Diagnostic tests in the evaluation of dementia. A prospective study of 200 elderly outpatients.

We studied the components of the diagnostic evaluation in 200 patients older than 60 years of age with suspected dementia who received standardized diagnostic evaluation and follow-up. The most common dementia diagnoses were Alzheimer's-type dementia (74.5%) and dementia due to toxic effects of drugs (9.5%). Eleven patients with hypothyroidism, metabolic encephalopathies due to hyponatremia, hyperparathyroidism, and hypoglycemia required laboratory tests for diagnosis, whereas the other dementia diagnoses were made primarily on the basis of data available on the history and physical and neurologic examinations. The complete blood cell count, blood chemistry battery (especially sodium, calcium, and glucose concentrations), and thyroid function tests were of definite value for the diagnosis of unsuspected disease and were useful as routine tests in evaluating patients for dementia. A careful history and physical examination accompanied by complete blood cell count, chemistry battery, and a thyroid function test would have been effective in diagnosing treatable illnesses causing cognitive impairment. Other diagnostic tests could have been used selectively based on results of the examination and screening tests. Estimated diagnostic charges from a selective approach would be 25% to 34% of those for the "routine" evaluation.

Erythrocyte transketolase activity and sudden infant death.

Postmortem heart blood aspirates from 24 consecutive sudden infant deaths and 23 consecutive infant deaths from other causes yielded evidence of erythrocyte transketolase activity (ETKA) in every instance. ETKA measurements from cadaver specimens have not been previously reported. ETKA values did not correlate with the interval from death to sampling or with age at death. Activity coefficients from postmortem material corresponded closely to those from previous studies on living subjects which suggests that the method of Bayoumi and Rosalki yields valid measurements at least for 77 h postmortem. Statistical comparisons of the sudden infant deaths with non-sudden infant deaths revealed no significant differences. This investigation failed to disclose evidence in favor of the hypothesis, advanced by Read, that unsuspected thiamin deficiency may explain some cases of the sudden infant death syndrome.

Sudden infant death trends in six metropolitan communities, 1965-1974.

Data from six geographically dispersed metropolitan areas in the United States in which special sudden infant death syndrome (SIDS) surveillance programs for detection and autopsy diagnosis existed during the period 1965 through 1974 reveal considerable diversity in overall ten-year incidence rates as well as in annual rate distribution patterns. A downward trend in SIDS incidence occurred in some areas but not in others. Non-SIDS postneonatal death rates, which were used for comparison, also decreased in some areas. Rate trends for whites and nonwhites were not consistent. During the same period, the fertility rate in the United States decreased by about a third for both whites and nonwhites. To explain the observed trends we postulate that concomitants of the fertility rate decline may have reduced the number of "high mortality risk babies" to a variable degree in different places and at different times.

Noninvasive predictors of sudden cardiac death in men with coronary heart disease. Predictive value of maximal stress testing.

In a follow-up study of 1,852 men with coronary heart disease, 195 deaths occurred within the first 3 years (33 +/- 13 months [mean +/- standard deviation]). Analysis of these cases indicated that the risk of sudden cardiac death in ambulatory men with clinical manifestations of coronary heart disease may be readily estimated from noninvasive clinical and exercise criteria. The important predictors are indexes of the severity of coronary heart disease and impairment of peak left ventricular function demonstrated with symptom-limited maximal exercise. The advantages of these predictors are that they may be elicited on the initial study as well as on follow-up noninvasive examinations of ambulatory patients. The appearance of nonelectrocardiographic predictors in serial examinations may provide an indication for invasive studies and be a more important finding than the ischemic S-T reponse to exertion.

The sudden infant death syndrome and infant botulism.

Fecal and serum specimens taken from 30 cases of sudden infant death and from eight cases of nonsudden infant death that were diagnosed at a single facility in King County, Wash., were examined for the presence of Clostridium botulinum organisms and toxin. Organisms, but not toxin, were recovered from a fecal specimen in one case of sudden infant death, results that parallel those from studies previously reported by investigators in California. Studies made in our laboratory of a nonfatal case of infant botulism revealed that an estimated 366,000 mouse minimal lethal doses of toxin were excreted in feces collected by purging the infant. Organisms and toxin were excreted for at least 15 days after the infant was hospitalized. Observations made in our laboratory of atypical responses in mice to both fecal and serum extracts, coupled with recently described experiments in which mice were used as an animal model for infant botulism in humans, provide a biologically plausible foundation for the hypothesis that C. botulinum may be implicated etiologically in some sudden infant deaths. Additional microbiologic, physiologic, and toxicologic data are needed to adequately test this hypothesis.

Epidemiologic comparisons of the sudden infant death syndrome with other major components of infant mortality.

All 1998 resident infant deaths in the 1969--1977 King County, Washington birth cohort of 139,132 resident live births comprise the data base for epidemiologic comparisons of the sudden infant death syndrome (SIDS) with eight other major infant mortality components: hyaline membrane disease; respiratory distress syndrome; asphyxia of the newborn; immaturity; birth injury; congenital malformation; infection; and "all other." These components were compared with respect to age at death; sex; race; prior fetal loss; prior live-born, now dead; birth plurality; birth weight; maternal age; birth order; marital status; prenatal care; and season of death in an attempt to determine the uniqueness of these purported SIDS risk factors. Only the age at death distribution unequivocally distinguished SIDS from the other components. The combination of low maternal age and multiparity was demonstrated to be putatively synergistic for risk of SIDS, hyaline membrane disease, and respiratory disease syndrome. Only deaths from infection exhibited seasonal variation similar to SIDS. These observations probably reflect secondary associations with as yet unidentified primary risk factors relatable to maternal experience.

