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The authors report on progress in the use of a two-channel, microprocessor-based electroencephalographic (EEG) device and the statistical strategy of prediction intervals for characterizing the normal limits of variability in cerebral state in older subjects and recognition of excessive change caused by mildly toxic medications. Prediction intervals for relative delta, theta, alpha, and beta power were calculated from repeated EEG measures on 54 medically stable elderly subjects. The authors subsequently evaluated the effects of diphenhydramine (25-75 mg) administered to 10 additional subjects. Significant drug-induced changes at the group level were apparent only in relative theta power. Significant change in relative theta power at the individual level was observed in five of nine subjects for whom data at 50 mg were available., (Copyright © 1995 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

This study sought to determine if depression and/or anxiety is uniquely related to pain after controlling for the strong association between anxiety and depression. Both depression and anxiety were assessed in an elderly institutionalized sample using: (1) research-based diagnoses based on Diagnostic and Statistical Manual-revised 3rd edition (DSM-IIIR) criteria, and (2) evaluations of one's recent affective states using the Profile of Moods States (POMS). Pain was assessed by pain intensity and number of pain complaints. A series of path models indicated that: (1) both research-based anxiety and depression share unique variance with pain, and (2) only POMS anxiety is uniquely related to pain. A path model using both measures of anxiety and depression indicated that only the anxiety measures are significantly related to pain. However, POMS anxiety sustained a significantly greater relationship with pain than did research-based anxiety.

To investigate the significance of subsyndromal depressive states in geriatric patients, the authors used data from ongoing studies of depression in older patients in residential care to evaluate the clinical correlates of dysphoria. They find that dysphoria is, in general, a persistent state associated with increased medical illness, pain, self-care deficits, and mortality relative to euthymic subjects; thus it is clinically significant. Differences between dysphoria and major depression in the extent of associated disability and mortality, but not in measures of medical illness, pain, or persistence, remain significant after controlling for self-ratings of depression from the Geriatric Depression Scale. This finding suggests that dimensional assessments can account for some of the correlates of depression, but that categorical diagnoses are required for others., (Copyright © 1995 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the validity of the Cumulative Illness Rating Scale (CIRS) in a geriatric institutional population by examining its associations with mortality, hospitalization, medication usage, laboratory findings and disability., Design: A validation of the CIRS using self- and physician-report surveys, with archival data drawn from medical charts and facility records., Setting: Long-term care facility with skilled nursing and congregate apartments., Participants: Four hundred thirty-nine facility residents selected on the basis of completeness of self-report data and physician ratings., Primary Measures: Composite measures of illness severity and comorbidity, based on physicians' CIRS ratings; time to death or acute hospitalization after assessment; medication use, drawn from pharmacy records; medical chart data on laboratory tests; self-reported functional disability., Results: CIRS illness severity and comorbidity indices, as well as individual CIRS items, were significantly associated with mortality, acute hospitalization, medication usage, laboratory test results, and functional disability. The CIRS showed good divergent validity vis a vis functional disability in predicting mortality and hospitalization., Conclusions: The CIRS appears to be a valid indicator of health status among frail older institution residents. The illness severity and comorbidity composites performed equally well in predicting longitudinal outcomes. Item-level analyses suggest that the CIRS may be useful in developing differential illness profiles associated with mortality, hospitalization, and disability.

To explore the extent to which treatment of depression affects survival, we evaluated the association between use of antidepressant medications and death rates among the residents of a large residential-care facility for the elderly using a retrospective record-review study (N = 624). One year survival, among those taking antidepressants (10.9%), was 11.8% compared to 11.1% among the remainder of the population. A second study followed a group of 32 patients in the same institution who had participated in a therapeutic trial of nortriptyline treatment for major depression. Patients who experienced adverse medical events during treatment exhibited significantly increased mortality; among treatment completers, there was no significant relationship between mortality and therapeutic response. These findings suggest that the inability to tolerate treatment with an antidepressant can be considered a manifestation of physiologic frailty and increased vulnerability to mortality from disease. The previously reported decrease in survival among residential-care patients with major depression is not paralleled by a similar effect in those taking antidepressants. This may reflect selection factors with respect to the ability to tolerate antidepressants, rather an effect of treatment.

