Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients.

BACKGROUND: We investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway. METHOD: We measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-1, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-1, cAMP, and ATF-2 proteins. RESULTS: We found a significant increase in the protein levels of Elk-1 (mean+SD, 4489+/-659 vs 2915+/-583 arbitrary densitometric units [P<.001]), CREB (mean +/- SD, 2149 1061 vs 904+/-711 arbitrary densitometric units [P=.003]) and ATF-2 (mean+/-SD, 1421 854 vs 512+/-394 arbitrary densitometric units [P=.003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications. CONCLUSION: Taken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia.

Comparison of [125I]iodomelatonin binding sites in infant cerebellum of sudden infant death syndrome and non-sudden infant death syndrome.

[125I]Iodomelatonin bindings sites in human infant cerebellum were studied by radioligand receptor binding assay and in vitro quantitative autoradiography. The binding sites characterized in membrane preparations revealed saturable, reversible and highly specific binding sites with a Kd value of 21.2 +/- 8.33 pM and a Bmax value of 2.02 +/- 0.52 fmol/mg protein. 10 microM of GTP gamma S significantly reduced the binding capacity, suggesting the possible G-protein coupling of the binding sites. Autoradiographic study showed that the labelling was mainly located in the cerebellar cortex. On comparison of the binding parameters from cerebellum of sudden infant death syndrome (SIDS) and non-SIDS infants, no significant change in binding capacity and binding affinity was detected. These findings suggest that the binding sites in cerebellum may not be related to the etiology of SIDS.

Bilateral carotid-cavernous fistulae of mixed types with unusual radiological and neuropathological findings.

This report describes a case of bilateral post-traumatic carotid-carotid-cavernous fistulae (CCF), of both typical and atypical types, with delayed clinical deterioration. Unusual neuropathological lesions, distinctive from those due to direct cerebral trauma, are related to combined arterial ischemia and venous hypertension. Atypical CCF is not necessarily a benign disorder. Radiological monitoring is essential to detect spontaneous progressive intracranial shunting, to predict areas that are at risk from venous hypertension, and to identify remote sites of circulatory vulnerability.

Death during recreational exercise in the State of Rhode Island.

From January 1, 1975 to May 1, 1982, 81 individuals died during or immediately after recreational exercise in the State of Rhode Island. Deaths occurred during a variety of activities, but the majority of deaths occurred during golf (23%), jogging (20%), and swimming (11%). Atherosclerotic coronary heart disease (ASHD) was the presumed cause of 88% of the deaths, primarily in subjects over age 29 with known cardiac abnormalities. Only 7% of ASHD victims had no relevant medical history or ASHD risk factors and were considered healthy by their families and physicians. In contrast, deaths in young subjects were rarely associated with ASHD or prior knowledge of cardiovascular disease. Only six deaths in individuals aged 29 or younger occurred during the study period. These deaths were associated with congenital cardiovascular disease (N = 2), valvular heart disease (N = 1), hemorrhagic gastritis (N = 1), idiopathic myocardial hypertrophy (N = 1), and hypertrophic cardiomyopathy with ASHD (N = 1). A diagnosis was made before death only in the individual with valvular disease. We conclude that death during recreational exercise is predominantly due to ASHD and occurs in men with recognized ASHD risk factors, relevant medical histories, or known disease. Death during exercise in asymptomatic subjects is rare and relatively more frequent in younger age groups.

Extravasation of plasma proteins in brain trauma.

The cellular distribution of extravasated plasma proteins in cortical contusions was studied with an immunoperoxidase method using polyclonal antibodies against human plasma albumin, alpha 1-acid glycoprotein, alpha 2-macroglobulin, alpha 1-antitrypsin, transferrin, hemopexin, haptoglobin, fibrinogen, fibronectin and immunoglobulin G. The material consisted of 24 human autopsy brains with a primary diagnosis of cerebral contusion due to blunt trauma. The time interval between injury and death ranged between minutes and 7 years. Immediately after the trauma, a complete breakdown of the blood-brain barrier (BBB) occurred with hemorrhage and extravasation of all types of plasma proteins. This was followed by spreading of edema fluid within the extracellular space in and around the wound. Uptake of extravasated protein by glial cells began on the 3rd day followed by proliferation of reactive astrocytes whose ample cytoplasm appeared to serve as a reservior for the extravasated plasma proteins. Within the reactive astrocytes, plasma proteins and S-100 protein had a similar and diffuse distribution in the immunostained sections. The plasma proteins once incorporated into the glial cells remained unchanged for several years with little sign of degradation. It is suggested that the extravasated plasma proteins subsequent to uptake and processing by the glial cells, may serve some important physiological function in wound healing.

