Use of the Medication Event Monitoring System to estimate medication compliance in patients with schizophrenia.

OBJECTIVE: To determine the feasibility of using the Medication Event Monitoring System (MEMS) to estimate medication compliance in patients with schizophrenia or schizoaffective disorder. SUBJECTS AND SETTING: Fourteen of 35 consecutive patients admitted to a psychiatric inpatient hospital with schizophrenia or schizoaffective disorder who met eligibility requirements and gave informed consent. INTERVENTION: After random assignment to either risperidone or typical antipsychotic treatment, medication upon discharge from hospital was dispensed in a bottle with a MEMS cap which recorded the number of bottle openings and the date and time of each opening. The first 6 patients were asked to return monthly for data downloading. The next 8 were asked to return weekly during the first month and every 2 weeks thereafter; they were also paid $5 for returning each bottle. OUTCOME MEASURES: MEMS data collected over a 6-month period and hospital readmission data. RESULTS: Patient medication compliance data were collected from 10 (71%) of 14 patients during the first month, from 7 (58%) of 12 (2 patients dropped out) during the second and from 5 (45%) of 11 (a third patient dropped out) during months 3-6. Mean compliance rates were 63% for the first month and ranged from 56% to 45% over the next 5. First-month compliance rates were significantly lower for those who were subsequently readmitted to hospital (n = 7) than for those who were not (p < 0.01). CONCLUSIONS: Electronic monitoring devices can be used to estimate compliance with medication regimens in patients with severe schizophrenic disorders, but there are methodological improvements that can be made to increase data recovery and compliance, and these are discussed.

Intersubjectivity and interaction in the analytic relationship: a mainstream view.

The authors conceptualize intersubjectivity as a meta-theory that reflects the inherent nature of human relatedness and is conceptually independent of any particular theory of mind or school of psychoanalysis. Their view of intersubjectivity joins the emotional life of the analyst to that of the patient and places the analytic relationship at the center of the analytic process. They contrast intersubjectivity with traditional classical conflict theory so as to clarify the relevance of intersubjectivity for psychoanalytic clinical theory and therapeutic practice. In so doing, they hope to direct analysts more firmly toward the study of the unconscious dyadic contributions to the affective, inactive, and interactive dimensions of the analytic situation and their impact upon the patient's actions within and experience of the analytic relationship. To illustrate their thesis, two hours from an analysis are presented in detail.

Erik Erikson's dream specimen paper. A classic revisited.

This paper offers an overview of Erik Erikson's contribution to psychoanalysis, contrasting the humanistic perspective from which he viewed psychoanalysis with the biological perspective adopted by Heinz Hartmann. The vehicle for this comparison and for the explication of Erikson's extension of the work of Freud and Hartmann is Erikson's analysis of Freud's Irma dream, as presented in his Dream Specimen paper. I hope to show that: (1) Erikson's analysis of Freud's Irma dream provides a masterful illustration of the richness and complexity of past and current life themes and conflicts that inform the dreamer's construction of the manifest surface of the dream. (2) Erikson's examination of the relationship between the manifest content of the dream and the current life context of the dreamer leads him to propose a connection between trauma and the origins of the dream. This view complements Freud's discovery of the instinctual motivation for dreaming and anticipates subsequent discoveries concerning the role of dreams and REM sleep in defensive ego functioning and adaptation. (3) The Dream Specimen paper presents readers with a humanistic ego psychology that rests upon--but is subtly different from--the work of Hartmann and the other biologically oriented analysts of his day. In this sense, Erikson's paper is an elegant "specimen" of ego psychology carried to its most creative heights.

The analyst's participation in the analytic process.

The analyst's moment-to-moment participation in the analytic process is inevitably and simultaneously determined by at least three sets of considerations. These are: (1) the application of proper analytic technique; (2) the analyst's personally-motivated responses to the patient and/or the analysis; (3) the analyst's use of him or herself to actualise, via fantasy, feeling or action, some aspect of the patient's conflicts, fantasies or internal object relationships. This formulation has relevance to our view of actualisation and enactment in the analytic process and to our understanding of a series of related issues that are fundamental to our theory of technique. These include the dialectical relationships that exist between insight and action, interpretation and suggestion, empathy and countertransference, and abstinence and gratification. In raising these issues, I do not seek to encourage or endorse wild analysis, the attempt to supply patients with 'corrective emotional experiences' or a rationalisation for acting out one's countertransferences. Rather, it is my hope that if we can better appreciate and describe these important dimensions of the analytic encounter, we can be better prepared to recognise, understand and interpret the continual streams of actualisation and enactment that are embedded in the analytic process. A deeper appreciation of the nature of the analyst's participation in the analytic process and the dimensions of the analytic process to which that participation gives rise may offer us a limited, although important, safeguard against analytic impasse.

