Danna E. Johnson

Inhibition of accelerated coronary atherosclerosis with dehydroepiandrosterone in the heterotopic rabbit model of cardiac transplantation.

BackgroundAccelerated coronary atherosclerosis has become a critical problem in cardiac transplantation. Although the pathogenesis of this disease is unknown, hypercholesterolemia has been shown to be a major risk factor. Methods and ResultsTo study this problem, a hypercholesterolemic rabbit model of heterotopic cardiac transplantation was developed to study accelerated graft atherosclerosis. Based on suggestions in the literature, it was hypothesized that dehydroepiandrosterone (DHEA) may retard the progression of the disease. Using semiquantitative light microscopy, a predilection for the development of small vessel occlusive disease in the transplanted hearts was found. Chronic DHEA administration produced a 45% reduction in the number of significantly stenosed vessels in the transplanted hearts (p<0.05) compared with controls and a 62% reduction in the nontransplanted hearts (p<0.05), yielding an overall 50% reduction in the number of significantly stenosed vessels in both the transplanted and nontransplanted hearts. This reduction in luminal stenosis was observed in the absence of any significant alterations in lipid profiles. ConclusionsIt is concluded that chronic DHEA administration in a hypercholesterolemic rabbit model of heterotopic cardiac transplantation significantly retards the progression of accelerated atherosclerosis in both the transplanted heart and in the native heart.

Platelet-Derived Growth Factor Induces Fetal Wound Fibrosis

The fetal response to cutaneous injury differs markedly from that of the adult, proceeding with only minimal inflammation, minimal fibroblast proliferation, and only essential collagen deposition. Although the sequence of events in adult wound healing is well defined and thought to be controlled in part by potent polypeptide cytokines, relatively sparse information exists regarding growth factor involvement in fetal wound repair. Thus, the authors sought to examine the effect of platelet-derived growth factor (PDGF), a putative adult wound healing regulator, on the cellular and extracellular matrix events at a fetal wound site. SILASTIC wound implants containing 0, 1.0, 5.0, or 10.0 ng of human PDGF were placed subcutaneously on the backs of 24-day-gestation fetal rabbits (full term, 31 days) and then harvested after either 1, 3, or 5 days in utero. The specimens underwent standard histological processing and were evaluated in a blinded fashion. Compared with controls, PDGF-treated implants had a marked increase in acute inflammation, fibroblast recruitment, and collagen and hyaluronic acid deposition; these differences appeared to be largely time- and PDGF dose-dependent. Thus, the fetal system is responsive to an adult wound healing mediator, and these data suggest that fetal repair proceeds in the absence of PDGF.

Biology of fetal repair: The presence of bacteria in fetal wounds induces an adult-like healing response☆

The minimal acute inflammatory response to tissue injury is one of the most dramatic differences between fetal and adult wound healing. Considering the prominent role of inflammation in adult tissue repair, this study tested the hypothesis that the minimal fetal inflammatory response to tissue injury plays a central role in the scarless fetal repair process. Sponge implants were treated with lethally irradiated or live bacteria and placed subcutaneously in fetal rabbits to test the ability of the fetus to mount an acute inflammatory response to bacterial antigens present at the wound site and to analyze the effects of this inflammatory response on fetal fibroplasia and neovascularization. After harvest, these implants were examined histologically for inflammation, fibroblast infiltration, collagen deposition, and neovascularization, and collagen deposition was measured using hydroxyproline quantitation by high-performance liquid chromatography. Bacteria-treated implants showed dose-dependent acute inflammatory responses and significant increases in collagen deposition compared with control sponges. Implants containing live bacteria demonstrated maximal fibroplasia and neovascularization. These findings suggest that, despite neutropenia and immaturity of the fetal immune system, the fetus is capable of mounting an acute inflammatory response to avirulent bacteria present at the wound site. Fetal inflammatory cells which respond to this bacterial stimulus appear capable of initiating an adult-like healing response. Thus, by failing to provide a bacterial stimulus for leukocyte recruitment at the site of tissue injury, the sterile fetal environment appears to play a role in effecting scarless fetal wound healing.