As emphasized in the recent NIH Consensus Statement on the Diagnosis and Treatment of Depression in Late Life, depression in the elderly is a persistent or recurrent disorder that can result from psychosocial stress or physiological effects of disease and can lead to excess disability, cognitive impairment, increased symptoms from medical illness, physiological effects, increased utilization of health care services, and increased rates of suicide and nonsuicide mortality. Primary prevention can target high-risk groups including those with specific medical illnesses, disabling chronic diseases, widows/widowers, and spousal caregivers. Secondary prevention of recurrences of major depression is possible through maintenance treatment with antidepressant medications. Secondary prevention of behavioral complications such as suicide and alcoholism and of excess disability, morbidity, and utilization of general health services in patients with psychiatric-medical comorbidity can be facilitated by systematic approaches to case identification and treatment for depression in medical patients.

More than half of the people residing in nursing homes in the United States have dementia. A long history of basic contradictions in the conceptualization of nursing home care in the United States has resulted in a serious mismatch between the needs of residents with dementia and the resources of nursing homes to care for these residents. Concern for this discrepancy, and the resultant inadequate and inappropriate care, provided a major impetus for nursing home reform. OBRA 87 was a broad public policy initiative intended to improve the quality of life of nursing home residents. The spirit of the legislation is embodied in federal regulations that explicitly recognize the importance of psychological and social domains of the lives of nursing home residents; restrict the use of psychotropic drugs and physical restraints; and advocate for activities and services to attain or maintain patients' highest practicable physical, mental, and psychosocial well-being. Although the impact of OBRA 87 on the quality of life of residents with dementia is unknown, the federal regulations constitute a major step in the movement for nursing home reform and toward improved quality of care.

Repeated measures of cognitive functioning may provide a clinically feasible supplement to standard operational criteria for the diagnosis of delirium or toxic or metabolic encephalopathies in older adults. This research reports on the feasibility of detecting change in cognitive functioning through repeated assessments. The findings demonstrate that the method of identifying excessive cognitive changes through repeated assessments is not compromised by fatigue or practice effects. Further, a controlled drug trial validated this method for detecting change in a situation in which investigators would expect mild cognitive change to occur. Significant change in memory functioning was detected after administration of 50 mg of diphenhydramine. The results suggest that repeated monitoring of cognitive functioning may be an objective tool for measuring cognitive change that may facilitate the identification of subclinical toxic and metabolic encephalopathies., (Copyright © 2012 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Antipyrine half-life determined on three to five separate occasions over a period ranging from 3 weeks to 1 year was highly reproducible in each of 20 elderly subjects (12 women and 8 men; mean age, 83 years). The mean within-subject coefficient of variation for antipyrine half-life was 9.6%, whereas the between-subject coefficient of variation was 33.3%. These findings indicate high reproducibility of individual rates of drug metabolism in medically stable elderly subjects.

Findings from an exploratory study of the relationships between routine clinical laboratory tests and the clinical status of elderly patients living in a nursing home or congregate housing facility demonstrate that low albumin and anemia are associated with decreased survival and with self-care deficits, cognitive impairment, depression, and summary measures of the severity of medical illness. The interrelationships observed among these variables support the usefulness of the concept of failure to thrive. Although albumin can serve as a nutritional marker, findings on its relationship with sedimentation rate, triiodothyronine uptake, fasting plasma amino acids, and retinol-binding protein levels suggest that the low albumin related to failure to thrive is not a simple reflection of steady-state deficits in protein-calorie nutrition; it appears to be sensitive to more direct effects of disease and inflammation or to the interactions between nutrition and illness.

