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MAF is a transcription factor that may act either as a tumor suppressor or as an oncogene, depending on cell type. We have shown previously that the overexpressed miR-1290 influences MAF protein levels in LSCC (laryngeal squamous cell carcinoma) cell lines. In this study, we shed further light on the interaction between miR-1290 and MAF, as well as on cellular MAF protein localization in LSCC. We confirmed the direct interaction between miR-1290 and MAF 3′UTR by a dual-luciferase reporter assay. In addition, we used immunohistochemistry staining to analyze MAF protein distribution and observed loss of MAF nuclear expression in 58% LSCC samples, of which 10% showed complete absence of MAF, compared to nuclear and cytoplasmatic expression in 100% normal mucosa. Using TCGA data, bisulfite pyrosequencing and CNV analysis, we excluded the possibility that loss-of-function mutations, promoter region DNA methylation or CNV are responsible for MAF loss in LSCC. Finally, we identified genes involved in the regulation of apoptosis harboring the MAF binding motif in their promoter region by applied FIMO and DAVID GO analysis. Our results highlight the role of miR-1290 in suppressing MAF expression in LSCC. Furthermore, MAF loss or mislocalization in FFPE LSCC tumor samples might suggest that MAF acts as a LSCC tumor suppressor by regulating apoptosis.

Mammalian Pumilio (PUM) proteins are sequence-specific, RNA-binding proteins (RBPs) with wide-ranging roles. They are involved in germ cell development, which has functional implications in development and fertility. Although human PUM1 and PUM2 are closely related to each other and recognize the same RNA binding motif, there is some evidence for functional diversity. To address that problem, first we used RIP-Seq and RNA-Seq approaches, and identified mRNA pools regulated by PUM1 and PUM2 proteins in the TCam-2 cell line, a human male germ cell model. Second, applying global mass spectrometry-based profiling, we identified distinct PUM1- and PUM2-interacting putative protein cofactors, most of them involved in RNA processing. Third, combinatorial analysis of RIP and RNA-Seq, mass spectrometry, and RNA motif enrichment analysis revealed that PUM1 and PUM2 form partially varied RNP-regulatory networks (RNA regulons), which indicate different roles in human reproduction and testicular tumorigenesis. Altogether, this work proposes that protein paralogues with very similar and evolutionary highly conserved functional domains may play divergent roles in the cell by combining with different sets of protein cofactors. Our findings highlight the versatility of PUM paralogue-based post-transcriptional regulation, offering insight into the mechanisms underlying their diverse biological roles and diseases resulting from their dysfunction.

Neonates are at increased risk of infections compared to adults. To dissect the mechanisms that contribute to neonatal immune deficiency, we compared MHC-II antigen processing and presentation by monocytes from umbilical cord blood and unrelated adult controls. Antigen-specific, co-stimulation-independent murine T hybridoma cells were used to detect peptide:HLA-DR complexes. Relative to adult monocytes, neonatal monocytes were significantly defective in processing and presentation of protein antigens and presentation of exogenous peptide. Defects in responses to protein antigens and exogenous peptide were of similar magnitude (56-81% decrease), indicating that the defect lies in antigen presentation as opposed to intracellular antigen processing. Average surface MHC-II levels on neonatal monocytes were 38% less than on adult monocytes. However, there was no correlation between decreased MHC-II expression on individual neonatal monocyte samples and reduced T cell responses. We demonstrate for the first time that neonatal monocytes are defective in MHC-II antigen presentation by a mechanism not correlated with decreased MHC-II expression.

