Schizophrenia: how should we look at it?
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Antipsychotic Agents↗
Biomedical subjects
A L Miller
Publications and source records attributed to A L Miller.
64-year-old woman with chronic epigastric pain.
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Abdominal Pain↗
A comparison of instrument sensitivity to negative symptom change.
Accurate assessment of negative symptom changes in schizophrenic patients is crucial to determining the efficacy of new treatments. The present study examined the sensitivity to change over the course of hospitalization in negative symptomatology assessed by the Scale for the Assessment of Negative Symptoms (SANS), the Negative Symptom Assessment (NSA), and an expanded version of the Brief Psychiatric Rating Scale (BPRS) in a sample of 60 schizophrenic patients. Symptoms were assessed when the patients were acutely ill and again when they were stabilized. Effect sizes were compared across all three rating scales. The retardation factor of the BPRS had a relatively small effect size (0.32). Effect size for the total NSA was 0.78 and ranged from 0.38 to 0.87 for the SANS. Individual factors had moderate to large effect sizes that ranged from 0.18 to 0.91 for both scales. Separate analyses were performed to calculate effect sizes for a five-factor version of the NSA and to examine only those symptoms specified in DSM-IV (alogia, affective flattening, and avolition). Effect sizes relatively comparable to those found for the entire SANS and NSA scales were found for the separate calculations. Results indicate that the addition of a negative symptom assessment instrument to research protocols increases the ability to detect changes in negative symptoms with substantially fewer subjects than would be required with the BPRS retardation factor alone.
Adult↗
Structure and location of the murine adrenoleukodystrophy gene.
X-linked adrenoleukodystrophy (ALD) is a degenerative neurological disease characterized by the accumulation of very long chain fatty acids in various tissues and demyelination of the central nervous system. The human gene responsible for the disease encodes a membrane-bound ATP-binding transporter protein that is located in peroxisomes. We isolated the mouse adrenoleukodystrophy gene, determined its structure, and mapped it both cytogenetically and genetically. The mouse gene is very similar in structure to the human gene, consisting of 10 exons arranged over a 22-kb genomic region. We localized it in band B of the mouse X chromosome by fluorescence in situ hybridization analysis and, using a new microsatellite repeat polymorphism, determined the map location as 47 cM from the X centromere. We found evidence for other sequences in the mouse genome related to the 3' end of Aldgh. This study paves the way for the construction of gene-targeting plasmids that may be used to develop an animal model of ALD.
ATP Binding Cassette Transporter, Subfamily D, Mem↗
Purification and characterization of human lymphoblast N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase.
The enzyme N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase (EC 3.1.4.45; uncovering enzyme) catalyzed the removal of N-acetylglucosamine from the N-acetylglucosamine-alpha-phospho-mannose portion of selected lysosomal enzyme oligosaccharide chains, thereby forming the mannose 6-phosphate signal which is responsible for the targeting of these lysosomal enzymes for transport into lysosomes. The uncovering enzyme has been purified approximately 7000-fold to electrophoretic homogeneity from Epstein-Barr virus-transformed human lymphoblast cells. The purification sequence involves solubilizing this membrane-bound enzyme with Tergitol NP-10, affinity chromatography on Lentil lectin-Sepharose 4B, ion-exchange chromatography on DEAE-Sephacel, chromatography on zinc(II)-IDA-Sepharose 6B, and preparative SDS-PAGE electrophoresis. The purified enzyme migrated as a single band of 114 kDa which was coincident with enzyme activity on analytical SDS-PAGE electrophoresis. Characterization studies of the purified enzyme demonstrated that catalytic activity was maximal at pH 6.95 and that the enzyme retained full activity following incubation for 10 min at 60 degrees C. No requirement was found for a divalent cation, but Zn2+, Hg2+, and Cu2+ were found to reduce the enzyme's activity by 30-40%. The highest catalytic efficiency was observed with N-acetylglucosamine-phospho-methylmannoside as a substrate while uridine diphosphate-N-acetylglucosamine, N-acetylglucosamine-phosphomannose-uteroferrin, and N-acetylglucosamine-phosphate were also cleaved by the enzyme with decreasing efficiency. Acetamino-deoxycastanospermine was a potent inhibitor of the human enzyme with a Ki of 0.35 microM, while N-acetylglucosamine phosphate (Ki 1.58 mM) and N-acetylglucosamine (Ki 5.1 mM) inhibited the enzyme to a lesser degree.
Chromatography, Affinity↗
The relationship between parental communication deviance and relapse in schizophrenic patients in the 1-year period after hospital discharge. A pilot study.
