Postmenopausal hypertrophy of neurons expressing the estrogen receptor gene in the human hypothalamus.

Computer microscopy and in situ hybridization were used to investigate neuronal hypertrophy in the infundibular nucleus of postmenopausal women. In the first experiment, hypothalami from premenopausal (n = 3) and postmenopausal (n = 3) women were formalin fixed, paraffin embedded, serially sectioned, and stained with cresyl violet. Soma areas of more than 3500 neurons were digitized using an image-combining computer microscope. The mean cross-sectional area of infundibular neurons in the postmenopausal women was 30% greater than that in premenopausal women, with no change in cell density. The mean cross-sectional area of mammillary neurons was unchanged, indicating that the infundibular neuronal hypertrophy was not an artifact of tissue processing. In the second experiment, hypothalami from premenopausal (n = 3) and postmenopausal (n = 2) women were frozen, serially sectioned, and incubated with a 48-base synthetic cDNA probe complementary to estrogen receptor (ER) mRNA. Adjacent sections were incubated with a cDNA probe complementary to GnRH mRNA. Morphometric analysis revealed that the mean cross-sectional area of infundibular neurons expressing the ER gene in the postmenopausal women was twice as large as the mean area in premenopausal hypothalami. The hypertrophied neurons did not contain GnRH mRNA. Finally, analysis of the infundibular nucleus from an oophorectomized 38-yr-old woman also revealed hypertrophied neurons containing ER mRNA. These data support the hypothesis that hypertrophy of infundibular neurons in postmenopausal women is secondary to loss of the inhibitory feedback of ovarian steroids.

Simultaneous sudden infant death syndrome in twins.

Nine cases of twin infants dying suddenly and simultaneously are described, two of which the author examined personally. A review of this phenomenon described in other literature is also presented. It is hoped that increased awareness of this phenomenon will decrease the profound suspicions of both lay and professional persons that the deaths were due to criminal instrumentality.

Incidental myocarditis with intravenous drug abuse: the pathology, immunopathology, and potential implications for human immunodeficiency virus-associated myocarditis.

Human immunodeficiency virus (HIV)-associated myocarditis is well reported. Many of these patients are also intravenous (IV) drug abusers. This study examined sudden death victims from the Office of the Chief Medical Examiner, State of Maryland, for active myocarditis. A group of HIV-negative drug abusers is compared with a group of HIV-negative victims without any known risk factors for the acquired immunodeficiency syndrome. Using modified Dallas criteria combined with an avidin-biotin-labeled immunoperoxidase procedure, the cases were classified as active, borderline, or absent myocarditis. Serologic analysis for circulating antimyocardial antibody was performed along with phenotypic analysis of the infiltrate. Of the 15 IV drug abuse cases examined, none were positive for HIV (enzyme-linked immunosorbent assay and Western blot). With IV drug abuse as the primary risk factor, five cases demonstrated active myocarditis, while five others had borderline myocarditis. Only one of 10 low-risk patients had a lymphocytic infiltrate consistent with borderline myocarditis. Drug abuse-related myocarditis was associated with cardiac pathology resulting in sudden death in only one case. Antimyocardial antibodies were positive in four of the 15 IV drug abuse cases, including patients with active, borderline, and absent myocarditis. The phenotypic expression of the lymphocytic infiltrates was similar to the findings reported for idiopathic and HIV-related myocarditis (Am J Pathol 137:1365-1371, 1990). Toxicology studies did not implicate any particular drug of abuse, but the increased frequency of myocarditis observed may reflect complications of cocaine or the combined effects of opiates and cocaine. Intravenous drug abuse is an independent risk factor for myocarditis and must be taken into consideration in studies of HIV-associated myocarditis.

Pulmonary artery medial hypertrophy in cocaine users without foreign particle microembolization.

A reduction in the DCO has been reported among "free-base" cocaine smokers. We reviewed the pulmonary histopathology in 20 deaths due to cocaine intoxication for either parenchymal or vascular abnormalities which might explain this physiologic finding. Pulmonary artery medical hypertrophy in the absence of foreign particle microembolization was present in four of 20 cases (20 percent). Hemosiderin-laden macrophages were found in seven of 20 cases (35 percent). These abnormalities were not seen in a matched control group. We conclude that in the absence of foreign particle microembolization, pulmonary artery medial hypertrophy occurs among cocaine users, although the mechanism of these vascular changes is unknown. In addition, occult alveolar hemorrhage occurs more frequently among cocaine users than is clinically recognized.