This research reports on the practicality of performing repeated measures of cognitive functioning in older adults. The detection of acute or subacute changes in cognitive functioning in the clinical setting could be facilitated by the development of an objective screening tool. Such a tool would not depend on the observation of symptoms only in pathological states, but rather, would depend on monitoring the cognitive functioning of patients over time. These repeated assessments allow us to define the magnitude of normal fluctuations in performance, thereby allowing us to define the magnitude of change in performance that represents a significant decrement or improvement in functioning. The findings reveal that routine monitoring of cognitive performance could allow identification of acute or subacute cognitive change in older adults., (Copyright © 1993 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the association between self-reported pain and cognitive impairment among frail elderly institution residents., Design: A cross-sectional correlational study., Setting: A large urban nursing home and congregate apartment complex housing predominantly Jewish elderly., Participants: Seven hundred fifty-eight elderly institution residents (30% in the nursing home, 70% in congregate apartments). The sample was 70% female and averaged 83.3 years of age., Measurements: Respondent self-reports tapped pain intensity, number of localized pain complaints, cognitive status, and disability in performance of activities of daily living. Attending physicians or physician assistants rated respondents' health status., Main Results: Pain intensity and number of localized pain complaints bore small but significant negative relationships to cognitive impairment. Pain was positively associated with physician-rated ill health and functional disability. The association between pain and cognitive status remained significant even when controlled statistically for effects of physical health and functional disability. Item-by-item examination of localized pain complaints indicated that markedly cognitively impaired individuals were less likely to report pain in the back and joints. However, examination of possible physical causes of reported pain revealed no differences between pain reports of cognitively impaired versus intact individuals in either the presence or the absence of a likely physical cause., Conclusions: These data provide no evidence for the "masking" of pain complaints by cognitive impairment. They suggest instead that, although cognitively impaired elderly may slightly underreport experienced pain, their self-reports are generally no less valid that those of cognitively intact individuals. Limitations of the research are acknowledged and implications for treatment of cognitively impaired institution residents are discussed.

The priorities for future research from the NIH Consensus Development Conference on the Diagnosis and Treatment of Depression in Late Life, as republished in the previous article, included recommendations to "conduct clinical trials and observational studies of treatment in the very old, the elderly in institutional setting, and the elderly with medical illnesses," that is, in the frail elderly. The present article reviews recent research in this field and outlines the potential for future developments. The importance of these areas of investigation follows from epidemiological findings suggesting that the prevalence of major depression in community populations, in general, decreases as a function of age but that depressions of all types occur more frequently in the "oldest-old," in patients seen in medical care settings, and in those with chronic disease and disability. The psychopharmacological literature, as summarized for the Consensus Conference in the review by Salzman and the meta-analyses of Klawansky, Greenhouse, and Schneider, indicates that antidepressant medications remain effective in elderly patients with moderate to severe degrees of major depression. Questions remain, however, about the value of drug treatment for those depressions that are most common in late life, including those that occur in extremely old patients and in patients with significant medical illness.

The authors assessed anxiety and depression among nursing home and congregate housing residents at yearly intervals. At baseline, modified DSM-III-R criteria yielded a 3.5% prevalence rate for anxiety or panic disorders. Another 13.2% reported milder symptoms not meeting diagnostic criteria. Anxiety was strongly associated with depression and with physical health, functional disability, and cognitive status. Follow-up data yielded an overall incidence rate of 2.3% for possible anxiety disorders; the majority of these cases were among those with mild anxiety at baseline. Change in anxiety was strongly associated with depression and, less consistently, with functional disability and cognitive status. Results are interpreted as indicating the indistinguishability of anxiety from depression in this frail elderly population., (Copyright © 1993 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

A one-year longitudinal study examined incidence and persistence of depression among nursing home and congregate apartment residents. Of 868 persons interviewed at Time 1, 15.7% displayed research-diagnosed possible major depression, and 16.5% displayed minor depressive symptoms. A follow-up interview a year later (T2; n = 448) yielded an incidence rate for possible major depression of 6.6% among persons with only minor or no depression in the previous year. For T1 nondepressives (i.e., excluding minor depressives), the incidence of possible major depression was 5.6%, and of minor depression, 6.3%. More than 40% of T1 possible major depressives showed no remission of symptoms a year later. In contrast, more than half of T1 minor depressives showed no depression at T2; however, another 16.2% appeared at follow-up to suffer possible major depression. Change in depression was associated with cognitive status, functional disability, and physical health. In general, persistence of depression was associated with greater decline, although patterns differed somewhat for the three functional indicators. Clinical and research implications of findings are discussed.