The present pilot study examined the ability of parental communication deviance (CD) to predict relapse in schizophrenic patients in the 1-year period after hospital discharge. Measures of CD were obtained from verbatim transcripts of family problem-solving discussions for 20 schizophrenic patients and their parents at an initial assessment and before the patients' hospital discharge. Relapse was assessed using the Brief Psychiatric Rating Scale at 3-month intervals after discharge. Findings indicated that parental CD measured at an assessment immediately before the patient's release from the hospital was moderately correlated (r = .49, p < .05) with relapse in the 1-year follow-up period. Results are discussed with respect to the possible role of parental CD as an environmental stressor in the period after discharge. Potential contributors to parental CD, including genetically transmitted cognitive deficits and stress resulting from resuming the care-giver role, are also discussed.
Adult↗
Serum levels of the soluble low affinity receptor for IgE and soluble interleukin-2 receptor in childhood, and their relation to age, gender, atopy and allergic disease.
Identifying immune factors associated with the development of atopy can enhance our understanding of the in vivo mechanisms involved and may have utility in paradigms designed to prevent disease. Two candidates suggested for such roles are the soluble low affinity receptor for IgE (sCD23) and the soluble interleukin-2 receptor (sCD25). To assess serum levels of these factors blood samples were collected at birth and at age 6 in a large nonselected population from Tucson, AZ. Log mean sCD23 and sCD25 levels decreased from birth to age 6, (for sCD23 0.60 ffi 0.26pg/l, n = 340 and 0.53 + 0.28pg/l, n = 333 and for sCD25 1.95 i 0.14pM, n = 304 and 1.86 ffi 0.20pM, n = 327, for the two ages respectively. Anglo children had lower sCD23 levels at birth compared to Hispanic children (p < 0.01); no effect of gender was observed. Skin test reactivity at age 6 was directly related to sCD25 levels at age 6 (p = 0.007) and even levels at birth showed a similar trend (p = 0.06). These relations were distinct from any relation to total serum IgE. No relation was observed with sCD23 levels for either skin test reactivity or serum IgE. The prevalences of asthma, rhinitis and eczema by age 6 were unrelated to sCD25 or sCD23 levels. The results indicate that soluble CD23 and CD25 have higher levels at birth than later in childhood and that the development of skin test reactivity may be associated with regulatory mechanisms involving sCD25, whereas sCD23 was not similarly implicated.
Age Factors↗
Analysis of the calcium transient at NEB during the first cell cycle in dividing sea urchin eggs.
Accumulating evidence from several systems suggests that nuclear envelope breakdown (NEB) is triggered by an endogenous transient of free calcium. Using h- and f-semisynthetic aequorins as cytosolic calcium indicators, we have clearly and regularly visualized a single large, global calcium transient just before first NEB in normally developing, monospermic Lytechinus eggs. Although similar transients were not observed at NEB in subsequent cell cycles, microinjection of the calcium buffer BAPTA into one blastomere of the two-celled embryo resulted in the inhibition of NEB. The NEB transient in the first cell cycle was some five-fold smaller than the one associated with egg activation. Our data suggest that this transient takes the form of a calcium wave that spreads inwards from the periphery of the egg toward the nucleus. We confirmed that these NEB transients did not require extracellular Ca2+. In polyspermic eggs, NEB-associated transients were four-fold larger than in monospermic eggs and were periodically repeated. Examination of the distribution of fluorescein-conjugated aequorins with a laser scanning confocal microscope indicated that aequorin both enters the nucleus and is evenly distributed within the cytosol of the egg. The use of h- and f-aequorins did not reveal any NEB transients during subsequent cell cycles, nor did we detect transients associated with other cell cycle events. However, a complex train of calcium transients in the form of both localized pulses and propagated waves was detected from embryos beginning at about the morula-to-blastula transition and continuing through to hatching.
Aequorin↗
Negative symptoms of schizophrenia: where do we go from here?
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Depression↗
Propagated and nonpropagated calcium transients during egg activation in the annelid, Chaetopterus.
