Patrick A. Lento

Fulminant and fatal gas gangrene of the stomach in a healthy live liver donor

A 57‐year‐old male with a history of hypercholesterolemia and anxiety but otherwise in good health volunteered to donate the right lobe of his liver to his brother. The operation was performed uneventfully, without transfusion. Postoperatively he did well, until he developed tachycardia, profound hypotension, and coffee ground emesis on postoperative day 3. Despite resuscitative measures, he arrested and expired. Autopsy demonstrated gas gangrene of the stomach as the underlying cause of the hemorrhage and numerous colonies of Gram‐positive bacilli were identified. Subsequent polymerase chain reaction (PCR) analysis identified these bacteria to be Clostridium perfringens (C. perfringens) type D. This patients death was devastating, both to his family and his medical team. The impact of his death has transcended that of an individual occurrence. In conclusion, herein we present the facts and discuss this extraordinary example of florid clostridial infection and toxin‐mediated shock. It was completely unexpected and probably unpreventable, and its cause was almost inconceivable. (Liver Transpl 2004;10:1315–1319.)

Human immunodeficiency virus (HIV) infects human arterial smooth muscle cells in vivo and in vitro: implications for the pathogenesis of HIV-mediated vascular disease.

Human immunodeficiency virus (HIV) infection is associated with accelerated atherosclerosis and vasculopathy, although the mechanisms underlying these findings have not been determined. Hypotheses for these observations include: 1) an increase in the prevalence of established cardiac risk factors observed in HIV-infected individuals who are currently experiencing longer life expectancies; 2) the dyslipidemia reported with certain HIV anti-retroviral therapies; and/or 3) the proinflammatory effects of infiltrating HIV-infected monocytes/macrophages. An unexplored possibility is whether HIV itself can infect vascular smooth muscle cells (SMCs) and, by doing so, whether SMCs can accelerate vascular disease. Our studies demonstrate that human SMCs can be infected with HIV both in vivo and in vitro. The HIV protein p24 was detected by fluorescence confocal microscopy in SMCs from tissue sections of human atherosclerotic plaques obtained from HIV-infected individuals. Human SMCs could also be infected in vitro with HIV by a mechanism dependent on CD4, the chemokine receptors CXCR4 or CCR5, and endocytosis, resulting in a marked increase in SMC secretion of the chemokine CCL2/MCP-1, which has been previously shown to be a critical mediator of atherosclerosis. In addition, SMC proliferation appeared concentric to the vessel lumen, and minimal inflammation was detected, unlike typical atherosclerosis. Our data suggest that direct infection of human arterial SMCs by HIV represents a potential mechanism in a multifactorial paradigm to explain the exacerbated atherosclerosis and vasculopathy reported in individuals infected with HIV.

Haptoglobin Genotype Is a Major Determinant of the Amount of Iron in the Human Atherosclerotic Plaque

OBJECTIVES We sought to test the hypothesis that haptoglobin (Hp) genotype is a determinant of the amount of iron in the atherosclerotic plaque. BACKGROUND In atherosclerotic lesions, intraplaque hemorrhage releases free hemoglobin (Hb), whose incorporated iron can act as an oxidant and inflammatory stimulus. These effects are antagonized by Hp, which binds free Hb and facilitates its clearance from the plaque. The Hp gene has 2 alleles (1 and 2), giving rise to 3 genotypes: Hp 1-1, Hp 2-1, and Hp 2-2. We previously hypothesized that Hp 2-2 individuals with diabetes mellitus (DM) have impaired clearance of Hb and its iron cargo from the plaque. METHODS We identified the presence or absence of Perls iron stain in 189 plaques obtained from 37 decedents at autopsy. RESULTS Among DM, the prevalence of Perls iron stain was increased in Hp 2-2 compared with that seen in Hp 1-1 or 2-1 (46.2% vs. 11.8%). After accounting for the within-decedent correlation of plaques, the prevalence ratio of Perls iron stain associated with Hp 2-2 was 3.97 (95% confidence interval: 1.38 to 11.5; p = 0.025). In non-DM plaques, there was a nonsignificant trend towards a higher prevalence of iron staining in Hp 2-2 compared with that in Hp 1-1 or 2-1 (26.8% vs. 11.1%; prevalence ratio =2.40 [95% confidence interval: 0.81 to 7.09]; p = 0.114). CONCLUSIONS These data support an impaired clearance of Hb from plaques in Hp 2-2 individuals, particularly in DM. The higher prevalence of plaque iron in Hp 2-2 DM individuals may contribute to the increased incidence of atherothrombotic events in these patients.