The authors present an overview of research questions related to psychopathology in elderly patients. Specific research questions in the areas of organic mental disorders, affective disorders, personality disorders, anxiety disorders, psychotic disorders, and substance abuse are presented. Clinical investigators are encouraged to pursue some of these specific questions in order to facilitate diagnosis and to develop specific effective treatment strategies for psychopathology in older patients.

To elucidate the mechanism by which platelet factor 4 (PF4), a secreted platelet protein, and its C-terminal peptides alleviate suppression of the antibody response in vivo, their immunoregulatory activity was studied in vitro, using cultured spleen cells from BALB/c mice primed with sheep red blood cells (SRBC). When addition of 48 h cultured concanavalin A (Con A) blasts at 5 x 10(5)/ml significantly suppressed the anti-SRBC plaque-forming cell response, suppression was alleviated in 25 of 29 experiments by 0.2 micrograms/ml recombinant (r)PF4 (6.4 nM if rPF4 is a tetramer). The effect of Con A blasts was abolished by cimetidine, a histamine type 2 (H2) antagonist. Dimaprit, an H2 agonist, at 1-2 x 10(-4) M, or splenic T cells that had been incubated for 1 h with dimaprit and washed, also caused significant suppression that was alleviated by 0.2 micrograms/ml rPF4 (n = 8), and by 0.02 micrograms/ml in six of these tests. The C-terminal 13 amino acid peptide of PF4 was active at 0.02-0.2 micrograms/ml (0.01-0.11 microM), but peptides from the middle or N-terminal end of the molecule, or IL-8, which shares structural homology with PF4, were inactive. IL-1 and IL-2 raised control responses without affecting suppression or its alleviation by rPF4. Neutralizing antibody to transforming growth factor beta 1 (TGF-beta 1) did not affect Con A blast-induced suppression and suppression induced by exogenous TGF-beta 1 (0.5 ng/ml) was not counteracted by rPF4. Blocking prostaglandin production with 0.2 or 2 microM indomethacin did not affect suppression significantly but reduced rPF4 activity; prostaglandin D2 restored the effect of rPF4.(ABSTRACT TRUNCATED AT 250 WORDS)

This study examined the association between depression and mortality among a group of nursing home and congregate apartment residents (initial n = 898) over a 30-month period. Baseline [Time 1 (T1)] and 1-year follow-up [Time 2 (T2)] assessments yielded research-based diagnoses of possible major, minor, or no depression, along with measures of functional disability, cognitive status, and physician-rated health. Event history analyses were used to assess differential mortality as a function of level of depression after T1 and of change in depressive status from T1 to T2. Significant effects for T1 depression at 6, 12, and 18 months after the interview reflected an increased death rate among possible major depressives as compared with other respondents. An effect of change in depressive status from T1 to T2 appeared to be caused by long-term negative effects of T1 depression. Finally, none of the observed associations remained significant when controlled for effects of physical health, functional disability, and cognitive status. Thus, the effects of depression on mortality among this sample appeared to be attributable strictly to the correlation of depression with ill health. However, cautious interpretation is recommended inasmuch as causal paths between depression, ill health, and death remain unclear.

Interrelations between depression (Geriatric Depression Scale) and cognitive impairment (Blessed test) were examined among 201 nursing home and congregate apartment residents in a 2-year, 3-wave study. In structural equations models that controlled autocorrelations and within-occasion correlated residuals, introducing paths from depression to subsequent cognitive status significantly reduced unexplained variance, whereas paths from cognitive status to subsequent depression did not. Subsidiary analyses indicated that the relation of depression to subsequent cognitive status was strongest among persons with borderline (vs. impaired or intact) cognitive status, but only for the first time interval. Discussion addresses explanations for obtained results and implications for monitoring and treating depression among elderly long-term care residents.

Current approaches to the diagnosis of delirium are based upon the recognition of symptoms that emerge in the pathological state. As an alternative, we propose an approach to case identification for research purposes based on the recognition of significant changes in the cognitive or cerebral state of the individual patient. Categorical change can be defined using prediction intervals calculated from repeated measures on a population of medically stable subjects. Data from subjects enrolled in a prospective study of delirium in a long-term care population were utilized to calculate prediction intervals for the Mini-Mental Status Examination and for measures of the electroencephalographic background frequency as obtained with a two-channel microprocessor-based EEG device. Preliminary findings support the validity of this quantitative approach for defining changes in brain state. Future research should evaluate both cognitive and electrophysiological techniques for monitoring vulnerable patients.