Background: Elevations in serum C-reactive protein measured by high-sensitivity assay (hs-CRP) have been associated with unstable coronary syndromes. There have been no autopsy studies correlating hs-CRP to fatal coronary artery disease., Methods and Results: Postmortem sera from 302 autopsies of men and women without inflammatory conditions other than atherosclerosis were assayed for hs-CRP. There were 73 sudden deaths attributable to atherothrombi, 71 sudden coronary deaths with stable plaque, and 158 control cases (unnatural sudden deaths and noncardiac natural deaths without conditions known to elevate CRP). Atherothrombi were classified as plaque ruptures (n=55) and plaque erosion (n=18); plaque burden was estimated in each heart. Total cholesterol, high-density lipoprotein cholesterol, diabetes, smoking history, and body mass index were also determined. Immunohistochemical stains for CRP and numbers of thin cap atheromas per heart were quantitated in coronary deaths with hs-CRP in the highest and lowest quintiles. The median hs-CRP was 3.2 microg/mL in acute rupture, 2.9 microg/mL in plaque erosion, 2.5 microg/mL in stable plaque, and 1.4 microg/mL in controls. Mean log hs-CRP was higher in rupture (P<0.0001), erosion (P=0.005), and stable plaque (P=0.0003) versus controls. By multivariate analysis, atherothrombi (P=0.02), stable plaque (P=0.003), and plaque burden (P=0.03) were associated with log hs-CRP independent of age, sex, smoking, and body mass index. Mean staining intensity for CRP of macrophages and lipid core in plaques was significantly greater in cases with high hs-CRP than those with low CRP (P=0.0001), as were mean numbers of thin cap atheromas (P<0.0001)., Conclusions: hs-CRP is significantly elevated in patients dying suddenly with severe coronary artery disease, both with and without acute coronary thrombosis, and correlates with immunohistochemical staining intensity and numbers of thin cap atheroma.

Background: Blacks have a high rate of sudden coronary death (SCD). We determined the rate of SCD in men and women 30 to 69 years of age in a 6-year period recorded at a state Medical Examiner's Office., Methods and Results: In a subset of 327 whites and 130 blacks, hearts were systematically studied to determine the extent of coronary disease, presence and type of thrombus (acute rupture, acute erosion, stable plaque), and heart weight. These parameters were correlated with the presence of conventional risk factors. The estimated rate of SCD in blacks was similar to that in whites under the age of 40 years but increased compared with whites with advancing age, becoming 1.5 times the rate for whites in the 7th decade (95% of the increase in the 6th decade was due to sudden death with stable plaque). Among the autopsied group with severe coronary atherosclerosis, HDL cholesterol was higher and hypertension more prevalent in blacks, but there was no difference in the prevalence of healed infarcts, plaque burden, heart weight, acute thrombi, or rates of diabetes, cigarette smoking, and total cholesterol., Conclusions: When compared with a control autopsy group of 568 deaths, multivariate analysis showed a significant association in blacks between stable plaque and left ventricular hypertrophy (risk ratio, 7.6), type 1 diabetes (risk ratio, 3.6), hypertension (risk ratio, 3.5), elevated total cholesterol (risk ratio, 3.1) and type 2 diabetes (risk ratio, 2.9). Because these risk factors are associated with SCD in blacks, they may be important targets for reducing the disparately high rate of SCD in blacks as compared with whites.

Senile plaques (SP) and neurofibrillary tangles (NFT) are the lesions characteristic of Alzheimer's disease (AD). In this study, we examined variation in the proportion of individuals who had these lesions by race, age, and gender in a series of 138 autopsies conducted at the Office of the Chief Medical Examiner of the State of Maryland between 1990 and 1998. Cases were selected on the bases of age between 40 to 79 years and non-natural manner of death, and included 73% males, 61% subjects < 65 years of age, and 42% African Americans. Observations were conducted on histologic sections of the hippocampus, entorhinal cortex, and inferior temporal cortex stained with silver (Hirano method) and immunostained for Abeta-amyloid. We found that SP and NFT are strongly associated with age. These lesions begin to appear in the early to late 40s, depending on the anatomic location, and become common in the 6th decade, preceding by one to two decades the age at which AD becomes clinically prevalent. No difference in the prevalence of SP or NFT was found by gender or between whites and African Americans. The latter is in contrast to epidemiologic studies that suggest AD is more prevalent in African Americans than in whites.