Inflammation, neovascularization and intra-plaque hemorrhage are associated with increased reparative collagen content: Implication for plaque progression in diabetic atherosclerosis

Sustained inflammation may stimulate a reparative process increasing early reparative type III collagen synthesis, promoting atherosclerotic plaque progression. We evaluated inflammation, neovascularization, intra-plaque hemorrhage (IPH), and collagen deposition in human aortic atherosclerotic plaques from patients with and without diabetes mellitus (DM). Plaques were procured at autopsy from lower thoracic and abdominal aorta from DM (n = 20) and non-DM (n = 22) patients. Inflammation and neovascularization were quantified by double-label immunochemistry and the IPH grade was scored using H&E-stained sections. Type I and type III collagens were quantified using Picro-Sirius red stain with polarization microscopy and computerized planimetry. In non-DM plaques, 27%, 40%, and 33% had mild, moderate and severe inflammation in the fibrous cap and shoulder compared with 2%, 30% and 68% in DM plaques (p < 0.001). The geometric mean neovessel count was increased in DM versus non-DM plaques (140 [95% CI: 119—165] versus 59 [95% CI: 51—70]; p < 0.001). The IPH grade was increased in DM verses non-DM plaques (0.82 ± 0.11 versus 0.29 ± 0.11; p < 0.001) (percentage grade). The density of type III was increased in DM plaques (0.16 ± 0.01 versus 0.06 ± 0.01; p < 0.001) with a non-significant reduction in type I density in DM when compared with non-DM (0.28 ± 0.03 versus 0.33 ± 0.03; p = 0.303) (content per mm2). The increase in type III collagen content correlated with total neovessel content (r = 0.58; p < 0.001) in DM plaques. In conclusion, our study suggests that enhanced type III collagen deposition was associated with inflammation, neovascularization and IPH, and may be a contributing factor in DM plaque progression.

Increased expression of oxidation-specific epitopes and apoptosis are associated with haptoglobin genotype: possible implications for plaque progression in human atherosclerosis.