Application of a rapid assay for detection of antibodies to human immunodeficiency virus in urine.

The use of rapid, simple tests to detect antibodies to human immunodeficiency virus (HIV) in urine could be valuable for several testing situations, such as in private offices, for epidemiologic surveys, and in developing countries. The authors evaluated the performance of the SUDS HIV type 1 test to detect antibody to HIV-1 peptides in urine. Test performance and applicability of the SUDS test were compared with a routine Food and Drug Administration-licensed enzyme-linked immunosorbent assay (ELISA) and Western blot using 139 serum and urine pairs collected from autopsy cases. Using a modified procedure when testing urine by the SUDS test, results indicated that a total of 15 serum/urine pairs were HIV-1 antibody positive by both the SUDS test and ELISA; all could be confirmed positive by Western blot. One sample produced discrepant results. The SUDS test produced no false-positive results when testing serum or urine, as compared with ELISA, and no false-negative results when compared with the Western blot. For optimal accuracy of detection of antibodies using urine, at least 100 microL of sample was required. By Western blot analysis, antibody profiles in urine were generally weaker than in serum, but confirmation of positivity was not compromised when larger volumes were used. The authors concluded that this rapid HIV-1 test, when used to detect antibodies to HIV-1 in urine, is accurate, easy to perform, and appropriate for use in certain testing situations.

Fatal firearm-related injury surveillance in Maryland.

CONTEXT: Maryland began a statewide firearm-related injury surveillance system in 1995. The system now focuses on firearm-related deaths; a system to monitor nonfatal injuries is being developed. The system is passive; it accesses, integrates, and analyzes data collected by Maryland's Office of the Chief Medical Examiner, Maryland State Police, and Division of Health Statistics. OBJECTIVE: To evaluate the surveillance system's ability to ascertain cases in the absence of a standard for the true number of cases. DESIGN: Link records of the same firearm-related death captured by the surveillance system's multiple data sources, comparing the rate of false positives and false negatives, and assessing errors in linkage variables. SETTING: Maryland, 1991-1994. PARTICIPANTS: All deaths occurring in the state of Maryland as a result of a firearm-related injury. MAIN OUTCOME MEASURES: Sensitivity and positive predictive value. RESULTS: The system is extremely sensitive, detecting 99.61% of cases, and it has a very high positive predictive value, with 99.87% of the cases identified from medical examiner's office data being confirmed as actual cases. CONCLUSIONS: Maryland's database of information from the medical examiner's office is highly accurate for ascertaining firearm-related deaths that occur in the state. A unique identifier common across data sources would ease record linkage efforts, and improve the system's ability to monitor firearm-related deaths.

Sudden death due to rupture of ectopic pregnancy concurrent with therapeutic abortion.

We report three cases of sudden death resulting from internal hemorrhage associated with the rupture of an ectopic pregnancy. In each case, the woman had undergone therapeutic abortion before death. The ectopic pregnancies, however, were not suspected or identified before the women left the treatment facility. Subsequently, all three women suffered fatal rupture of a tubal pregnancy and associated massive intraperitoneal hemorrhage during the postabortive period (range, 14 to 32 days). Our investigation of these cases has identified the lack of standardized procedures for the adequate monitoring of tissue recovered during therapeutic abortion. Such monitoring could have resulted in identification of the ectopic pregnancy and possibly led to successful intervention. We discuss the causes and risks of failure to diagnose ectopic pregnancy during the postabortive period.

Pathogenesis of vertebral artery occlusion following cervical spine manipulation.

Sporadic cases of vertebral artery occlusion following neck manipulation have been reported since 1947. The pathogenesis of occlusion, however, has remained largely speculative. Autopsy examination of the intracranial and extracranial portions of the vertebral arteries in the case presented here clearly demonstrates that intramural hematoma arising within granulation tissue in the tunica media was the acute, occlusive event. Furthermore, prior neck manipulation may have caused asymptomatic development of granulation tissue within the tunica media, thereby predisposing the patient to acute intramural hematoma during subsequent neck manipulation.