Background: Subclinical episodes of plaque disruption followed by healing are considered a mechanism of increased plaque burden. Detailed pathological studies of healed ruptures, however, are lacking., Methods and Results: We identified acute and healed ruptures from 142 men who died of sudden coronary death and performed morphometric measurements of plaque burden, luminal stenosis, and smooth muscle cell phenotype. Healed ruptures were found in 61% of hearts and were associated with healed myocardial infarction, increased heart weight, dyslipidemia, and diabetes. Multiple healed rupture sites with layering were frequently found in segments with acute and healed rupture; the percent area luminal narrowing increased with increased numbers of healed sites of previous rupture. The underlying percent luminal narrowing for acute ruptures (mean 79+/-15%) exceeded that for healed ruptures (mean 66+/-14%, P:=0.0001), and the area within the internal elastic lamina was significantly less in healed ruptures than in acute ruptures, when segments were grouped by distance from the ostium. Healed ruptures favored the accumulation of immature smooth muscle cells at repair sites, with a cellular proliferation index of 0.40+/-0.09%, significantly higher than the index at the sites of rupture (P:=0.008)., Conclusions: These data provide evidence that silent plaque rupture is a form of wound healing that results in increased percent stenosis. Healed ruptures occur in arteries with less cross-sectional area luminal narrowing than acute ruptures and are a frequent finding in men who die suddenly with severe coronary atherosclerosis.

Although apoptosis is a well-recognized phenomenon in chronic atherosclerotic disease, its role in sudden coronary death, in particular, acute plaque rupture is unknown. Culprit lesions from 40 cases of sudden coronary death were evaluated. Cases were divided into two mechanisms of death: ruptured plaques with acute thrombosis (n = 25) and stable plaques with and without healed myocardial infarction (n = 15). Apoptotic cells were identified by staining of fragmented DNA and confirmed in select cases by gold conjugate labeling combined with ultrastructural analysis. Additional studies were performed to examine the expression and activation of two inducers of apoptosis, caspases-1 and -3. Ruptured plaques showed extensive macrophage infiltration of the fibrous cap, in particular at rupture sites contrary to stable lesions, which contained fewer inflammatory cells. Among the culprit lesions, the overall incidence of apoptosis in fibrous caps was significantly greater in ruptured plaques (P < 0.001) and was predominantly localized to the CD68-positive macrophages. Furthermore, apoptosis at plaque rupture sites was more frequent than in areas of intact fibrous cap (P = 0. 028). Plaque rupture sites demonstrated a strong immunoreactivity to caspase-1 within the apoptotic macrophages; staining for caspase-3 was weak. Immunoblot analysis of ruptured plaques demonstrated caspase-1 up-regulation and the presence of its active p20 subunit whereas stable lesions showed only the precursor; nonatherosclerotic control segments were negative for both precursor and active enzyme. These findings demonstrate extensive apoptosis of macrophages limited to the site of plaque rupture. The proteolytic cleavage of caspase-1 in ruptured plaques suggests activation of this apoptotic precursor. Whether macrophage apoptosis is essential to acute plaque rupture or is a response to the rupture itself remains to be determined.

We measured concentrations of cocaine and its major metabolites (benzoylecgonine, ecgonine methylester, norcocaine, and cocaethylene) in 15 autopsied brain regions of 14 human chronic cocaine users. Only slight differences were observed in concentrations of cocaine and its metabolites amongst the examined brain areas. Although it is likely that some postmortem redistribution of the drug must have occurred, our data are consistent with the possibility that behaviorally relevant doses of cocaine are widely distributed throughout the brain of humans who use the drug on a chronic basis. Consideration should therefore be given to the possible pharmacological and toxicological actions of cocaine in both striatal and extra-striatal brain areas in human users of the drug.