OBJECTIVES The purpose of this study was to test the hypothesis that increased oxidative stress is associated with apoptosis in human plaques with the haptoglobin (Hp) 2-2 genotype. BACKGROUND Intraplaque hemorrhage releases free hemoglobin (Hb). Impaired Hb clearance induces oxidative stress leading to plaque progression. The binding of Hp to Hb attenuates iron-induced oxidative reactions. METHODS Twenty-six human aortic plaques were Hp genotyped. Hp2-2 plaques (n = 13) were compared with control (Hp1-1/2-1) (n = 13). The iron grade was measured by Perls staining. Immunostaining was used to detect oxidation-specific epitopes (OSEs) reflecting oxidized phospholipids and malondialdehyde-like epitopes. The percentages of apoptotic cells and apoptotic morphological features were quantified. DNA fragmentation and active caspase-3 were measured by in situ end-labeling and immunohistochemistry, respectively. RESULTS In Hp2-2 plaques, iron content was increased (1.22 ± 0.15 vs. 0.54 ± 0.08; p < 0.0001) along with expression of oxidized phospholipid- (78.9 ± 5.8 vs. 38.8 ± 3.8; p < 0.0001), and malondialdehyde-like OSEs (93.9 ± 7.9 vs. 54.7 ± 3.9; p < 0.0001). The total percentages of apoptotic cells (11.9 ± 0.44 vs. 3.5 ± 0.28; p < 0.0001), nuclear fragmentation (11.8 ± 0.50 vs. 3.3 ± 0.26; p < 0.0001), nuclear condensation (10.9 ± 0.58 vs. 3.4 ± 0.20; p < 0.0001), chromatin margination (14.2 ± 0.57 vs. 6.5 ± 0.37; p < 0.0001), cytoplasmic blebs (1.6 ± 0.28 vs. 0.8 ± 0.14; p < 0.002), and eosinophilia (10.8 ± 0.74 vs. 4.2 ± 0.27; p < 0.0001) were increased in Hp2-2 plaques. Furthermore, DNA fragmentation (119.9 ± 1.40 vs. 57.5 ± 0.80; p < 0.001), and active caspase-3 density (84.7 ± 7.62 vs. 50.6 ± 7.49; p < 0.004) were increased in Hp2-2 plaques. Logistic regression analysis identified correlation between the percentage of apoptotic cells and the density of OSEs (r = 0.56; p < 0.003). CONCLUSIONS These findings provide insights into genetic predisposition to oxidative stress and the relationship between OSEs and macrophage apoptosis that may explain advanced atherosclerosis in human Hp2-2 plaques.

Increased macrophage infiltration and neovascularization in congenital bicuspid aortic valve stenosis

OBJECTIVES Patients with congenital bicuspid aortic valves have aortic valve stenosis at a relatively young age compared with patients with tricuspid aortic valves. We hypothesize that aortic valve stenosis evolves from a more aggressive inflammatory process, with increased macrophage/T-cell and neovessel content in congenital bicuspid aortic valveswhen compared with that seen in tricuspid valves. METHODS Fifty-one severely stenotic aortic valves were obtained at the time of aortic valve replacement. A total of 17 bicuspid and 34 tricuspid aortic valves were evaluated. Macrophage/T-cell infiltration (CD68 plus CD3) and neovessel density (CD34) were evaluated with immunohistochemical staining. Leaflet calcification and ossification were also quantified. Real-time polymerase chain reaction was used to assess expression of chondromodulin 1 and vascular endothelial growth factor. RESULTS The density of macrophages/T cells was greater in congenital bicuspid aortic valves than in tricuspid valves (51 ± 31 vs 23 ± 13 cells/mm(2), P = .002). Neovascularization was more frequently noted in congenital bicuspid aortic valves when compared with tricuspid valves (31 ± 10 vs 21 ± 9 vessels/mm(2), P = .0005), and calcification was more severe (P = .03). Expression of chondromodulin 1 demonstrated a 6-fold downregulation (P = .0003) and expression of vascular endothelial growth factor demonstrated a 2-fold increase (P = .02) in congenital bicuspid aortic valves compared with that seen in tricuspid valves. Multivariable analyses demonstrated significant associations between bicuspid aortic valve anatomy and increased inflammatory cell infiltration (β = 25.8, P = .0007) and neovascularization (β = 9.4, P = .001), despite adjusting for measured covariates. CONCLUSIONS The pathogenesis of aortic valve stenosis in bicuspid aortic valves is associated with a more aggressive inflammatory process with increased macrophage infiltration and neovascularization when compared with that seen in tricuspid valves.