Transient waves of Ca2+ release cross-fertilizing deuterostome eggs from the point of sperm entry to its antipode and provide much of the activating stimulus for the egg. Based on several indirect lines of experimental evidence, it was proposed that protostome eggs are activated by a prolonged uptake of Ca2+ from the medium due to sperm-induced membrane depolarization and that this uptake then starts an activation wave similar to those in deuterostomes, except that it moves inward from the whole surface rather than through the egg from pole to pole. To test these hypotheses, we microinjected oocytes of the polychaete annelid, Chaetopterus pergamentaceus, with semisynthetic recombinant aequorins and measured light emission in response to both fertilization and artificial activation by excess K+. Both fertilization and K(+)-activation induced multiple, brief Ca2+ transients in the eggs. The first transient did not propagate, but it was followed by a series of globally propagated Ca2+ waves interspersed with additional nonpropagated pulses. The waves traversed the egg at about 30 micrometer/sec. Sequential propagated waves and nonpropagated pulses generally originated at different regions of the egg surface, except the last few, which originated in the same "pacemaker" region. These new data are consistent with the hypothesis that the activation of protostome eggs is initiated by Ca2+ waves. However, the fact that these waves propagated from pole to pole like those in deuterostome eggs refutes the notion that Ca2+ waves in activating protostome eggs move inward from the whole surface.
Animals↗
Psychological stress and immunological responsiveness in normally cycling, follicular-stage women.
Nineteen women in the follicular stage of their menstrual cycles were assessed for immunological responsiveness to a 50-min series of three psychological tasks which reliably elicit cardiovascular and neuroendocrine stress responses. Ten follicular-stage women not subjected to stress served as controls. Stress decreased lymphocyte responsiveness to PHA and PWM, percent of CD4+ cells and the ratio of CD4+/CD8+ cells. Conversely, stress increased natural killer cell number and cytolytic activity, white blood cell, lymphocyte, T and B cell count. Except for natural killer cell number, none of these changes was exhibited by controls. Most of these stress responses are similar to those reported for men and form the basis for a continuing study of the effects of reproductive hormones and stress on cardiovascular and immunological function in women.
Adult↗
Effects of electrode configuration on threshold functions for electrical stimulation of the cochlea.
Psychophysical detection threshold vs frequency functions for sinusoidal electrical stimulation of the deafened cochlea were measured in 18 nonhuman primate subjects. Functions for monopolar or widely-spaced ( > 2.5 mm) bipolar stimulation were lower and usually had steeper slopes than those for more narrowly-spaced ( < 2.0 mm) bipolar stimulation. In 56% of the cases the difference between thresholds for narrowly-spaced bipolar of monopolar stimulation was greater for low frequency stimuli (63 or 100 Hz) than for high frequency stimuli (800 or 1,000 Hz) by 5 dB or more. Two cases were compared in more detail using pulsatile stimuli. For sinusoidal stimuli, one of these cases showed a moderate frequency dependent effect of electrode configuration and the other did not. The case with the frequency dependent effect of electrode configuration for sinusoids also showed a phase-duration dependent effect of electrode configuration for detection of single biphasic pulses: strength-duration curves (detection threshold in decibels vs pulse duration in ms/phase) were steeper for monopolar stimulation than for narrowly-spaced (0.7 mm) bipolar stimulation. This effect was not seen in the case that showed little or no frequency dependence in the effect of electrode configuration for sinusoidal stimuli. Slopes of threshold vs pulse rate functions where pulse duration was held constant at 2 ms/phase were not affected by electrode configuration in either subject.
Animal Welfare↗
Longitudinal analysis of communication deviance in the families of schizophrenic patients.
Considerable research on the family's contribution to the psychopathology and coping of mentally ill offspring has focused on disturbed parental communication patterns, in which parents are unable to share a common focus of attention and meaning with their children. This style of communication has been referred to as communication deviance (CD - Wynne and Singer 1963). Specifically, CD refers to instances in which speakers leave ideas incomplete, use language in an odd manner, use unclear referents, contradict previously made statements with little explanation, or make unintelligible or tangential statements.
Adult↗
Schizophrenia among Hispanics: epidemiology, phenomenology, course, and outcome.
A number of studies point to the influence of culture and ethnicity on the presentation and course of schizophrenia. In general, a relatively powerful influence of environmental factors is identified. This article reviews the literature on schizophrenia among Hispanics in the United States and uses the results of this review as a basis for identifying directions for future study. Research is divided into three major areas: epidemiology, phenomenology, and illness course and outcome. Ethnic comparisons suggest similar prevalence rates of schizophrenia. However, differences in illness phenomenology between certain subgroups of Hispanics are also observed. Moreover, culture can affect various aspects of the illness process, including illness definition, help- seeking behavior, response to treatment, and post-treatment adjustment. Proposed guidelines to direct future research ventures include (1) better delineation of the sociocultural attributes of the group under study, (2) validation of assessment instruments across ethnic groups, (3) use of innovative approaches to assess incidence and prevalence, (4) incorporation of qualitative methodology, (5) use of illness behavior models to provide a conceptual framework to guide investigations, and (6) integration of cross-cultural and biological studies.