Anomalous inferior vena cava with azygos continuation.

Five patients who underwent cardiac catheterization at three separate institutions during a period of 6 years were found to have anomalous inferior vena cava with azygos continuation. Although it is not uncommon to detect this defect in pediatric patients with congenital heart disease, it may be an unusual finding for an angiographer who works primarily with adults. This article serves as a reminder of the existence of this potentially confusing anomaly, usually associated with other congenital cardiac abnormalities.

Granulocyte-macrophage colony-stimulating factor and other cytokines regulate surface expression of the leukocyte adhesion molecule-1 on human neutrophils, monocytes, and their precursors.

There is increasing evidence that cytokines such as granulocyte-macrophage (GM)-CSF can profoundly affect the adhesion, aggregation, and mobility of neutrophils both in vitro and in vivo. However, the mechanisms whereby these factors might alter the adhesive properties of neutrophils are incompletely understood. A new family of cellular adhesion molecules has recently been identified by cDNA cloning. The members of this family include human leukocyte adhesion molecule-1 (LAM-1), the human endothelial-leukocyte adhesion molecule, and the mouse leukocyte homing receptor for high endothelial venules, MEL-14. LAM-1 is the human homologue of murine MEL-14, and is believed to mediate binding of leukocytes to human high endothelial venules. LAM-1 can be identified by mAb TQ-1, Leu 8, or anti-LAM1.1. The expression and regulation of LAM-1 on granulocytes, monocytes, and their precursors was investigated using flow cytometry and the anti-LAM-1.1 mAb. Neutrophils, eosinophils, monocytes, marrow myeloid cells, granulocyte/macrophage colony-forming unit, and burst-forming unit for erythroid cells were LAM-1+ by flow microfluorimetry. The regulation of LAM-1 expression was tested by treating various cell populations with cytokines or other stimuli for 0-90 min. Exposure of neutrophils, monocytes, and marrow myeloid cells to GM-CSF induced rapid and complete loss of LAM-1 from the cell surface, but had no effect on LAM-1 expression by lymphocytes. The loss of LAM-1 was temporally correlated with up-regulation of CD11b (Mo1), an adhesion molecule involved in neutrophil aggregation. Several other factors known to activate neutrophils also caused down-regulation of LAM-1 and up-regulation of CD11b, including TNF, FMLP, and leukotriene B4. Interestingly, granulocyte-CSF and IFN-gamma had minimal effects on neutrophil LAM-1 expression. Similar results were observed on monocytes and myeloid precursor cells. Thus, exposure of neutrophils to GM-CSF results in a profound change in surface expression of adhesion molecules, with coordinated up-regulation of CD11b and down-regulation of LAM-1. These changes in adhesion proteins are likely to alter aggregation and mobility of both mature myeloid cells and their precursors in patients receiving certain types of cytokine therapy.

Expression of the human leukocyte adhesion molecule, LAM1. Identity with the TQ1 and Leu-8 differentiation antigens.