Histopathologic correlates of unstable ischemic syndromes in patients undergoing directional coronary atherectomy: in vivo evidence of thrombosis, ulceration, and inflammation.

Complex coronary morphologic abnormalities with thrombus and ulceration have been recognized in acute ischemic syndromes by angiography, angioscopy, and autopsy. However, in vivo histopathologic correlates of unstable ischemic syndromes have not been described. The purpose of this study was to characterize intracoronary lesion morphologic abnormalities by analyzing specimens excised by directional atherectomy in patients with different ischemic syndromes. Tissue specimens removed by directional coronary atherectomy of primary lesions in native vessels were matched blindly to the clinical status of 130 patients representing 43% of a consecutive directional coronary atherectomy population of 300 patients; 824 specimens (range per patient 1 to 30, mean 6.3) were obtained. Clinical subgroups were prospectively classified as recent myocardial infarction (< or = 15 days, mean 6, range 1 to 15 days), 48 patients; prolonged rest angina, 34 patients; crescendo angina, 29 patients; and stable angina, 19 patients. Shavings were prospectively analyzed for presence of thrombus, ulceration, or chronic inflammatory cells. Thrombus was observed in 33 (69%) patients with recent myocardial infarction, 17 (50%) with rest angina, 12 (41%) with crescendo angina, 7 (37%) with stable angina (p = 0.048). Plaque ulceration was identified in 12 (25%) patients with recent myocardial infarction, 4 (12%) with rest angina, 2 (7%) with crescendo angina, and 1 (5%) with stable angina (p = 0.09). Inflammatory cells were noted in the specimens of 32 (67%) patients with recent myocardial infarction, 16 (45%) with rest angina, 12 (41%) with crescendo angina, and 9 (45%) with stable angina.(ABSTRACT TRUNCATED AT 250 WORDS)

Superior myocardial preservation with modified UW solution after prolonged ischemia in the rat heart

Cardiac transplantation remains constrained by poor graft tolerance of prolonged cold ischemia. University of Wisconsin solution has remarkably extended ischemic preservation in pancreas, kidney, and liver transplantation. To assess its efficacy in cardiac preservation, modified University of Wisconsin solution flush and storage were tested against St. Thomas cardioplegia flush and normal saline solution storage after six hours of ischemia at 0 degrees C in 46 isolated rat hearts. After ischemia, groups were compared before and after reperfusion. After ischemia but before reperfusion, University of Wisconsin solution hearts had significantly less tissue water (3.8%), superior tissue sodium, potassium, calcium, and magnesium profiles, and elevated adenosine and inosine levels, and tended toward better histological preservation. After reperfusion, University of Wisconsin solution more effectively preserved left ventricular compliance (75% versus 35% of baseline), developed pressure (71% versus 45% of baseline), histological integrity, and tissue potassium and calcium profiles than St. Thomas solution. The University of Wisconsin solution provided superior preservation of systolic and diastolic ventricular function, tissue histology, tissue water, and tissue electrolytes than did St. Thomas cardioplegia and normal saline solution storage in this experimental model, and might result in improved graft tolerance of ischemia in clinical cardiac transplantation.

Histologic analysis of directional coronary atherectomy samples. A review of findings and their clinical relevance.

Abstract Histologic analysis of atherectomy samples from >400 patients who received directional coronary atherectomy at 3 separate institutions disclosed 2 major categories of tissue: atherosclerotic plaque (with or without thrombus) and intimal proliferation (hyperplasia, with or without thrombus). The predominant tissue type in atherectomy samples from native, primary, or de novo coronary artery stenoses was atherosclerotic plaque. The predominant tissue type in atherectomy samples from restenosis lesions (prior balloon angioplasty, atherectomy, or both) was intimal proliferation with variable amounts of atherosclerotic plaques (with or without thrombus). Deep vessel wall components (media, adventitia) were identified at varying frequencies. The clinical relevance of atherectomy tissue is reviewed.

