Striatal dopaminergic abnormalities in human cocaine users.

OBJECTIVE: Previous human postmortem experiments have shown an abnormally high number of dopamine uptake sites in the striatum of chronic cocaine users, which might contribute to cocaine withdrawal symptoms such as depression and suicidality. Previous inconsistencies in results were perhaps related to selective radioligand affinity changes or a coexisting loss of dopamine neurons. METHOD: In the present study, binding of the cocaine analog [3H]WIN 35428 to the dopamine transporter was assayed in postmortem striatal samples from 15 cocaine-using subjects and 15 matched comparison subjects to determine whether there were differences in number of binding sites or in affinity. Binding to the vesicular monoamine transporter, a measure of total dopaminergic terminals, was also assessed by using the radioligand (+)-[3H]dihydrotetrabenazine (DTBZ). RESULTS: Striatal [3H]WIN 35428 binding sites were significantly more numerous in the cocaine users: the mean Bmax value was 9.0 fmol bound/microg protein (SD = 2.8) for the cocaine users but only 6.0 (SD = 1.7) for the comparison subjects. Severity of chronic cocaine use was significantly related to [3H]WIN 35428 binding level. [3H]DTBZ binding was significantly lower in the cocaine users (mean = 330 nCi/mg, SD = 42) than in the comparison subjects (mean = 374, SD = 68). CONCLUSIONS: The present results confirm that cocaine users have a high number of dopamine transporter binding sites on dopaminergic neurons, despite an apparent low number of total dopamine terminals. These abnormalities may contribute to the abnormalities in subjective experience and behavior characteristic of chronic cocaine abusers.

Brain dopamine transporter messenger RNA and binding sites in cocaine users: a postmortem study.

BACKGROUND: Results of recent radioligand binding experiments suggest that chronic cocaine exposure increases dopamine transporter (DAT) synthesis throughout the striatum of humans. However, detection of cocaine binding site increases in animals and humans has varied depending on the radioligand used. The present experiment tested the hypothesis in cocaine-using humans that synthesis of midbrain DAT messenger RNA increases parallel with increased striatal DAT binding sites. METHODS: Striatal and midbrain samples were collected during autopsy examination from human cocaine users (n = 34) and from age-, sex-, and race-matched control subjects (n = 36). Levels of DAT messenger RNA were quantified in the medial and lateral midbrain regions using in situ hybridization, and striatal DAT binding sites were assessed by quantitative autoradiography using the DAT-specific radioligand [3H]WIN 35428. RESULTS: Striatal DAT binding sites were markedly increased in cocaine users, but, paradoxically, medial DAT messenger RNA levels were decreased. CONCLUSION: Cocaine exposure has a marked effect on DAT function, but the mechanisms involved may be complex.

Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels.

OBJECTIVE: Earlier platelet and postmortem brain studies have found alterations in serotonin transporter function in ethanol-abusing human subjects. The present investigation tested the hypothesis that brain serotonin transporter function is altered in chronic users of ethanol and cocaine, which might be related to a common serotonin transporter promoter polymorphism. METHOD: Serotonin transporter binding sites, serotonin transporter mRNA levels, and serotonin transporter promoter variants were quantified in postmortem samples from a group of human subjects who had been ethanol users or cocaine users and then compared to those of a matched group of comparison subjects. Quantitative autoradiographic and in situ hybridization assays were performed in midbrain samples that contained the dorsal and median raphe nuclei (the location of serotonin cell bodies that innervate the forebrain). RESULTS: There was a significant overall cocaine-by-ethanol-by-genotype interaction. Dorsal raphe [125I]CIT binding to the serotonin transporter was lower in cocaine users than in comparison subjects. In addition, serotonin transporter binding and serotonin transporter mRNA levels varied significantly by genotype. It was also found that serotonin transporter binding in subjects with either the short or heterozygote genotype was significantly higher in the ethanol-user subjects. CONCLUSIONS: Serotonin transporter binding sites were regulated in a region-specific and substance-specific pattern, which was not simply a local response to functional blockade. Also, a reciprocal relationship appeared to exist between cocaine and ethanol effects in the dorsal raphe, which may have interesting clinical implications for dual-diagnosis patients. It is possible that serotonin transporter promoter genotype may play a complex role in chronic ethanol dependence.

Tetrachloroethylene intoxication in an autoerotic fatality.

This case report describes an accidental death due to the inhalation of tetrachloroethylene during an autoerotic episode. Tetrachloroethylene was administered from a can of Fix-A-Flat tire repair. Analysis of tetrachloroethylene was performed using headspace gas chromatography and electron capture detection. The blood tetrachloroethylene concentration of 62 mg/L was consistent with acute tetrachloroethylene intoxication.

Cocaine-associated intracranial hemorrhage: absence of vasculitis in 14 cases.

Complications associated with the use of cocaine are varied, and include cerebral hemorrhage and ischemia, with vasculitis and vasospasm as possible etiologies. We reviewed selected brain samples from 14 autopsy cases of cocaine-related cerebrovascular disease. Intracerebral or subarachnoid hemorrhage was present in 12 cases. Intracranial arterioles were either normal or showed nonspecific changes. From these observations, we suggest that intracranial hemorrhages occur in the absence of readily detectable vascular abnormalities.

The value of the medical examiner as a member of the multidisciplinary trauma morbidity-mortality committee.