Sudden infant death syndrome and maternal age: etiologic implications.

During a 12-year period (1969 through 1980), 431 episodes of sudden infant death syndrome (SIDS) occurred in King County, Washington. Longitudinal analysis of these data confirms the inverse association of SIDS occurrence with maternal age, which has been reported repeatedly from previous cross-sectional analyses. Risk of SIDS increases with increasing birth order, but the inverse maternal age gradient remains constant within each birth-order category. Available evidence suggests that maternal age may be a more important clue to SIDS causation than previously supposed. Assessment of established SIDS risk factors in relation to maternal age deserves further attention. The role of nutrition of pregnancy in relation to maternal age and SIDS risk may also be a productive avenue for future investigation.

The cloning, expression and purification of cervine interleukin 2.

The cloning, sequencing and expression of cervine interleukin 2 (IL-2) is described. Cervine IL-2 cDNA is 489 base pairs long and shows high homology to bovine and ovine IL-2 (approximately 94%) with lower homologies to human (50%) and mouse (53%). The predicted protein sequence is 162 amino acids long with a signal sequence containing 20 amino acids. A molecular weight of 16273 Da was predicted for the mature protein. The expression plasmid pTRXFUS was redesigned to allow recombinant proteins to be expressed at high levels in a soluble form and subsequently affinity purified. This new plasmid, pTRXHIS, has been used to express the first cervine cytokine, IL-2. The fusion of the cervine IL-2 gene to the thioredoxin gene (TRX) stabilizes the recombinant product allowing the high expression of soluble IL-2. A polyHis (6 x Histidines) tag has been inserted between the two fusion partners which allows the fusion product to be affinity purified on a nickel-nitrilo-tri-acetic acid (Ni-NTA) column. The purified cervine IL-2 fusion protein was shown to be biologically active despite the presence of the TRX at the amino terminus. The TRX can be removed enzymatically with enterokinase releasing the biologically active IL-2 molecule. This expression system has several features that are useful in producing and purifying large quantities of biologically active cytokines.

T cell responses to Mycobacterium bovis in red deer, a large animal model for tuberculosis.

Red deer (Cervus elaphus) represent an appropriate large animal model to study the immunology of tuberculosis, being naturally susceptible to Mycobacterium bovis infection. Cell-mediated immune responses were investigated in deer displaying protective- or disease-type reactions, following immunization with M. bovis bacille Calmette-Guerin (BCG) or infection with virulent M. bovis, respectively. T cell responses were measured as antigen-dependent cell proliferation and production of T cell growth factor (TCGF) following in vitro stimulation with M. bovis antigens (live or heat-killed BCG, or PPD). T cells from immunized deer proliferated less in response to soluble denatured culture antigen (purified protein derivative, PPD) than to particulate BCG, although there were no differences in the magnitude of these responses between the two groups of animals. Cells derived from immunized deer produced less TCGF than cells from infected deer when stimulated with PPD in vitro, although responses to BCG antigens were similar between the two groups. The majority of TCGF activity was neutralized by anti-IL-2 antibodies, regardless of the animal group or source of antigen used for in vitro stimulation. After 7 days in vitro culture with antigen, blast cells staining positively for alpha beta (CD4, CD8) and gamma delta T cell receptors were recorded. The majority of blasts were CD4+, although in immunized deer fewer CD4+ blasts were produced following in vitro stimulation with PPD than with BCG antigens. These results, together with previous reports from our laboratory, represent the only detailed examinations of T cell responses to M. bovis in this naturally-susceptible ruminant species.

Diagnostic evaluation of 200 elderly outpatients with suspected dementia.

A standardized diagnostic evaluation was performed on 200 consecutive patients over age 60 with suspected dementia. Diagnoses were confirmed by consensus and subsequently by follow up. Over 70% had Alzheimer's type dementia; 31% had more than one illness contributing to the dementia state, with overlap between the two groups. The most common so-called "treatable" illnesses were drug toxicity, hypothyroidism, and other metabolic diseases; 248 other medical diseases were recognized in 124 patients. Improvement occurred in 55 patients (27.5%) and persisted in 28 (14%) for at least a year during follow up, but only 2 patients recovered normal mental function. Our results emphasize the importance of recognizing and treating the multiple illnesses that contribute to dementia in elderly adults. The distribution of illnesses in demented elderly outpatients is different from that reported in younger patients with dementia. Diagnostic strategies and expectations need to be based on data obtained from studies of elderly patients with suspected dementia.

Features of potentially reversible dementia in elderly outpatients.

A standardized evaluation was carried out in two separate groups of patients with dementia to determine the features that characterize those with potentially reversible or treatable dementia. In both groups, Alzheimer's-type dementia was the most common diagnosis (65% and 70%); the most common cause of potentially reversible cognitive impairment was medication toxicity. In both groups, patients with potentially reversible dementia had a shorter duration of symptoms, less severe dementia and used more prescription drugs. Because of this association, these features may be considered risk factors but are not distinguishing or diagnostic features of patients with potentially reversible dementia. Other, previously undetected, treatable illnesses not often considered in the differential diagnosis of potentially reversible or treatable dementia were also prevalent in these patients.