe hydrolysis prior to analysis. Metabolic ethyl mercaptan is sufficiently bound to be undetectable by the methods used without hydrolysis. Human subjects were exposed to a flammable mixture of air and propane odorized with ethyl mercaptan. The analyses of the blood from these subjects produced results which were comparable with those for the explosion victims, establishing that the question of odorant adequacy can be addressed at the autopsy of propane explosion victims. It is extremely important that the pathologist and toxicologist investigating gas explosion deaths recognize the valuable evidence existing in the victim's blood.