Medical examiner asthma death autopsies: a distinct subgroup of asthma deaths with implications for public health preventive strategies.

OBJECTIVE: Asthma deaths have been increasing in the United States and worldwide. We studied medical examiner asthma death autopsy (MEADA) records for the state of Maryland, compared selected characteristics with state and national total asthma deaths (TADs), and comprehensively reviewed relevant literature to define characteristics of asthma deaths and to provide insight for the design of future preventive strategies directed at this subgroup. DESIGN: Protocols for autopsy and clinical data. SETTING: The Office of the Chief Medical Examiner of the State of Maryland. SUBJECTS: All MEADAs in the state of Maryland from 1988 through 1992. MAIN OUTCOME MEASURES: Descriptive analysis. RESULTS: Maryland MEADAs (63 cases) represented 16.62% of Maryland TADs (379 cases). Most common characteristics of individuals on whom autopsies were performed: inner-city residence; single; black male; 15 to 54 years old; history of asthma; no other significant medical condition; fatal episode more likely to begin at home; pronounced dead at hospital; time of death between midnight and 6 AM; no particular seasonality; and typical gross and/or microscopic pathology. Analysis also revealed that 17.46% of deceased asthma patients had a history of drug abuse; 12.69% had positive toxicology for drugs of abuse; 9.52% were infants and young children up to 4 years old, all of whom were found, unresponsive, at home; and white females comprised the highest number of TADs but the lowest number of MEADAs. CONCLUSION: Asthma education programs focused on asthmatic inner-city black males, especially those with a history of drug abuse, and on parents of inner-city asthmatic infants and children may be a useful preventive strategy. International, national, and regional MEADA databases may also be of use in the design and monitoring of preventive strategies directed at this subgroup.

A case of familial angiolipomatosis with Lisch nodules.

Familial angiolipomatosis is a rare syndrome that may be confused clinically with neurofibromatosis type 1. This condition is most often inherited in an autosomal recessive manner; however, several reports have been published suggesting an autosomal dominant mode of inheritance. Angiolipomatosis, although somewhat disfiguring, is a benign condition with no known association with malignant neoplasms. This is in contradistinction to neurofibromatosis, an autosomal dominant syndrome associated with a myriad of benign and malignant neoplasms. It is, therefore, important to discriminate this entity from neurofibromatosis when a patient presents with multiple subcutaneous tumors and a family history of similar lesions. Described is a case of a prison inmate with a history of seizures and "neurofibromatosis" without clinical documentation. Lisch nodules were noted on the irides. Postmortem examination showed multiple subcutaneous yellow tumors on the chest and arms. Fine-needle aspiration of 1 mass yielded adipose tissue with prominent vessels; histologic sections of another mass showed angiolipoma. The remainder of the autopsy showed significant coronary artery disease and a remote cerebral infarction of the temporal lobe but no signs of neurofibromatosis. We feel that the presence of multiple angiolipomas in combination with Lisch nodules lends credence to the proposed relationship between fatty tumors and neurofibromatosis suggested by other authors.

Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome.

CONTEXT: Down syndrome patients who live to middle age invariably develop the neuropathologic features of Alzheimer disease, providing a unique situation in which to study the early and sequential development of these changes. OBJECTIVE: To study the development of amyloid deposits, senile plaques, astrocytic and microglial reactions, and neurofibrillary tangles in the brains of young individuals (<30 years of age) with Down syndrome. METHODS: Histologic and immunocytochemical study of a series of autopsy brains (n = 14, from subjects aged 11 months to 56 years, with 9 subjects <30 years) examined at the Office of the Chief Medical Examiner of the State of Maryland and The Johns Hopkins Hospital. RESULTS: The principal observations included the presence of intraneuronal Abeta immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of Abeta) and the formation of senile plaques and neurofibrillary tangles. CONCLUSIONS: We propose the following sequence of events in the development of neuropathologic changes of Alzheimer disease in Down syndrome: (1) intracellular accumulation of Abeta in neurons and astrocytes, (2) deposition of extracellular Abeta and formation of diffuse plaques, and (3) development of neuritic plaques and neurofibrillary tangles with activation of microglial cells.