Clinical setting and extent of premortem evaluation do not predict autopsy discrepancy rates

Autopsy rates have been affected by a number of factors, including technological advances and clinician beliefs of the diminished value of the autopsy. Such factors have resulted in a cultural shift in medicine away from the autopsy. Despite this shift, a number of studies have shown significant differences between antemortem clinical diagnoses and postmortem findings. Surveys of clinician beliefs about the autopsy have pointed toward antemortem diagnostic advancements as an important factor in declining rates. No study to date has addressed the hypothesis that such perceptions in diagnostic certainty have been matched by an actual decay in the yield of valuable or new information obtained by the autopsy. To address this hypothesis, we retrospectively compared the class I and class II discrepancies identified in 284 patients who died in three clinical settings with differing intensities of antemortem diagnostic workup. Despite a significantly different intensity of antemortem workup for patients in each clinical setting, including patients on a medical intensive care unit, patients on a surgical service and patients in an affiliated nursing home, discrepancy rates were found to be similar. Overall discrepancy rates for the medical intensive care unit, surgery service and nursing home patients were 27.8, 32.7 and 31.3%, respectively (P=0.84). In addition, we found no statistical difference in the complexity of workup in discrepant and nondiscrepant cases in each clinical setting. Our study data refute the hypothesis that the intensity of antemortem diagnostic evaluation correlates with an actual decrease in the rate of major diagnostic discrepancies identified at autopsy.

Giant Blastoconidia of Candida albicans A Case Report and Review of the Literature

We describe a patient with extranodal non-Hodgkin lymphoma who developed systemic candidiasis after treatment with a cyclophosphamide-based chemotherapy regimen. Histologically, the fungal organisms demonstrated markedly enlarged blastoconidia with a variety of morphologic forms, mimicking other mycotic organisms, such as Cryptococcus neoformans, Blastomyces dermatitidis, and Paracoccidioides brasiliensis. The in vivo occurrence of such giant forms is rare, and when observed histologically may result in an erroneous diagnosis or a diagnosis of multiple mycotic organisms.

Microscopic Pulmonary Tumor Emboli: An Unusual Presentation of Breast Cancer

Abstract: We report a rare case of microscopic pulmonary tumor embolism from breast cancer in a young woman with no prior medical history. The patient presented with progressive dyspnea and questionable abnormalities of the left breast and axilla on physical examination. Results of an axillary lymph node biopsy and subsequent radiologic studies raised the possibility of either microscopic pulmonary tumor emboli or lymphangitic spread of cancer as a cause of the dyspnea. The patient died due to advanced breast cancer confirmed at autopsy despite chemotherapy.

Increased Thickness of Abdominal Subcutaneous Adipose Tissue Occurs More Frequently in Steatohepatitis Than in Simple Steatosis

CONTEXT The incidence of obesity is increasing and contributes to the rising incidence of fatty liver. Body mass index (BMI) is used to assess the degree of obesity but does not take into account the pattern of body fat distribution. OBJECTIVES To confirm the increasing incidence of fatty liver in an autopsy study. We hypothesized that a standardized measurement of abdominal subcutaneous adipose tissue (ASAT) might be a good noninvasive method for differentiating steatohepatitis from steatosis. DESIGN Consecutive complete adult postmortem cases were studied and liver sections were assessed with a steatohepatitis scoring system. Spleen weight, ASAT, and clinical information were obtained. Spleen histology was assessed in a subset of patients having splenomegaly in the absence of cirrhosis. RESULTS Patients with human immunodeficiency virus, hepatitis C virus, and appreciable alcohol use were excluded. Of 306 cases, the frequency of fatty liver was 51.6% with 33.3% having simple steatosis and 18.3%, having steatohepatitis. Mean ASAT was 3.7 cm in the steatohepatitis group versus 2.6 cm in the steatosis group (P < .001); this difference was greater in patients with a BMI less than 25 kg/m(2) (P = .05). Fibrocongestive splenomegaly was noted in 9 of 38 patients with nonalcoholic steatohepatitis (24%) in the absence of cirrhosis. CONCLUSIONS In this series of autopsy cases, a dramatic increase in the prevalence of fatty liver disease is demonstrated. Thicker ASAT is associated more with steatohepatitis than with simple steatosis, especially in patients with BMI below 25 kg/m(2). Fibrocongestive splenomegaly may occur in the absence of cirrhosis in the presence of steatohepatitis.