Background: Neither clinical prediction models nor noninvasive imaging tests that detect coronary artery calcification identify all patients who experience acute coronary events. Variations in culprit plaque morphology may account for these inaccuracies., Methods and Results: We compared the 10-year Framingham risk index, histologic coronary calcification, and culprit plaque morphology in 79 consecutive adults with sudden cardiac death. There was a modest relationship between the Framingham risk index and the extent of histologic coronary calcification (r=0.35, P=0.002). Agreement in risk classification between the histologic calcification score and the Framingham risk index occurred in 50 of 79 cases (63.3%, P=0. 039). Either a focus of coronary artery calcification >/=40 micromol/L (62% of cases) or a Framingham risk index score >/= average risk for age (62% of cases) were present in 66 of 79 (83.5%) cases. Cases with plaque erosion (n=22) had significantly less coronary calcification (P=0.003) and lower Framingham risk index (P=0.001) scores than stable (n=27) or ruptured (n=30) plaques. Fourteen of 22 (63.6%) cases of plaque erosion were classified as low risk by both the Framingham risk index and the histologic calcification score., Conclusions: The prediction of sudden cardiac death using the Framingham risk index and the measurement of coronary calcification are distinct methods of assessing risk for sudden cardiac death. Excessive reliance on either method alone will produce errors in risk classification, particularly for patients at risk of plaque erosion, but their combination may be complementary.

Objectives: We sought to evaluate the plaque and patient variables related to arterial remodeling responses of early, de novo atherosclerotic lesions involving the left coronary artery., Background: Coronary artery remodeling is a lesion-specific process involving either enlargement or shrinkage of atherosclerotic coronary arteries. There are little histologic data available correlating plaque morphologic and patient clinical characteristics with the degree and type of arterial remodeling in early atherosclerosis., Methods: We studied 736 serial arterial sections from the left coronary system of 97 autopsy cases (mean age 33 +/- 11 years) by correlating the arterial remodeling response to plaque with demographic, serologic and histologic variables. Using the most proximal section as a reference, and considering the expected degree of internal elastic lamina tapering, remodeling was classified as positive (including neutral remodeling or compensatory enlargement) or negative., Results: Remodeling was classified as positive in 84.3% (compensatory in 30.6%) and negative in 15.7% of sections with an overall mean luminal stenosis of 10.4 +/- 9.9%. In the lesions with the greatest arterial cross-sectional narrowing from each case, compensatory enlargement was associated with higher high-density lipoprotein (HDL) cholesterol (59.4 +/- 27.2 mg/dl) compared with either neutral (49.3 +/- 15.5 mg/dl) or negative remodeling (30.4 +/- 5.2 mg/dl; p = 0.019). In subjects with advanced atherosclerosis (maximum American Heart Association histologic grade 5 atherosclerosis), there was a modest linear relationship between higher HDL cholesterol and the propensity for positive remodeling (r2 = 0.37; p = 0.025). On multivariate analysis, only HDL cholesterol was related to the arterial remodeling response., Conclusions: Negative arterial remodeling occurs in early atherosclerosis. Higher HDL cholesterol may favor positive remodeling.

Arrhythmogenic right ventricular cardiomyopathy is emerging as a relatively common cause of exercise-induced sudden death in the young. The diagnostic criteria at autopsy are, however, not fully established, leading to both over- and underdiagnosis. We report a young man and a young woman dying suddenly of right ventricular dysplasia during exercise, in whom the gross autopsy findings in the right ventricle were minimal or even absent. However, the histologic features in both right and left ventricles were typical of the disease, and consisted of fibrofatty infiltrates with typical myocyte degeneration of the right ventricle and subepicardial regions of the left ventricle. These cases illustrate that microscopic findings are diagnostic and may be present in the absence of gross findings. Marked fat replacement is not essential for the diagnosis of right ventricular dysplasia, and the right ventricle should be extensively sampled histologically in all cases of sudden unexpected death, especially those that are exercise related.

Cognitive impairment has been reported in some chronic users of psychostimulants, raising the possibility that long-term drug exposure might damage brain neuronal systems, including the cholinergic system, which are responsible for normal cognition. We measured the activity of choline acetyltransferase (ChAT), the marker enzyme for cholinergic neurones, in autopsied brain of chronic users of cocaine, methamphetamine, and, for comparison, heroin. As compared with the controls, mean ChAT levels were normal in all cortical and subcortical brain areas examined. However, the two of 12 methamphetamine users, who had the highest brain/blood drug levels at autopsy, had a severe (up to 94%) depletion of ChAT activity in cerebral cortex, striatum, and thalamus. Based on the subjects examined in the present study, our neurochemical data suggest that brain cholinergic neurone damage is unlikely to be a typical feature of chronic use of cocaine, methamphetamine, or heroin, but that exposure to very high doses of methamphetamine could impair, at least acutely, cognitive function requiring a normal nucleus basalis cholinergic neuronal system. Reduced brain ChAT might be explained in part by a hyperthermia-related mechanism as low ChAT levels have also been observed in brain of some patients with neuroleptic drug-associated hyperthermia. Studies of cognitive and brain cholinergic status in high dose users of MA are warranted.