The LAM1 molecule is a member of the new family of cellular adhesion/homing molecules that contain a lectin-like domain at their amino-terminal end followed by an epidermal growth factor-like domain and short consensus repeat units like those found in C3/C4 binding proteins. Two mAb that react with the leukocyte adhesion molecule 1 (LAM1) were produced and used to examine the cell-surface expression of LAM1. The anti-LAM1 antibodies were reactive with the majority of blood lymphocytes, NK cells, neutrophils, and monocytes. LAM1 was also expressed by subpopulations of phenotypically immature and mature thymocytes. Blood lymphocytes rapidly modulated LAM1 from the cell surface during PMA exposure for 60 min. Coordinate with the loss of LAM1 from the cell surface, PMA-treated lymphocytes lost the ability to bind to lymph node high endothelial venules, indicating that expression of LAM1 may play a role in lymphocyte homing. Mitogen stimulation of blood T and B lymphocytes also resulted in decreased LAM1 expression, but at a slower rate. LAM1 was only weakly expressed by a minority of spleen lymphocytes. However, culturing spleen lymphocytes in media alone resulted in increased expression of LAM1 by a subpopulation of the cells (40 to 60%). Concomitant mitogen stimulation of spleen lymphocytes resulted initially in down-regulation of LAM1 expression followed by increased expression of LAM1 and then subsequent loss of LAM1 from the cell surface. The pattern of anti-LAM1 antibody reactivity was identical to that reported for the TQ1 and Leu-8 antibodies, and all of these antibodies reacted with cells transfected with the LAM1 cDNA. Thus, LAM1 is broadly expressed by leukocytes, and binding of LAM1 may participate in the process of leukocyte extravasation into lymphoid organs or sites of acute inflammation with subsequent loss of LAM1 from the cell surface.

Cryptococcosis of the nasopharynx in mice and rats.

An attempt to infect the upper respiratory tract of mice and rats with various bacteria and fungi by intranasally instillation was performed. Cryptococcus neoformans was the only agent to invade the tissue. The infection was limited to the nasopharynx, a phenomenon which probably indicates the presence of a specific chemotaxis or receptor.

The T11 (CD2) molecule is functionally linked to the T3/Ti T cell receptor in the majority of T cells.

Most mature human T lymphocytes express both the multichain T3 (CD3)/Ti T cell receptor for antigen (TCR), and the biochemically distinct 55-kDa T11 (CD2) glycoprotein. Stimulating the T11 molecule causes profound T cell proliferation and functional activation in vitro, but the relationship of T11-mediated activation to antigenic stimulation of T lymphocytes in vivo remains unknown. We now present evidence that T11 function is directly linked to TCR components in T3/Ti+ T11+ human T cells. First, we found that stimulating peripheral blood T cells with the mitogenic combination of anti-T11(2) cells with the mitogenic combination of anti-T11(2) plus anti-T11(3) monoclonal antibodies caused the phosphorylation of TCR T3 chains. The predominance of T3-gamma-phosphorylation that occurred in anti-T11(2) plus anti-T11(3)-treated T cells is similar to the pattern previously observed in antigen-stimulated T cell clones. Second, T11 function depended upon concurrent cell-surface expression of the TCR. Thus, when peripheral blood T cells were deprived of cell surface T3/Ti by anti-T3 modulation, anti-T11(2) plus anti-T11(3)-induced mitogenesis and transmembrane signal generation in the form of calcium mobilization were inhibited. The mechanism of TCR-T11 interdependence was investigated in a series of TCR-deficient variants of a T cell lymphoblastoid cell line. T3/Ti negative variants expressed cell surface T11, but anti-T11(2) plus anti-T11(3) failed to cause detectable calcium mobilization. The TCR-deficient variants also failed to express T11(3) activation epitopes after incubation with anti-T11(2) antibodies, suggesting that T11(3) expression is an essential and TCR-dependent intermediate in the T11 activation mechanism in these cells. Taken together, our results suggest that T11 function depends upon cell-surface expression of TCR in many T3/Ti+ T11+ T lymphocytes, and T11-mediated activation is intimately interconnected with TCR activation mechanisms. A model in which stimulating signals delivered via T11 may be a part of antigenic activation of T lymphocytes is presented.

Growth inhibition of human T cells by antibodies recognizing the T cell antigen receptor complex.