Sudden infant death and liver phosphoenolpyruvate carboxykinase analysis.

In an effort to substantiate the impaired gluconeogenesis-terminal hypoglycemia hypothesis of sudden infant death syndrome (SIDS), 52 infants ranging from 3 weeks to 7 months of age which had been brought to autopsy were studied. The stomach contents, vitreous humor glucose concentrations, hepatic glycogen content and hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity were measured as part of the laboratory component of the postmortem investigation. The stomach contents, vitreous humor glucose concentrations and liver glycogen content were similar in SIDS/and non-SIDS victims. PEPCK activity was, however, significantly lower in SIDS (p < 0.001) victims and in SIDS with other findings (p < 0.01) victims when compared to non-SIDS victims. Despite the fact that SIDS victims had lower hepatic PEPCK activity and hence potentially lower gluconeogenic capacity, terminal hypoglycemia could not be demonstrated in this group as compared to the SIDS with other findings and the non-SIDS infants. The impaired gluconeogenesis-terminal hypoglycemia hypothesis thus could not be substantiated.

Human postmortem interval estimation from vitreous potassium: an analysis of original data from six different studies.

The investigation of the postmortem interval (PMI) by determining potassium levels in the vitreous humor (KV) has been a subject of forensic pathology research for more than a quarter of a century. The numerous studies to date have yielded a variety of linear or piecewise-linear relationships between KV and PMI, i.e., different estimated intercepts and slopes of regression line(s) as well as different reliabilities of these estimates. This lack of agreement is due in part to the variable numbers of cases reported from study to study, differing observed ranges of KV and PMI, and the unaccommodated effects of factors on potassium concentration, including age of subject, amount of urea nitrogen, ambient temperature, and presence of illness. Original data from six of these studies, for a total of 790 cases, are reanalyzed together. The relationship between KV and PMI is not completely linear, and the residual variability of KV as a function of PMI is not constant. Thus, two main assumptions of the simple linear model, linearity and constant variance, are not supported by the data. It is clearly problematic to report statistical summaries such as the slope of an estimated regression line and the reliability of that estimate based on a model with faulty assumptions. Yet even after rescaling the data in an attempt to achieve linearity in the KV-PMI relationship and to stabilize residual variation, the relationship continues to be non-linear and its variability unstable. A new approach is developed for modeling KV and PMI that accommodates non-linearities and changing residual variability. A local regression model, specifically a loess smooth curve, is fitted separately to the data from each of the six studies. The loess smooth curve adapts locally to the changing and possibly non-linear relationship between KV and PMI across their observed ranges. The data from all six studies are then combined to yield a single loess curve with 95% confidence bands. The estimated loess curve and confidence bands are used in an inverse prediction method to construct low, middle and high PMI estimates at given values of KV. The reliability of estimated PMI decreases as KV increases. Although the confidence bands surrounding the overall curve widen in the extreme high end due to there being fewer available data in that region, PMI estimates are more precise over the entire range of KV and PMI than those obtained from any single study alone. A cross-validation procedure provides an independent check of the predictive performance of the method.

Melatonin concentrations in the sudden infant death syndrome.

To examine a possible relationship between pineal function and the sudden infant death syndrome (SIDS), samples of whole blood, ventricular cerebrospinal fluid (CSF) and/or vitreous humor (VH) were obtained at autopsy from 68 infants (45 male, 23 female) whose deaths were attributed to either SIDS (n = 32, 0.5-5.0 months of age; mean +/- S.E.M., 2.6 +/- 0.2 months) or other causes (non-SIDS, n = 36, 0.3-8.0 months of age 4.3 +/- 0.3 months). The melatonin concentrations were measured by radioimmunoassay. A significant correlation was observed for melatonin levels in different body fluids from the same individual. After adjusting for age differences, CSF melatonin levels were significantly lower among the SIDS infants (91 +/- 29 pmol/l; n = 32) than among those dying of other causes (180 +/- 27; n = 35, P less than 0.05). A similar, but non-significant trend was also noted in blood (97 +/- 23, n = 30 vs. 144 +/- 22 pmol/l, n = 33) and vitreous humor (68 +/- 21, n = 10 vs. 81 +/- 17 pmol/l, n = 15). These differences do not appear to be explainable in terms of the interval between death and autopsy, gender, premortem infection or therapeutic measures instituted prior to death. Diminished melatonin production may be characteristic of SIDS and could represent an impairment in the maturation of physiologic circadian organization.