Intermediate targets becoming secondary projectiles in gunshot wounds is a well recognized phenomenon. Secondary projectiles usually possess a fraction of the kinetic energy compared to the primary projectile, leading to superficial wounds of skin and soft tissue. We describe the case of a foreign object that was propelled by the primary bullet with sufficient energy to penetrate not only skin and soft tissue, but also temporal skull and brain. The report also examines the energy requirements for an object to penetrate bone and unique radiographic findings.

Background: Traditional risk factors have been linked to atherosclerotic heart disease in women. However, the effect of risk factors and menopausal status on the mechanism of sudden coronary death is unknown., Methods and Results: We examined 51 cases of sudden coronary death and 15 hearts from women who died of trauma. Coronary deaths were divided into four mechanisms of death: ruptured plaque with acute thrombus (n = 8), eroded plaque with acute thrombus (n = 18), stable plaque with healed infarct (n = 18), and stable plaque without infarction (n = 7). Vulnerable plaques prone to rupture were defined as those with a thin, fibrous cap infiltrated by macrophages and were quantitated in coronary deaths and control subjects. Total cholesterol (TC), HDL cholesterol, glycosylated hemoglobin, cigarette smoking, and hypertension were determined in each case. Compared with control subjects, women with plaque ruptures had elevated TC (270 +/- 55 versus 194 +/- 44 mg/dL, P = 0.002), and those with erosions were more likely to be smokers (78% versus 33%, P = 0.01). Women with stable plaque and healed infarct had elevated glycosylated hemoglobin (10.2 +/- 5.0% versus 6.4 +/- 0.4% in control subjects, P = 0.001) and were more likely to be hypertensive (50% versus 15% in control subjects, P = 0.03). By multivariate analysis, cigarette smoking was associated with plaque erosion (P = 0.03, odds ratio [OR] 21), glycoslyated hemoglobin with stable plaque and healed infarct (P = 0.03, OR 41), TC with plaque rupture (P = 0.02, OR 7), and hypertension with stable plaque with healed infarct (P = 0.02, OR 15). Seven of 8 plaque ruptures occurred in women > 50 years of age versus 3 of 18 erosions (P = 0.001). In cases of coronary death, vulnerable plaques were associated with elevated cholesterol (P = 0.002) and age > 50 years (P = 0.002), independent of other risk factors., Conclusions: In women, traditional risk factors have distinct effects on the mechanisms of sudden coronary death, which vary by menopausal status. Effective risk factor modification may therefore differ between younger and older women and may be targeting different mechanisms of plaque instability.

Although studies indicate abnormalities in the striatum of schizophrenic people, little information exists on the synaptic changes that may be present at the ultrastructural level. Autopsy specimens of striatal tissue from people with schizophrenia, normal controls, and psychiatric controls were obtained from the Maryland Brain Collection. Several abnormalities were noted in the schizophrenic group that were not present in the normal or psychiatric controls. In schizophrenic tissue, the density and/or proportion of symmetric synaptic profiles, particularly those ending on spines, were lower in the caudate vs. the putamen, implying an imbalance in inhibitory synaptic transmission between these two structures. The density of perforated synaptic profiles, cortical afferents thought to be involved in synaptic turnover and cognition, was lower in the striatum of the schizophrenic group compared to the control groups. The density of axodendritic synaptic profiles, particularly of the asymmetric type, was decreased in the caudate, but not the putamen, of a subset of schizophrenic cases that were nondyskinetic and off drugs (NDODS). The proportion of asymmetric axospinous synaptic profiles was elevated in the caudate of the NDODS cases in comparison to normal controls. The variety of synapses affected in the schizophrenic group implies the involvement of several neuronal circuits. The alterations observed in the schizophrenic striatum were usually due to changes in the caudate, but not the putamen, which argues against drug-related alterations. Since the striatum, particularly the caudate nucleus, is involved in cognition and emotion, these neuroanatomical changes could underlie, in part, aspects of schizophrenic psychopathology.