Monoclonal antibodies that bind to the T cell MHC-antigen recognition complex (anti-T3 or anti-Ti) are known to either mimic ligand binding and activate T cells or block ligand binding, leading to an inhibition of T cell activation. In the present experiments, we demonstrate a direct inhibitory effect on the growth of human T cells by anti-T3 or anti-Ti antibodies. The proliferation of human peripheral blood T cells preactivated by exposure to PHA was inhibited in a specific manner by anti-T3. Colony formation in soft agar by REX cells, a leukemic cell line of early T cell phenotype, was completely inhibited by anti-T3 or anti-Ti antibodies, whereas isotype-matched antibodies to a variety of other T cell markers had no effect. Growth of REX cells in suspension culture was not affected by anti-T3 or anti-Ti. A cell line, T3.N1, was established from an agar colony of anti-T3-resistant REX cells. T3.N1 was phenotypically identical to REX except for failure to express any detectable T3 or Ti surface antigen. T3.N1 colony formation in soft agar was not inhibited by anti-T3 or anti-Ti. There was no rise in [Ca2+]i of T3.N1 cells after anti-T3 or anti-Ti exposure. These results indicate that in addition to the well-known positive regulatory effects of ligand binding to the T3/Ti complex, T3/Ti binding can also result in a down-regulatory signal for human T cell growth.

Hormonal effects of ketoconazole in vivo in the male rat: mechanism of action.

Ketoconazole, an antifungal agent, has been shown to lower serum testosterone (T) in man. Measurements of circulating precursors of T suggest that ketoconazole may inhibit 17,20-desmolase activity in the testis. To further elucidate its mechanism of action in vivo, we studied its effects on the pituitary-gonadal axis in the male rate. Two groups of normal male Sprague-Dawley rats were treated with either oil or 25 mg ketoconazole in oil by im injection every 8 h for 21 days. Serum ketoconazole concentrations in the rat 2 h after the 25-mg dose were similar to those after oral administration of a much lower (1/33rd) dose to man. Ketoconazole treatment led to 50% suppression of serum T and prostate and seminal vesicle weights. Testis weights were not significantly affected. Intratesticular T concentrations showed a 50% decrease below the control level. Testicular 17 alpha-hydroxylase, 17,20-desmolase, and 17 beta-hydroxysteroid dehydrogenase activities in the ketoconazole-treated animals were significantly decreased in proportion to the decreases in serum and intratesticular T concentrations. Elevations of serum LH and FSH concentrations in the ketoconazole-treated rats were not proportionate to the decline in serum T concentration. Therefore, to exclude an additional inhibitory effect of ketoconazole at the pituitary level, we treated two groups of castrated male Sprague-Dawley rats with the same dose of ketoconazole or oil for 3 days. Serum LH and FSH concentrations were not significantly different in the two groups. In separate experiments, combined treatment of intact rats with GnRH agonist and ketoconazole for 21 days led to lower mean serum T concentrations and accessory organ weights than those achieved with either agent alone. We conclude that ketoconazole inhibits T synthesis, primarily by inhibiting the activity of multiple enzymes in the T biosynthetic pathway and has no direct effect at the pituitary level; ketoconazole metabolism in the rat is considerably different from that in man; and ketoconazole enhances the inhibitory effects of GnRH agonist.

Inhibition of testosterone production with ketoconazole alone and in combination with a gonadotropin releasing hormone analogue in the rat.

Ketoconazole is a well-tolerated, synthetic, imidazole derivative currently in widespread therapeutic use against mycotic infections. Recent evidence that it depresses testosterone synthesis in humans prompted us to investigate the effects in rats of its administration alone or in combination with the gonadotropin releasing hormone superagonist analogue leuprolide. Plasma luteinizing hormone, testosterone, and ketoconazole levels as well as ventral prostate weight and tumor growth in rats bearing the androgen-dependent Dunning R3327H model of prostate adenocarcinoma were measured. Doses of 30 mg/kg twice daily of ketoconazole alone depressed plasma testosterone levels by approximately 75% to a nadir of 0.47 +/- 0.08 (SE) ng/ml on day 20 (P less than 0.001 versus basal). This effect of ketoconazole was exerted directly at the testicular level since plasma luteinizing hormone levels were not suppressed. In response, ventral prostate weight declined and growth of the Dunning R3327H tumor was retarded to rates observed in castrate controls. Leuprolide alone lowered basal testosterone levels to 0.20 +/- 0.02 ng/ml after 35 days of daily administration but persistent androgen increments after each injection (acute-on-chronic effect) were observed (i.e., to 4.41 +/- 0.62 ng/ml). The addition of ketoconazole to leuprolide inhibited the acute-on-chronic rise in testosterone to 0.33 +/- .07 ng/ml and also lowered basal testosterone levels further to 0.11 +/- 0.01 on day 10 of combined administration. Ketoconazole also blunted the response to the first injection of leuprolide from a 3-h peak level of 8.74 +/- 0.53 to 4.17 +/- 0.80 with the 40 mg/kg dose. These results indicate that combining ketoconazole with leuprolide achieves greater suppression of testosterone than either agent alone. When such protocols are applied to humans with prostate cancer, more extensive effects may be expected because of the greater sensitivity of patients than of the rodent species to these agents.