Decreasing incidence of sudden death due to undiagnosed primary central nervous system tumors.

CONTEXT: Although most fatal brain tumors are diagnosed well before a patient's death, occasionally medical examiners and coroners encounter cases in which the presence of a primary tumor of the central nervous system (CNS) was not suspected prior to death. Analysis of such cases can shed light on specific pitfalls hindering the diagnosis of brain tumors. In addition, by analyzing the incidence of these cases in a large autopsy series, one can draw conclusions about the evolving effectiveness of medical diagnosis. OBJECTIVE: To determine the incidence of deaths due to undiagnosed primary CNS tumors in the era of advanced neuroimaging techniques. DESIGN: Records from forensic autopsies performed during a 20-year period (1980-1999) at the Office of the Chief Medical Examiner of the State of Maryland were reviewed to identify cases in which death was caused by primary CNS tumors undiagnosed prior to the patient's death. RESULTS: We present 11 cases of undiagnosed primary CNS tumors resulting in sudden death that were identified among 54 873 forensic autopsies. Sudden deaths due to undiagnosed CNS neoplasms account for a significantly lower percentage of cases in our study (0.02%) than in similar series reported prior to 1980 (> or =0.16%). CONCLUSIONS: We hypothesize that improvements in imaging techniques, notably the introduction of computed tomography and magnetic resonance imaging, have resulted in increased early detection of CNS neoplasms. However, vague or short-term symptoms and limited health care access can dissuade patients from seeking medical attention and result in failure to diagnose these tumors correctly.

Tramadol distribution in four postmortem cases.

Four postmortem cases are reported in which the analgesic drug tramadol was identified. Tramadol is an alkaline extractable drug and elutes from a HP-5 column without the need for derivatization. Two metabolites of tramadol, N-desmethyl and O-desmethyl tramadol were also identified. Heart blood concentrations of tramadol in the four cases ranged from 0.17 to 4.4 mg/l. Tissue distribution of tramadol in the four cases failed to identify a sequestration site. None of the deaths reported were attributed to tramadol intoxication.

An unusual morphine fatality.

A case is presented of a 90-year-old white female who apparently died of natural causes in a nursing home. Subsequent investigation indicated that the decedent had been administered an unauthorized bolus of morphine just prior to her death. The embalmed body was exhumed, an autopsy performed, and specimens were collected for toxicologic analysis. The liver contained 1.5 mg/kg of free morphine as measured by radioimmunoassay. The presence of morphine was confirmed by gas chromatography/mass spectrometry. A review of the literature as well as in-house data collected from narcotic deaths clearly suggest that the morphine measured in this case was consistent with a lethal concentration. The manner of death was homicide.

The interpretation of cocaine and benzoylecgonine concentrations in postmortem cases.

This study examined cocaine and benzoylecgonine concentrations in 100 consecutive deaths where either compound was identified in blood or urine specimens to determine whether any relationship between these concentrations and cause of death can be found. Forty-seven of the 100 cases were deaths attributed to cocaine, narcotic or combined cocaine and narcotic intoxication. There were 13 cases of cocaine intoxication where no psychoactive substance other than ethanol was detected. The mean cocaine concentration in these deaths was 908 ng/ml; three cases had cocaine concentrations greater than 2000 ng/ml, while the other ten cases had cocaine concentrations less than or equal to 700 ng/ml. The mean cocaine concentration in non-cocaine deaths where no psychoactive substance other than ethanol was detected was 146 ng/ml. This difference was not statistically significant. However, the average blood benzoylecgonine concentration in the 13 cocaine deaths was significantly higher than in the 19 non-cocaine deaths. A review of combined cocaine and narcotic deaths suggest that the narcotic is the main causative agent in these deaths.

Cocaine fatality: an unexplained blood concentration in a fatal overdose.

A case is presented of a 26-year-old female who died as a result of cocaine intoxication. A blood cocaine concentration of 330 mg/l, about 1.5 times greater than the highest concentration previously reported, was found. Blood benzoylecgonine and ecgonine methyl ester concentrations were 50 and 18 mg/l, respectively. The unusually high blood concentrations of cocaine and the metabolites are suggestive of a massive administration, however, the history suggests a series of recreational uses. The manner of death was undetermined.