To examine the role of benzodiazepine (BZ) receptors in suicide and schizophrenia, we determined BZ receptors in post-mortem brain (Brodmann's area 10) obtained from suicide victims, schizophrenic patients, and control subjects using [3H]RO15-1788 as the radioligand. The maximum number of binding sites (Bmax) of BZ receptors in the cortex of suicide victims was significantly higher compared with controls, but this increase was mainly due to those suicide victims who died by violent means and whose Bmax was significantly higher than of those who died by non-violent means or control subjects. In schizophrenic patients, Bmax was not significantly different from that of control subjects. When the schizophrenic subjects were separated into two groups, those on neuroleptics and those off neuroleptics for at least 12 months, however, the mean Bmax of BZ receptors in the prefrontal cortex in post-mortem brain obtained from schizophrenic patients on neuroleptics was significantly lower than Bmax in drug-free schizophrenic patients or normal controls. There were no significant differences among groups in values of the apparent dissociation constant (KD) of [3H]RO15-1788 binding. These results suggest that BZ receptors are up-regulated in the cortex of suicide victims, specifically those who used violent means, and that neuroleptic treatment may result in decreased central BZ receptor binding in the cortex of schizophrenic patients. Thus, the method of suicide and previous exposure to neuroleptics should be considered in the interpretation of data on BZ receptors.

The mechanism of sudden cardiac death in patients with mitral valve prolapse is poorly understood. Twenty-four hearts from patients with mitral valve prolapse who suddenly died (mean age 34 +/- 8 years) and 16 trauma control hearts (mean age 30 +/- 7 years) were histologically studied. Dysplasia of the atrioventricular nodal artery was present in 18 of 24 hearts with mitral valve prolapse and four of 16 controls hearts (p = 0.003). The degree of luminal narrowing, as morphometrically measured, was significantly greater in hearts with mitral valve prolapse (p = 0.003). The degree of fibrosis in the base of the ventricular septum, as calculated by computerized morphometry, was greater in hearts with mitral valve prolapse (p = 0.0002) and independent of age, sex, and heart weight (p = 0.005). We conclude that arterial dysplasia in mitral valve prolapse may contribute to sudden cardiac death mediated by ventricular fibrosis.

Background: Cigarette smoking and abnormal serum cholesterol concentrations are risk factors for acute coronary syndromes, but the underlying mechanisms are poorly understood. We studied whether cigarette smoking and abnormal cholesterol values may precipitate acute coronary thrombosis and sudden death resulting from either rupture of vulnerable coronary plaques or erosion of plaques., Methods: We examined the hearts of 113 men with coronary disease who had died suddenly and also analyzed their coronary risk factors. We found an acute coronary thrombus in each of 59 men, and severe narrowing of the coronary artery by an atherosclerotic plaque without acute thrombosis (stable plaque) in 54. Cases of acute thrombosis were divided into two groups: 41 resulting from rupture of a vulnerable plaque (a thin fibrous cap overlying a lipid-rich core), and 18 resulting from the erosion of a fibrous plaque rich in smooth-muscle cells and proteoglycans. Vulnerable plaques that had not ruptured were counted in each heart., Results: Cigarette smoking was a risk factor in 44 (75 percent) of the men with acute thrombosis, as compared with 22 (41 percent) of the men with stable plaques (P<0.001). The mean (+/-SD) ratio of serum total cholesterol to high-density lipoprotein (HDL) cholesterol was markedly elevated in the men who died of acute thrombosis with plaque rupture (mean, 8.5+/-4.0) but only mildly elevated in the men without acute thrombosis (5.5+/-2.4; P<0.001) and in the men with thrombi overlying eroded plaques (5.0+/-1.8; P<0.001). Multivariate analysis showed an association between an elevated ratio of serum total cholesterol to HDL cholesterol and the presence of vulnerable plaques (P<0.001)., Conclusions: Among men with coronary disease who die suddenly, abnormal serum cholesterol concentrations - particularly elevated ratios of total cholesterol to HDL cholesterol - predispose patients to rupture of vulnerable plaques, whereas cigarette smoking predisposes patients to acute thrombosis.