Pseudallescheria boydii infections treated with ketoconazole. Clinical evaluations of seven patients and in vitro susceptibility results.

Seven patients infected with Pseudallescheria boydii were treated with oral ketoconazole, 200 to 600 mg/day for one to 13 months. Five patients had pulmonary infections; two had skeletal infections. Improvement of pretreatment abnormalities occurred in five patients, one of whom had concurrent arthrodesis of his infected knee. The other two patients were subsequently healed by surgical resection of their pulmonary lesions. Ketoconazole appeared less active than miconazole against 22 clinical isolates of P boydii when tested by two in vitro methods. We conclude that ketoconazole is effective treatment for some patients infected with P boydii, although this may not be predicted by current in vitro susceptibility tests. Further experience is needed to establish the optimal use of ketoconazole with respect to its dosage, duration of administration and concurrent surgical resection.

Immunologic responsiveness and safety associated with the Coccidioides immitis spherule vaccine in volunteers of white, black, and Filipino ancestry.

A trial of the killed Coccidioides immitis spherule vaccine was undertaken with 151 healthy skin test negative adult volunteers and controls to evaluate the safety of selected regimens, the induction of humoral and cell-mediated immune responses, and to determine if there were immunogenetic differences in these responses. The vaccine was given as three intra-deltoid doses over 8 weeks. No severe systemic symptoms were noted, although 3% of 3.5 mg doses (but no 1.75 mg doses) were associated with severe local reactions. Half the vaccinees had skin test conversions, which generally persisted greater than or equal to 6 months, two-thirds showed boosting of lymphocyte transformation in vitro, and 16% given three 3.5 mg doses developed antibody. There was an association between degree of local adverse vaccine reaction and immunostimulation, and a trend to immune response in persons of O blood type and with some HLA phenotypes. There was no evidence of deficient response to vaccination in subpopulations known to respond to coccidioidal infection poorly. A regimen of three 1.75 mg doses appears to be safe and without reduced immunogenicity, and there is no evidence dosage modification for certain subpopulations would be necessary in efficacy studies.

A direct comparison of oral treatments with BAY-n-7133, BAY-1-9139 and ketoconazole in experimental murine coccidioidomycosis.

Two new experimental antifungal azole drugs were compared with ketoconazole for the management of experimental murine coccidioidomycosis. The first, BAY-n-7133, a triazole, was superior to the second, BAY-1-9139, an imidazole derivative. Neither BAY drug was as effective as ketoconazole in early fulminant coccidioidomycosis of mice, in later disseminated disease and in deep-seated chronic disease. A possible limitation of BAY-n-7133 in the mouse model was its reported capacity to induce enzyme changes that accelerated its clearance from serum. Induction of such an enzyme response in human beings has been reported not to occur.

Treatment of coccidioidomycosis with ketoconazole: an evaluation utilizing a new scoring system.

The evaluation of the response of patients with coccidioidomycosis to any therapeutic modality is a major challenge. A numerical scoring system was devised to quantitate separately the severity of disease on clinical presentation, the findings on chest film, bone scan, gallium scan, serology and skin test with coccidioidin and spherulin. The scoring system was used to evaluate the response to treatment with ketoconazole of seven patients with infiltrate pulmonary coccidioidomycosis; 20 patients with chronic cavitary coccidioidomycosis; and 40 patients with disseminated coccidioidomycosis. Dissemination included the soft tissue in 15, bone in 15, synovium in 11 and skin in 18. In all categories clinical severity scores improved dramatically. Radiographic scores showed similar improvement in cases of infiltrative pulmonary coccidioidomycosis but showed no change in cavitary coccidioidomycosis. Serology scores improved significantly (-2 or more) in one of seven infiltrative pulmonary cases, three of twenty chronic cavitary cases and twenty-three of forty disseminated cases. Among those with adequate mycology followup, cultures converted to negative in two of three infiltrative pulmonary coccidioidomycosis; seven of fourteen chronic cavitary coccidioidomycosis; and sixteen of twenty-two with disseminated disease. Unfortunately, when ketoconazole was discontinued or interrupted, symptoms recurred in four of twenty (20 percent) with chronic cavitary and ten of forty (25 percent) of disseminated cases. The disease in two patients progressed while on ketonconazole. One of those developed meningitis.