Fatal acetaminophen poisoning with evidence of subendocardial necrosis of the heart

The authors describe a case of fatal acetaminophen overdose which occurred in a 16-year-old female. Her serum acetaminophen concentration 11.5 h postingestion was 154 mg/L. Antidotal therapy was unsuccessful, and after 9 days she died. Autopsy findings included centrilobular zonal liver necrosis, acute proximal renal tubular necrosis, and diffuse alveolar pulmonary damage. Her heart was transplanted into a young woman with congenital heart disease. The recipient expired 14 days after the transplant as a result of sepsis complicating bowel ischemia. The transplanted heart showed extensive subendocardial myocyte necrosis related to acetaminophen toxicity and not rejection.

Mechanism of directed transluminal atherectomy

Abstract Directed transluminal atherectomy is a new catheter-mediated technique for the treatment of symptomatic peripheral and coronary artery atherosclerosis. 1 Unlike angioplasty, which may improve vessel patency by disrupting the plaque and stretching the arterial wall, the Simpson atherectomy catheter was specifically designed for percutaneous resection and removal of atherosclerotic plaques. 1–3 It was hypothesized that such an approach would allow for more predictable clinical results with fewer acute complications compared to balloon angioplasty. In the current study, the mechanism of directed atherectomy was investigated through experimental procedures performed on diseased segments of human arteries.

Orotic acid improves left ventricular recovery four days after heterotopic transplantation

Orotic acid accelerates compensatory myocardial hypertrophy after regional ischemia and improves left ventricular function acutely after global ischemia. In this study, the effect of orotic acid on left ventricular function was investigated 4 days after global ischemia (75 minutes, 21 degrees C) using heterotopically transplanted rabbit hearts (n = 18). Experimental animals received daily 100-mg/kg doses of intraperitoneally administered orotic acid, starting 1 day before transplantation, and showed a threefold increase in the serum level of orotic acid by 4 days. After 1 hour of reperfusion, the developed pressure was equally depressed in both the control and experimental groups; however, 4 days later, the developed pressure in control animals was decreased by 3 +/- 3 mm Hg (versus the developed pressure measured at 1 hour) while the developed pressure in experimental animals was significantly increased by 25 +/- 8 mm Hg. Heterotopically transplanted hearts manifested diminished systolic function (stemming from ischemia and unloading) as well as decreased expression of adult myosin. Because orotic acid has been observed to produce an increase in protein synthesis in other models, we investigated whether this improvement in systolic function resulted from an orotic acid-mediated augmentation (or preservation) or normal adult myosin expression. Both orotic acid-treated and untreated hearts manifested decreased expression of the beta-myosin heavy chain protein and steady-state messenger RNA levels. Because function improved with decreased beta-myosin heavy chain expression, an alternate mechanism underlying orotic acid-mediated improvement in function is implicated. Nevertheless, orotic acid may be a therapeutic agent facilitating long-term recovery from global ischemia.

Parathyroid cysts : report of the sixth and youngest pediatric case

A nonfunctioning parathyroid cyst occurred in an 8-year-old girl, the youngest patient reported to have this diagnosis. Most cysts are asymptomatic; a few are associated with signs and symptoms of hyperparathyroidism. In asymptomatic patients with a lateral neck cyst, aspiration of clear fluid with an elevated parathyroid hormone level is diagnostic of a parathyroid cyst. If this results in disappearance of the cyst, without recurrence, no further treatment is necessary. If the cyst recurs, aspiration may be repeated. However, persistence of the cyst despite aspiration or recurrence after the second aspiration should prompt surgical removal, with intraoperative identification of all parathyroid glands, because functioning parathyroid cysts are associated with a high risk of hyperplasia or adenoma.