Evaluation of the change in performance on the Blessed Memory Information Concentration Test over a one-year period was used as a probe for the prevalence of reversible cognitive disorders among patients living in a residential care facility. Of 157 patients with cognitive impairment at the initial assessment, 10 (6.4%) improved by 6 points or more, 19 (12.1%) improved by 5 points or more, and 15 (9.6%) had a reduction in the number of errors by 33% or more. Thus, using improvement over time as an indicator, we estimate that 6% to 12% of the elderly patients in our sample had a reversible component to their cognitive impairment at the initial assessment. Retrospective review of medical records identified (one or more) possible causes for impairment at baseline in each of the ten patients who showed the greatest improvement: adverse drug effects in seven patients, depression in two, and metabolic encephalopathies in three.

Nursing home and congregate apartment residents (N = 598) were classified on the basis of a DSM-IIIR symptom checklist as suffering possible major, minor, or no depression; they also completed the Geriatric Depression Scale (GDS) and the Profile of Mood States (POMS). Possible major depressives reported more intense pain and a greater number of localized pain complaints than did minor depressives; nondepressed individuals reported the least intense pain and fewest localized complaints. The effect remained strong even when functional disability and health status were controlled statistically. Both pain intensity and number of localized complaints were correlated with GDS and POMS factor scores, but strength and direction of associations varied with level of depression. Item-by-item examination of localized complaints again indicated that more depressed individuals were more likely to report pain, particularly where physicians had identified a physical problem that might account for the pain. Results are compared with previous research on pain among younger individuals. Implications for treatment of depressed elderly are discussed.

While brain injury elicits local cellular proliferation, it is not known whether cells not originating in brain substantially participate in the response. We assessed the time course and phenotype of dividing cells following neuronal damage initiated by microinjection of the neurotoxin ibotenic acid into one caudate nucleus (CN) in adult rat. Proliferation was determined in an in vitro assay measuring incorporation of [3H]thymidine into cellular DNA in cultures of lesioned and uninjected CN. Cellular phenotypes were determined immunocytochemically. Our results show that the proliferative response to brain injury has a rapid onset, peaks within 2 weeks and persists. The majority of proliferating cells that respond to selective neuronal injury are not intrinsic to the central nervous system, but rather are of hematic origin, involving monocytes, macrophages and T-helper lymphocytes.

Several experiments were conducted to validate the use of a two-channel microprocessor-based electroencephalographic (EEG) device for detecting changes in EEG background rhythm in the clinic or at the bedside. The reliability of background measures in healthy individuals was evaluated by obtaining EEG data on 20 control subjects on two occasions separated by at least 1 day. The sensitivity to an experimental toxic encephalopathy was evaluated using measures of EEG and the Buschke Memory Selective Reminding Test after the administration of scopolamine hydrobromide, 0.86 mg subcutaneously, to three healthy volunteers. Postdrug measures of the EEG showed significant group differences from controls at 1 and 2 hours for relative alpha and relative theta power. The drug-induced change for each individual exceeded the predicted range calculated from data on control subjects. These findings suggest the feasibility and the potential utility of this method. This approach was extended to the elderly with measures on 102 subjects (average age, 85 years) living in an institutional setting. EEG measures in the population were of acceptable reliability and were significantly correlated with Mini-Mental State Examination (MMSE) scores (r = -.375 for theta and .357 for beta). Preliminary findings suggest that this method may detect metabolic encephalopathies in the elderly. The study demonstrates the potential value of this approach and suggests the need for further research.

A significant drug-placebo difference was found in a double-blind, placebo-controlled study of nortriptyline for treatment of major depression among frail elderly patients living in an institutional setting. This finding confirms the validity of the DSM-III-R diagnosis of major depression and establishes the need for specific psychiatric services for the chronically ill elderly living in nursing homes and congregate housing facilities. The incidence of adverse events requiring early termination of treatment was 34%, demonstrating the vulnerability of these patients and their need for careful monitoring during treatment. High levels of self-care disability and low levels of serum albumin were both associated with decreased therapeutic responses, demonstrating the need for further research on psychopathology in these settings.