Background: Intravenous drug (IVD) use is a wellknown risk factor for infectious endocarditis (IE), but there are few morphologic and epidemiologic data comparing IVD-related and non-IVD-related IE in cases of sudden death., Material and Results: Between 1992 and 1994, acute IE was diagnosed in 13 IVD users at the Office of the Chief Medical Examiner in Maryland, indicating a yearly incidence of IE-related sudden unexpected deaths of 12 per 100,000. Eleven (85%) cases of acute IE occurred on apparently previously normal valves, and there was one unicuspid valve and one infected porcine prosthesis. There were three right-sided (tricuspid) lesions (23%), nine left-sided lesions (69%), and one multivalvular lesion (8%). During the same period, there were five cases of healed IE in IVD abusers, three of which involved the tricuspid valve. The prevalence of incidental healed lesions in autopsies of IVD users was 0.2%. The healed tricuspid lesions consisted of smooth-edged defects in the valve leaflet without perforations characteristic of mitral or aortic IE. The mean age of the deceased with healed lesions was 45 +/- 6 years versus 34 +/- 10 years for those with acute endocarditis (p = 0.03). During the same time period, there were six cases of acute IE among non-drug users, indicating a yearly incidence of sudden unexpected death of 0.04 per 100,000. Acute IE occurred on congenitally malformed (n = 5) or prosthetic (n = 1) valves. There were two cases of incidental healed IE (mitral and aortic valves), indicating a prevalence of 0.02%., Conclusion: IVD users are 300 times more likely to die suddenly with IE than non-IVD users, and healed lesions are 25 times more common. Healed IE of the tricuspid valve is associated with IVD abuse, and has a characteristic gross appearance that differs from healed left-sided IE.

Background: Epidemiological studies have shown that hypertension and left ventricular hypertrophy (LVH) increase the risk of sudden cardiac death (SCD) in patients with severe coronary artery disease (CAD). However, autopsy studies comparing the morphological substrates for SCD in normotensives and hypertensives are lacking., Methods and Results: Heart weight and coronary plaque morphology were prospectively compared in SCD in 36 hypertensive and 63 normotensive individuals. The frequency of CAD was similar in hypertensives (69%, n = 25) and normotensives (73%, n = 46). In 71 hearts with CAD, acute coronary thrombi were present in 76% of normotensives versus 36% of hypertensives (P = .002), LVH was present in 64% of hypertensives versus 33% of normotensives (P = .01) and in 72% of hypertensives with one-vessel disease versus 17% of normotensives with one-vessel disease (P = .0005), and a healed or acute infarct without acute thrombus was present in 36% of hypertensives versus 9% of normotensives (P = .007). Heart weight was higher in all cases of plaque rupture (519 +/- 109 g) than eroded plaque (381 +/- 92 g, P = .0002). In contrast to hypertensives, normotensive hearts with severe CAD showed a stepwise increase in heart weight with one-, two-, and three-vessel disease (P = .01)., Conclusions: Severe CAD is present in most SCD in hypertensive and normotensive individuals, but acute thrombi are more common in normotensives. LVH is an important contributing mechanism of SCD in hypertensives, especially in cases of one-vessel disease. LVH is associated with plaque rupture and extent of disease in SCD in normotensives with severe CAD.

Depletion of striatal dopamine (DA) has been hypothesized to explain some of the neurological and psychiatric complications of chronic use of cocaine, including increased risk for neuroleptic-precipitated movement disorders. We measured levels of DA, as well as two DA nerve terminal indices, namely, the DA transporter (DAT) and the vesicular monoamine transporter (VMAT2) in autopsied brain of 12 chronic cocaine users. Mean DA levels were normal in the putamen, the motor component of the striatum; however 4 of the 12 subjects had DA values below the lower limit of the control range. DA concentrations were significantly reduced in the caudate head (head, -33%; tail, -39%) with a trend for reduction in nucleus accumbens (-27%). Striatal DAT protein (-25 to -46%) and VMAT2 (-17 to -22%) were reduced, whereas DAT determined by [3H]WIN 35,428 binding was normal. In conclusion, our data suggest that chronic cocaine use is associated with modestly reduced levels of striatal DA and the DA transporter in some subjects and that these changes might contribute to the neurological and psychiatric effects of the drug.