Abnormal heart rate response during newborn sucking behavior study: subsequent sudden infant death syndrome with cardiac conduction abnormality.

This report concerns a four-month-old white female infant who exhibited abnormal feeding behavior and EKG irregularities during a newborn sucking behavior study. The immediate post-birth history showed an irregular heart rate on two occasions, but a cardiac consultation elicited no unusual findings. During sucrose sucking conditions, the heart rate increased with a beat-to-beat variation of 50 beats per minute, noted to be due to premature atrial beats. At 39 days, an EKG showed a marked sinus tachycardia of 156, a PR interval of 0.08, QRS of 0.05 and a QT of 0.26. The infant was diagnosed as a sudden infant death syndrome (SIDS) following an unexpected death at home. Subsequent cardiac pathology revealed an anomalous tract between the right atrium and the atrioventricular (AV) bundle which formed an extensive bypass of the AV node (atrio-His tract), and two accessory AV connections between the left atrium and posterior left ventricle. These findings are consistent with the Wolff-Parkinson-White syndrome type A. Only further studies can determine whether such abnormal feeding behavior with EKG irregularities can be used to identify infants who are at high risk for sudden death.

Hypoglycemia as the responsible factor in a truck driver accident fatality.

A case of hypoglycemia causing a truck driver to lose control of his vehicle and his resulting traumatic asphyxia death is presented. The incident was considered suspicious in spite of poor visibility, because an experienced, healthy operator lost control in the early morning hours after a relatively short (4-h) drive. The autopsy revealed no evidence of natural disease and the driver had no alcohol or drugs in his system. Although this is apparently a rare occurrence, the diagnosis of underlying hypoglycemia as the causative factor in a traffic fatality can be reasonably suspected and accurately made if appropriate specimens are properly obtained and tested. Legislation mandating the retention of antemortem blood specimens on all trauma patients will permit more accurate assessment of most chemical etiologies of traffic accidents.

Lactic acid concentrations in vitreous humor: their use in asphyxial deaths in children.

Lactic acid concentrations in brain tissue of humans have been shown to increase with an extended agonal period. Infants and children dying from various causes are undergoing different stress conditions terminally and the postulate of this study is that natural death cases and traumatic asphyxia cases are characterized by varying agonal periods, the former being somewhat prolonged with the latter being rather brief. One-hundred-and-two cases of infants and children were examined for vitreous humor lactic acid concentrations. They were divided into two major categories, Sudden Infant Death Syndrome (SIDS) and non-SIDS cases. SIDS was further divided into SIDS without additional findings and SIDS with secondary findings which contributed to death. The non-SIDS category included traumatic asphyxia cases as well as those dying from blunt trauma, known respiratory diseases, and other causes. Categorical mean values and standard deviations were calculated. The vitreous humor lactic acid mean value for traumatic asphyxia was significantly lower than the mean value for SIDS. Also the mean value for known respiratory diseases was statistically lower than the mean value for SIDS with secondary findings. These findings are probably suggestive of agonal time differences and may be a reflection of the various mechanisms of death.

Sudden and unexpected deaths after the acute onset of diabetes mellitus.

Four cases of sudden and unexpected death caused by the acute onset of diabetes mellitus are reported. Three are examples of acute juvenile diabetes while the fourth demonstrated the aketotic form of diabetic coma. Such instances can present a diagnostic problem to the forensic pathologist. The usefulness of vitreous humor glucose analysis to diagnose such a condition is stressed.

Accidental asphyxial deaths involving infants and young children.

Forty-five cases of accidental asphyxial deaths in infants and young children below 2 years of age are described. The mechanism involved, the available historical information, and the possible preventive measures are discussed. Dangers such as bed- and tub-sharing, diaper and cleaning pails, plastic wrappers, balloons, small beds, toys on strings, broken or poorly designed cribs, and poorly positioned adult beds must be brought to the attention of the parent as consumer. The public heatlh considerations and the educational aspects relating to the community at large are cornerstones in the effort to reduce these tragic and untimely deaths.