We have compared levels of albumin and serum amino acids in a group of 87 recent admissions to a nursing home, average age 83 years, with a group of healthy moderately old subjects, average age 69 years. We found that the nursing home group was characterized by decreased levels of albumin, by increased total levels of the measured amino acids, and by increased levels of the nonessential amino acids. In contrast, there were no significant group differences in the essential amino acids. Among the nursing home patients, there was a negative correlation between essential amino acids and disability, consistent with nutritional deficits in the more disabled patients, and a positive correlation between essential amino acids and subjective complaints of pain, suggesting that pain is associated with breakdown or mobilization of endogenous protein stores. Though the nursing home patients had decreased serum levels of tryptophan, there was no association between serum tryptophan or other variables that could be related to the availability of tryptophan for transport into brain, with ratings of either depression or pain. Glutamine levels were significantly increased in the nursing home residents, and among these patients they were positively correlated with measures of cognitive impairment.

Syngeneic mixed lymphocyte-stimulating la+ lymphomas of SJL mice [reticulum cell sarcoma(s) (RCS)] were found to modulate immune responses in vivo. Simultaneous injection of 2 X 10(7) gamma-irradiated or glutaraldehyde-fixed RCS cells with the antigen sheep red blood cells (SRBC) or 2,4,6-trinitrophenol (TNP)-Ficoll markedly suppressed the subsequent plaque-forming cell response in the spleen. The suppression of the anti-SRBC response was prevented by pretreatment of the mice with cyclophosphamide, whereas the suppression of the anti-TNP-Ficoll response was not affected. RCS injection induced high interferon serum titers within 24 hours after injection, which were not prevented by pretreatment with cyclophosphamide. Injection of gamma-irradiated RCS cells (gamma-RCS) or RCS cell extract 2 days prior to antigen enhanced the anti-SRBC but markedly suppressed the anti- TNP-Ficoll response. Injection of RCS both on day -2 and day 0 enhanced the anti-SRBC response. SJL mice 8-9 months of age showed much less or no suppression when gamma-RCS cells were injected on day 0. Certain F1 hybrids of SJL also showed the gamma-RCS-induced suppression of the anti-SRBC response. Suppression was seen in SJL X BALB.B but not in SJL X BALB/c mice and in SJL X A.TH but not in SJL X A.TL mice, suggesting an I-region effect. F1 hybrids of SJL by B10 background mice showed no significant suppression. Enhancement of the anti-SRBC response by prior injection of gamma-RCS was seen in all F1 hybrid mice examined.

Seven schizophrenic (according to DSM-III criteria) inpatients completed a two-phase study; each phase had a 1-week drug-free period followed by 6 weeks of a drug trial. The first phase uniformly involved treatment with chlorpromazine, and in the second phase patients received either mesoridazine (N = 3) or thioridazine (N = 4). Clinical ratings (Brief Psychiatric Rating Scale and Clinical Global Impressions) and neuroleptic blood levels were obtained weekly throughout the study. Whereas patients failed to respond to chlorpromazine 1800 mg/day, response to mesoridazine 400 mg/day and to thioridazine 800 mg/day was established on all Brief Psychiatric Rating Scale factors except for anxiety-depression. A higher neuroleptic blood level was achieved with mesoridazine or thioridazine at less than half the reference chlorpromazine dosage. Correlations between neuroleptic blood level and clinical response were positive for mesoridazine, negative for chlorpromazine, and nonsignificant for thioridazine. These findings are consistent with earlier research. We conclude that drug-resistant schizophrenics seem to improve clinically with mesoridazine or thioridazine, unlike with chlorpromazine, and that for mesoridazine this difference may be a function of selective dopamine receptor blockade.