Compensatory arterial enlargement in response to atherosclerosis has been demonstrated for the left main coronary artery. Only limited data is available on the interaction of patient characteristics and atherosclerosis with coronary artery dimensions. The purpose of the present study was to evaluate the influence of age, race, body habitus, heart weight and atherosclerosis on coronary artery dimensions of young males. Hearts from 137 young men (age 32 +/- 8 years; 78 black, 59 white) with unnatural deaths (homicide, suicide, accident, drug overdose) were perfusion-fixed, and histologic sections were obtained from the left main, proximal left anterior descending and left circumflex coronary arteries. Computerized planimetry was performed on Movat stained sections. Multiple regression analysis was used to evaluate the relative contribution of plaque size, age, race, heart weight and body surface area on coronary dimensions and compensatory enlargement in response to atherosclerosis. In the left anterior descending and left main coronary arteries, black race, body surface area and age were independent predictors of increased lumen area. In the left circumflex, age was a predictor of lumen area. Plaque area, black race and body surface area independently predicted increased area enclosed by the internal elastic lamina area. There was compensatory enlargement of internal elastic lamina with increasing plaque size in both races in the three arteries, but the percent luminal stenosis was greater in whites due to smaller artery size. Luminal narrowing did not develop until plaques occupied 30% of internal elastic lamina area. Among a population of young men with non-cardiac deaths, blacks have larger lumen and area enclosed by internal elastic lamina than whites. Age and body surface area are major determinants of lumen areas, and compensatory arterial enlargement was seen in all examined arteries in the present study.

Background: Coronary thrombosis has been reported to occur most frequently in lipid-rich plaques with rupture of a thin fibrous cap and contact of the thrombus with a pool of extracellular lipid. However, the frequency of coronary artery thrombosis with or without fibrous cap rupture in sudden coronary death is unknown. In this study, we compared the incidence and morphological characteristics of coronary thrombosis associated with plaque rupture versus thrombosis in eroded plaques without rupture., Methods and Results: Fifty consecutive cases of sudden death due to coronary artery thrombosis were studied by histology and immunohistochemistry. Plaque rupture of a fibrous cap with communication of the thrombus with a lipid pool was identified in 28 cases. Thrombi without rupture were present in 22 cases, all of which had superficial erosion of a proteoglycan-rich plaque. The mean age at death was 53 +/- 10 years in plaque rupture cases versus 44 +/- 7 years in eroded plaques without rupture (P < .02). In the plaque-rupture group, 5 of 28 (18%) were women versus 11 of 22 (50%) with eroded plaques (P = .03). The mean percent luminal area stenosis was 78 +/- 12% in plaque rupture and 70 +/- 11% in superficial erosion (P < .03). Plaque calcification was present in 69% of ruptures versus 23% of erosions (P < .002). In plaque ruptures, the fibrous cap was infiltrated by macrophages in 100% and T cells in 75% of cases compared with 50% (P < .0001) and 32% (P < .004), respectively, in superficial erosions. Clusters of smooth muscle cells adjacent to the thrombi were present in 95% of erosions versus 33% of ruptures (P < .0001). HLA-DR expression was more often seen in macrophages and T cells in ruptures (25 of 28 cases) compared with expression in macrophages in superficial erosion arteries (8 of 22 cases, P = .0002)., Conclusions: Erosion of proteoglycan-rich and smooth muscle cell-rich plaques lacking a superficial lipid core or plaque rupture is a frequent finding in sudden death due to coronary thrombosis, comprising 44% of cases in the present study. These lesions are more often seen in younger individuals and women, have less luminal narrowing and less calcification, and less often have foci of macrophages and T cells compared with plaque ruptures.