The multidisciplinary trauma peer review process collects, reviews, discusses, and collates all morbidities and mortalities of injured patients to institute corrective action in a timely manner. The resultant remedial activity may include professional education, physician counseling, restriction of privileges, or changes in the trauma care system. Effective corrective action necessitates timely data input from the postmortem examination. Faced with an inordinate delay, skimpy reports, and expense in obtaining such reports from the medical examiner's office, the chief medical examiner was invited to become a member of the peer review committee. During a 12-month interval as a full-fledged member of the peer review process, the medical examiner was able to provide complete verbal reports on all deaths resulting in a synergistic benefit to the peer review process and to the medical examiner office. Two of 53 nonpreventable deaths were reclassified as possibly preventable in one and preventable in the other. Four of 15 possibly preventable deaths were reclassified based on the medical examiner report. In turn, the physician members of the team were able to augment the medical examiner's knowledge in certain areas that were critical for his analysis of accidents or homicide. Based on these findings, the medical examiner is recommended as a participating member of the trauma peer review committee.

Characterization and localization of [125I]RTI-121 binding sites in human striatum and medial temporal lobe.

Dopamine Transporter (DAT) binding sites in medial temporal lobe structures are much less dense than in striatum and have been difficult to image and quantitate. The recently synthesized compound [125I]RTI-121 ([125I]2 beta-carboxylic acid isopropyl ester-3 beta-(4-iodophenyl)tropane) has demonstrated high specificity and affinity for the DAT in preliminary animal studies. The present experiments were designed to delineate the pharmacological and anatomical characteristics of [125I]RTI-121 binding sites in the striatum and medial temporal lobe of normal humans. A series of saturation experiments performed with striatal membrane preparations generated a one-site model with a KD averaging 1.49 +/- 0.06 nM, and a Bmax that was comparable to those of earlier reports. Competition experiments confirmed the selectivity of [125I]RTI-121 for DAT binding sites. After the assay conditions for autoradiography were optimized, [125I]RTI-121 binding was visualized, pharmacologically characterized and quantitated in human temporal lobe structures. In the hippocampus, specific binding was distributed in the CA4 and CA3 pyramidal cell layers, the outer stratum radiatum and the dentate molecular layer, but not in the dentate granule cells or outer pyramidal cells. In the amygdala specific binding was limited to the basolateral nuclei. Dopamine nerve terminals, as identified with [125I]RTI-121 binding, also displayed a discrete and homologous innervation pattern in the amygdala and hippocampus of several other mammalian species. In summary, the kinetic, saturation, competition and autoradiographic experiments demonstrated that [125I]RTI-121 can be used to identify DAT binding sites and to assess their functional state in post mortem human brain samples.

Epidemiology of high grade prostatic intraepithelial neoplasia.

The prevalence of high grade prostatic intraepithelial neoplasia (HGPIN), the age at which this lesion starts and the potential racial or ethnic differences in its distribution are poorly documented. HGPIN is becoming increasingly implicated as a premalignant lesion for clinically significant prostatic carcinoma (PCa) with mounting evidence linking it to carcinoma according to morphologic immunohistochemical and recent genomic studies. We describe our experience with the age and race distribution of HGPIN resulting from two study populations of African-American (AA) and Caucasian (C) males. The first component of this report describes an autopsy study aimed at determining the prevalence of latent PCa and HGPIN in AA and C men 20 years of age or older; 370 (218 AA and 152 C) consecutive step-sectioned, totally embedded prostate glands were microscopically evaluated and mapped for HGPIN and PCa. HGPIN was first identified in the third decade and increased steadily with age. Latent PCa increased steadily with age with no significant difference in the prevalence between AA and C males in any age group (3rd to 8th decades). HGPIN, on the other hand, was more prevalent in AA men with 18, 31, 69, 78 and 86% in their 4th, 5th, 6th, 7th and 8th decades harboring the lesion. The corresponding figures for C men were 14, 21, 38, 50 and 63% respectively. When HGPIN was quantitated as focal and extensive according to the degree of glandular involvement, extensive HGPIN appeared earlier in AA males under 60 years of age compared to C males cohort. The difference in age distribution appeared to follow a chronological pattern, with HGPIN in AA preceding that of C males by approximately a decade. The second component of this report describes a surgical series of 345 consecutive radical prostatectomies from patients (155 AA and 190 C) with clinically localized PCa, which were thoroughly evaluated microscopically by two urologic pathologists. Similar to the findings in the autopsy study, extensive HGPIN was more prevalent in AA men 60 years of age or younger (57% vs. 33%). In both races, the mean percentage of the gland involved by HGPIN decreased with advancing age in contrast to the mean tumor volume that increased with patient age. These findings indicating a different prevalence of HGPIN in the two racial groups may help explain the higher incidence of prostatic cancer in African-Americans.

High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases.

The relationship of prostatic intraepithelial neoplasia (PIN) and invasive carcinoma of the prostate is not fully understood. It is generally accepted that HGPIN is a probable preinvasive malignant change or at least a marker lesion for carcinoma. The prevalence of HGPIN in younger men is not known. Two hundred and forty nine entirely processed prostates from men aged 20-69 were thoroughly evaluated for the presence of PIN and carcinoma. The histologic diagnosis of all positive cases was confirmed by two pathologists. Our results are summarized as follows: Seventy seven percent of the prostates with HGPIN harbored adenocarcinoma, whereas the frequency of cancer in prostates without HGPIN was 24%. HGPIN was encountered in 0, 5, 10, 41 and 63% of men in the 3rd, 4th, 5th and 7th decades, respectively. The corresponding figures for invasive carcinoma were 2, 29, 32, 55, and 64% respectively.

Concentration of alcohol in delayed subdural hematoma.

The medicolegal implications of a delayed subdural hemorrhage are described, with particular reference to the significance of the alcohol content in the hematoma versus that in the peripheral blood at the time of injury.