(a) The PR elicited by excitotoxic destruction of intrinsic neurons in the CN has a rapid onset, peaks within 2 weeks, and persists indefinitely; (b) the majority of the proliferating cells are not intrinsic to the CNS but are of hematic origin; (c) a small mirror-image response is seen in the contralateral CN; (d) the proliferating response in anterogradely degenerating terminals in SN differs in time course, magnitude, and phenotypically from that initiated by direct neuronal loss. We conclude that the majority of proliferating cells at the site of selective neuronal injury in brain are of hematic origin in contrast to that initiated during anterograde degeneration, which consists primarily of intrinsic cells of brain (glia).

Patients with acquired immunodeficiency disease syndrome (AIDS) show a complex spectrum of immunological abnormalities. We have examined B-lymphocyte function in 58 patients with AIDS and Kaposi's sarcoma. The major finding has been that the specific antibody response to sheep red blood cell antigen in vitro is severely depressed. Analysis of the defect in specific antibody production indicates that it is not caused by lack of T-cell help or excessive T-cell suppression, and suggests that it reflects an abnormality of the B-cell compartment itself. The defect does not affect the ability of B cells to respond to polyclonal stimulation. The possibility is considered that continuous hyperactivation of B cells in AIDS patients (as reflected in the increase in both immunoglobulin-secreting cells and serum immunoglobulin levels) results in depletion of the pool from which precursors for antigen specific B-cell responses are normally recruited.

The substrate dependence of tryptophan hydroxylase activity in rat striatal synaptosomes was examined. The Km for tryptophan in air to 8--13 microM, comparable to the concentration present in cerebrospinal fluid. The reaction is inhibited by amino acids with large nonpolar side chains. For leucine the inhibition appears competitive; it results from a decrease in the steady state levels of intrasynaptosomal tryptophan. The oxygen Km at 10 microM-tryptophan is 3--4 mm Hg, which is increased when the reaction is assayed with low levels of tryptophan in the medium, and in the presence of amino acids such as leucine. Similarly, the tryptophan Km is increased at low oxygen tensions; at 9 mm Hg of oxygen it is 23 microM. These interactions between tryptophan and oxygen dependence of the reaction are discussed in terms of likely physiological significance and implications for the pharmacological use of tryptophan.

A platelet-derived factor found in serum as well as in platelet releasate prepared either with calcium ionophore or with thrombin was shown to reverse Con A-induced suppression of the plaque forming cell (PFC) response to sheep erythrocytes (SRBC) in vivo in (CB6)F1 mice. In addition, as shown previously, lymphoma cell-induced suppression in SJL mice was similarly reversed. The factor could be injected prior to Con A on the day before SRBC injection, or on the same day as antigen with comparable results. It also enhanced PFC responses in the absence of Con A. Suppressor cell induction by Con A in vivo, as demonstrated by assay on PFC responses of normal spleen cells in vitro, was abrogated by simultaneous injection of the platelet factor. Cells from mouse spleen and lymph node, but not from thymus could absorb the factor from human serum at 4 degrees C. The phenotype of the relevant spleen cells was L3T4-, Ly1-, Ly2+, Thy1+, Ly22+, Qa1+, Qa4+, Qa5+, and Ly6.IE+. These results suggest that this factor binds to activated peripheral T cells of the suppressor cell phenotype.

Dopamine-beta-hydroxylase activity can be assayed in vitro in suspensions of rat hypothalamic synaptosomes by following tritium release from [2-3H]dopamine in the presence of monoamine oxidase inhibitors. The activity is inhibited by diethyldithiocarbamate, fusaric acid, amphetamine, reserpine, and desipramine. It is not sensitive to addition of tyrosine at the concentration present in cerebrospinal fluid, to added fumarate or to a rat heart extract known to contain potent inhibitors of the isolated enzyme. The reaction in air follows simple saturation kinetics with respect to variation in dopamine concentration with Km of 0.075 microM. There is reversible inhibition of activity when it is assayed at low oxygen tension. The apparent oxygen affinity is such that the enzyme does not appear saturated with respect to oxygen even at arterial oxygen tensions. Other reactions assayed exhibit less sensitivity to hypoxia: production of lactic acid from glucose becomes stimulated at 10-12 mm Hg; and oxidation of lactic acid is not inhibited at oxygen tensions above 3-4 mm Hg. Comparison of these data with the distribution of oxygen tensions present in brain suggests a basis for classifying oxygen dependent neurochemical reactions.