Fluoxetine and violent death in Maryland.

A retrospective Medical Examiner case review of all deaths in Maryland where either fluoxetine or tricyclic antidepressant (TCA) use was forensically detected was conducted for the time period January 1987-July 1991. Case records and toxicology reports from the Office of the Chief Medical Examiner were reviewed to determine cause and manner of death, circumstances of death, demographic information on the decedent, prior medical history of the decedent, and presence and level of either fluoxetine or TCA in various body fluids/tissues. Suicide was the manner of death most frequently associated with TCA and fluoxetine detection. Violent methods were more often associated with fluoxetine suicides than with TCA suicides (65% v. 23%, P < 0.001). Demographic characteristics of antidepressant-related deaths in Maryland were similar to those of the entire USA. Possible explanations for the results obtained include the inherent lower lethality of fluoxetine compared to the TCAs, necessitating the use of additional means to complete the act of suicide; that physicians may have switched more impulsive, high risk patients to this new agent as it became available, thus creating a selection bias for more violence-prone individuals in the fluoxetine group; or that fluoxetine may be associated with induction of violence and/or suicidal ideation. Further research examining the possible association of these agents with violent acts is warranted.

Distribution of sertraline in postmortem cases.

Sertraline is a potent inhibitor of serotonin reuptake in the central nervous system and is used clinically to treat depression and obsessive-compulsive behavior. Over the course of one year, there were seven cases investigated by the Office of the Chief Medical Examiner, State of Maryland, in which sertraline was identified in postmortem specimens. Heart blood concentrations in the seven cases ranged from 0.23 to 0.46 mg/L; desmethylsertraline concentrations ranged from 0.08 to 0.99 mg/L. One similarity with tricyclic antidepressants is the high liver concentrations of drug and metabolite relative to the blood. One unusual finding is the small concentrations of drug and metabolite in the urine relative to other specimens. In none of these cases was the cause of death related to sertraline intoxication.

Lamotrigine distribution in two postmortem cases.

Lamotrigine (Lamictal) is a new anticonvulsant drug recently approved for use in the United States. Although a therapeutic range for lamotrigine has not been definitively established, a range of between 2 and 14 mg/L has been reported. Two cases are presented in which lamotrigine was identified in cases investigated by the Office of the Chief Medical Examiner, State of Maryland. Lamotrigine was identified by gas chromatography-nitrogen-phosphorus detection following an alkaline extraction. A DB-5 column provided analytical separation; no derivatization was required. Confirmation was achieved by full scan electron ionization gas chromatography-mass spectrometry. In Case 1, primidone (11 mg/L) and phenobarbital (5.5 mg/L) were found in the heart blood in addition to lamotrigine (8.3 mg/L); in Case 2, no drugs other than lamotrigine (52 mg/L) were detected in the heart blood. The peripheral blood concentration in Case 2 was 54 mg/L. The liver lamotrigine concentrations in the two cases were 41 and 220 mg/kg. The medical examiner ruled that the cause of death in Case 1 was seizure disorder and the manner of death was natural. In Case 2, the medical examiner ruled that the cause of death was lamotrigine intoxication and the manner of death was undetermined.

A fatality due to alprazolam intoxication.

Alprazolam is one of the most widely prescribed benzodiazepines in the United States. It is generally considered a safe and effective drug for the treatment of anxiety disorders and panic attacks. Few overdoses that are due to the sole ingestion of alprazolam have been reported. This paper documents a fatality due to alprazolam intoxication and describes the distribution of alprazolam and an active metabolite, alpha-hydroxyalprazolam, in tissues obtained at autopsy. Qualitative identification of the drugs was achieved by full-scan gas chromatography-mass spectrometry, and quantitative analysis was performed by high-performance liquid chromatography. High concentrations of alprazolam were found in all specimens analyzed, but the metabolite was detected only in subclavian blood, urine, bile, and liver. A postmortem heart blood alprazolam concentration of 2.1 mg/L is the highest reported in the literature to date.