Cocaine babies: the scourge of the '90s.

Six cases of cocaine-related deaths of infants have covered the spectrum of potentially devastating effects. They include an intrauterine death of a 35-week-old fetus following acute maternal cocaine abuse; anoxic encephalopathy at birth with 3 months' vegetative survival from a similar episode; traumatic compression asphyxia in a 4-month-old; infectious cardiomyopathy with heart failure in a twin at age 21 months following maternal cocaine abuse at birth; malnutrition and dehydration in a 7-week-old during continuing cocaine abuse by the parents; and a teenage sibling's cocaine lacing of a baby milk bottle ingested by his 6-week-old brother. All the cases had positive toxicological screening for cocaine or metabolites or both in the mother at delivery or in the infant at birth, or both. There were no instances of sudden infant death syndrome (SIDS, or "crib death"). Pathologic and toxicologic, as well as birth, developmental, and social data are presented. An integrated medical, public health, law enforcement, and educational policy to prevent or at least ameliorate these tragic cases, now approaching epidemic proportions, has yet to be developed. A careful obstetrical history and examination of the mother, indication on the birth certificate of maternal drug abuse, and notification of health authorities (by birth certificate checking, among other ways) may send an early warning message to providers for intercession. Active ingestion/injection and passive inhalation by older children and teenagers require more intensive monitoring and aggressive interaction by pediatricians, social workers, school authorities, and employers.(ABSTRACT TRUNCATED AT 250 WORDS)

The Frye hearing in Florida: an attempt to exclude scientific evidence.

State Supreme Courts require a minimum threshold of reliability and acceptance in the scientific community for all medical and similar evidence to be admitted at trial. In Florida and some other states, the courts adhere to what is known as the Frye standard, whereas in most states and in Federal Courts, it is the so-called Daubert standard. The jurisdiction of the present case is Hillsborough County (Tampa), Florida. Forensic pathologists seldom, if ever, are requested to participate in such hearings, unlike their toxicological and basic science colleagues who are more involved in research methodology and technical procedures. The burden is on the proponent of the evidence to prove the general acceptance of both the underlying scientific principle of the test and procedures used to apply that principle to the facts of the case at hand. The trial judge has the sole discretion to determine this question and general acceptance must be established by a preponderance of the evidence. The authors describe in detail a hearing in a case in which they were all involved. One author (WQS) had researched and documented the original scientific methodology in the literature. The situation involved a car and tractor trailer crash with the two occupants of the car dying of multiple trauma, whereas the truck driver was not injured. Autopsy of the auto driver revealed multiple injuries with exsanguination, and only vitreous humor and liver tissue, but not blood, were tested for ethyl alcohol. The estate of the driver of the automobile brought suit against the owner of the trucking company for wrongful death. The plaintiff requested a Frye hearing to question the reliability of testing other body specimens to translate to probable blood alcohol level. The testimony, submitted documents, and eventual decision by the judge are discussed.

Laboratory investigation of deaths due to anaphylaxis.

To establish a useful laboratory protocol to investigate possible cases of fatal anaphylaxis, we measured mast-cell-derived tryptase levels and allergen-specific immunoglobulin E (IgE) antibody levels in sera obtained prior to or within 24 h after death from 19 anaphylaxis victims. Elevated serum tryptase levels (range = 12 ng/mL to 150 micrograms/mL) were found in nine of nine Hymenoptera sting fatalities, six of eight food-induced fatalities, and two of two reactions to diagnostic therapeutic agents. Tryptase levels were normal (less than 10 ng/mL) in 57 sequential sera obtained postmortem from six control patients. Tryptase could not be measured in pleural or pericardial fluids for technical reasons. Serum IgE antibodies were elevated in five of the nine Hymenoptera sting fatalities and in eight of the eight fatal food reactions; assays were unavailable for the two diagnostic/therapeutic agents. If elevated, the victim's serum IgE antibodies to food could be used to identify allergens in uneaten portions of foods consumed shortly before the anaphylactic event. IgE antibodies were moderately stable during storage in a variety of anticoagulants at room temperature for up to 11 weeks. Elevated mast-cell-derived tryptase levels in postmortem sera reflect antemortem mast cell activation and may be used as a marker for fatal anaphylaxis. If assays are available for IgE antibodies to relevant allergens, such assays provide evidence for antemortem sensitization; these assays may be modified to identify allergens in foods consumed by victims of food-induced anaphylaxis.