The fantasy residue: an antitherapeutic force on the psychiatric inpatient service.

This paper will attempt a model of organizational behavior to the study of the origin, perpetuation, and rectification of certain antitherapeutic forces (Sacks and Carpenter 1974) on inpatient services, which I shall call the ward's "fantasy residue." The fantasy residue consists of the enduring antitherapeutic patterns of dealing with patients that have become normative for a given ward and evolve from irrational staff responses to a variety of stresses in the absence of appropriate corrective administrative actions. Because they originate in irrational responses to complicated situations of patient management or staff relations, these forces can be called "fantastical." Because they tend to flourish and remain active long after the specific conditions which gave rise to them changed or cease to exist, they are "residual." Hence, the name "fantasy residue." Once established, the fantasy residue can persist either as unacknowledged maladaptive responses in the ward's milieu or as openly espoused, presumedly valid "methods of treatment." In either case, the ward staff an its leaders lose sight of both the irrational base and antitherapeutic consequences of these attitudes and actions. In this sense, a ward's fantasy residue is analogous to a person's ego syntonic character resistances and correction requires a process of confrontation, recognition, and facilitation of objective self-scrutiny among staff and patients.

Pharmacokinetics of ketoconazole in patients with neoplastic diseases.

Twenty-seven patients with advanced malignancies were given 200 mg of ketoconazole orally every 6 or 12 h. Blood samples were collected during these intervals and after the last dose to determine plasma concentrations and half-lives. The mean plasma concentrations measured after the initial dose were 1.7 +/- 1.1 microgram/ml at 2 h, 0.9 +/- 0.2 microgram/ml at 6 h, and 0.7 +/- 0.4 microgram/ml at 8 h. Plasma concentrations rose significantly in patients on the every-6-h schedule. Concentrations were more variable in patients on the every-12-h schedule, and changes in mean plasma concentrations after 7 and 14 days were not significant. Half-lives ranged from 1.3 to 11.6 h in individual patients. The mean half-life for all patients studied was 3.7 +/- 0.6 h on day 1. The calculated area under the curve was 12.0 +/- 4.7 micrograms-h/ml on day 1; it increased after 7 and 14 days of administration (every-6-h schedule), suggesting plasma binding or wide drug distribution or both. Saturation of storage compartments is also suggested. Less than 1% of the administered dose was recoverable as active drug from the urine over 6 h.

Stimulation and suppression of cell-mediated immunity by endosporulation antigens of Coccidioides immitis.

The culture filtrate of Coccidioides immitis induced to replicate in its parasitic phase in vitro, termed endosporulation antigens (EA), was assayed for ability to stimulate human lymphocyte blastogenesis in vitro. Stimulation of lymphocytes from skin test-positive healthy subjects by EA was comparable to stimulation by spherulin at optimal dilutions, but EA are 500 times more potent when compared on the basis of weight. Both preparations slightly stimulated lymphocytes from skin test-negative subjects. Heating or dialysis of EA enhanced the effect on skin test-positive subjects, but concentration depressed it. Concentrated EA also depressed nonspecific stimulation caused by phytohemagglutinin. Dialysis of concentrated EA reduced the ability to depress responses. EA from an avirulent strain of C. immitis were as stimulatory as EA from a virulent strain, but concentrating the former did not produce as much depression as concentrating the latter did. A survey of subjects with an optimal dose of EA in lymphocyte transformation showed that EA could separate skin test-positive from -negative subjects as well as spherulin could. The survey also showed that a delta cpm (the difference of incorporated counts of tritiated thymidine per minute in the presence or absence of the reagent) of 10,000 is useful for this separation. These results also indicate the presence of suppressive substances in EA which are only partially dialyzable and which were significantly more prominent in a preparation from the virulent strain.