Investigations on the symptoms associated with the use of anticholinergic medications by elderly patients demonstrated that these medications are frequently associated with persistent adverse effects that may go unrecognized by both patients and physicians. An increase in autonomic symptoms was readily demonstrated in a group of elderly outpatients taking anticholinergics. Cognitive effects, however, were not apparent, possibly due to the heterogeneity of the populations studied. A parallel study did, however, demonstrate an association between anticholinergic medications and slowing of EEG background frequency. Findings on the relationship between EEG background frequency and cognitive measures suggest the possible value of the combined use of psychological and electrophysiological measures for identifying patients who require further evaluation of their medication regimen.

Sir Martin Roth has stated, "where there is depression, there is hope," to emphasize the fact that depression can be a treatable source of excess disability, even when it is superimposed upon irreversible chronic medical illness. Both the potential benefits and the risks of antidepressant medications are increased in the frail elderly. This article presents an approach toward defining who should be treated and for ensuring that elderly patients receive adequate treatment.

The frail elderly, for whom chronic disease and disability are essentially universal, are at high risk for depression and are specifically vulnerable to the adverse effects of antidepressant medication. There have, however, been few investigations of either the pharmacokinetics or the clinical investigations of either the pharmacokinetics or the clinical response to antidepressants in such patients. We report on the pharmacokinetics of nortriptyline at steady state in a group of 22 patients, average age 84, living within an institutional setting. Comparison of our findings with those previously reported for younger and healthier subjects suggests that there are no clinically significant group differences in nortriptyline kinetics. Plasma levels of nortriptyline and those of both the trans- and cishydroxylated metabolites are linear with daily dose. Mean (and SD) for the parameter (plasma level/dose) was 1.21 (0.63) ng/ml/mg/day for the parent compound, 1.41 (0.86) for the trans metabolite, and 0.30 (0.16) for the cis metabolite. There was no significant correlation across individuals between the accumulation of the parent compound and the metabolites. Based upon these data, the average dose of nortriptyline required to achieve a plasma level of 100 ng/ml is 80 mg/day. Dose requirements, however, vary between individuals by a factor of 20. Plasma levels measured 24 hours after a 25-mg test dose of nortriptyline can allow early identification of slow metabolizers. Twenty-four-hour plasma levels (mean 8.8 ng/ml, SD 3.2) were significantly correlated with steady state levels at 25 mg/day (r = 0.71), steady state levels at 50 mg/day (r = 0.73), and each individual's average (plasma level/dose) (r = 0.57).

This communication describes conditions under which the monoamine oxidase-catalyzed metabolism of 3,4-dihydroxyphenylethylamine can be assayed in dopaminergic synaptosomes from the rat striatum. In contrast to the activity of the isolated enzyme or that of free mitochondria, the synaptosomal reaction exhibits sigmoidal kinetics with respect to substrate concentration. This is consistent with a kinetic mechanism in which intrasynaptosomal substate partitions between reaction and saturable storage in synaptic vesicles. The reaction is inhibited at moderately decreased oxygen tension, where catecholamine uptake is unaffected. The specificity of this effect suggests that it reflects limited availability of oxygen as an enzyme substrate.

The activity of a partially purified preparation of tyrosine hydroxylase (EC 1.14.16.2) from the bovine caudate nucleus was increased by heparin, chondroitin sulfate, phosphatidylserine, polyacrylic acid, polyvinyl sulfuric acid and both poly-D-, and poly-L-glutamic acids, all polyanions. A variety of salts both activated the enzyme and prevented the activation by the polyanions. The observations that activity is increased when the enzyme interacts with salts and with macromolecules of high negative charge density are used to infer a model for these interactions and for the structural change in the enzyme that accompanies activation.

The prevalence of depression among nursing home residents was estimated by screening a group of residents selected from a random sample on the basis of cognitive status; it ranged from 18-20% for major depression to 27-44% for other dysphoric states. Though individual patients were observed to change over a 6-month period, depression as assessed with the Geriatric Depression Scale was, in general, persistent. Major depression was clinically confirmed in 8 of 10 patients identified at screening. It was characterized by medical disorders that complicated diagnosis and treatment, and by increased mortality relative to the rest of the population.