Cross-Cultural Comparison↗
Clonidine plus haloperidol in the treatment of schizophrenia/psychosis.
Because of the evidence for increased norepinephrine (NE) production in psychotic patients, we studied the effects of combining the alpha 2-adrenergic agonist clonidine with haloperidol for the treatment of schizophrenic psychosis. Twelve hospitalized schizophrenic patients were taken off their antipsychotic medication for 2 to 4 weeks before double-blind treatment with haloperidol (20 mg/day) combined with either clonidine or placebo. The group receiving clonidine was significantly more improved on the thought disorder subscale of the Brief Psychiatric Rating Scale (p = 0.02). The groups differed initially in the level of negative symptoms, but not controlling for this difference statistically by analysis of covariance did not change the finding with regard to the superiority of combining clonidine with haloperidol. We conclude that larger treatment trials of combining haloperidol with clonidine are warranted.
Adrenergic alpha-Agonists↗
Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status.
OBJECTIVE: Interleukin-2, traditionally viewed as solely involved in immunological events, has recently been shown to exert profound effects on the development and regulation of the central nervous system. This study examined the relationships between interleukin-2 in the CSF and plasma of schizophrenic patients and clinical measures, including relapse and medication status. Plasma and CSF interleukin-1 alpha levels were also measured to ascertain the specificity of changes in cytokine levels. METHODS: Seventy-nine physically healthy male patients with schizophrenia (DSM-III-R) received diagnostic evaluation and behavioral ratings. Haloperidol treatment was withdrawn for up to 6 weeks and patients were evaluated for symptom recurrence. CSF and plasma were obtained by established procedures before haloperidol withdrawal (N = 79) and after (N = 64). RESULTS: CSF levels of interleukin-1 alpha decreased significantly after haloperidol withdrawal but showed no relation to clinical status. In contrast, levels of CSF interleukin-2 were associated with recurrence of psychotic symptoms. Relapse-prone patients, examined both while medicated and after drug withdrawal, had significantly higher levels of CSF interleukin-2 than patients who did not relapse. CSF interleukin-2 level during haloperidol treatment was a significant predictor of worsening in psychosis. CONCLUSIONS: Levels of interleukin-2, a molecule that plays both neurodevelopmental and neuroregulatory roles, may have a role in relapse in schizophrenia. Levels of CSF interleukin-2 appear to be affected by relapse mechanisms, while peripheral blood levels are not. These changes are specific to interleukin-2, since levels of interleukin-1 alpha were affected by medication withdrawal but not by change in clinical state.
Adult↗
Patterns of free calcium in multicellular stages of Dictyostelium expressing jellyfish apoaequorin.
To examine the patterns of high free cytosolic calcium or [Ca2+]i during Dictyostelium's development, we expressed apoaequorin in D. discoideum, reconstituted aequorin and observed the resultant patterns of calcium-dependent luminescence. Specific, high calcium zones are seen throughout normal multicellular development and are roughly coincident with those regions that later differentiate into stalk or stalk-like cells. A slug, for example, shows a primary high calcium zone within its front quarter and a secondary one around its tail; while a mound shows such a zone around the periphery of its base. Combined with previous evidence, our findings support the hypothesis that high [Ca2+]i feeds back to favor the stalk pathway. We also discovered several high calcium zones within the mound's base that do not coincide with any known prepatterns in D. discoideum. These include two, relatively persistent, antipodal strips along the mound's periphery. These various persistent zones of high calcium are largely made up of frequent, 10 to 30 second long, semiperiodic calcium spikes. Each of these spikes generates a correspondingly short-lived, 200 to 500 microns long, high calcium band which extends along the nearby surface. Similar, but relatively large and infrequent, spikes generate cross bands which extend across migrating slugs and just behind their advancing tips as well as across the peripheries of rotating mounds and midway between their antipodal strips. Moreover, calcium has a doubling time of about a second as various spikes rise. This last observation suggests that the calcium bands seen in Dictyostelium may be generated by so-called fast calcium waves.
Aequorin↗
Effects of electrical current configuration on stimulus detection.
Psychophysical detection of electrical stimulation of the cochlea was studied as a function of electrical-current configuration. Subjects were postlingually deaf humans with Nucleus 20 + 2, Nucleus 22, and Ineraid cochlear implants and nonhuman primates unilaterally deafened and implanted with a multielectrode array similar to the Nucleus implant. In nonhuman primate and human Ineraid subjects, which had percutaneous connectors, we compared threshold functions for sinusoids and pulse trains for quadrupolar, bipolar, monopolar, and parallel multipolar stimulation. Thresholds decreased across this set of configurations. In some cases, the effects of current configuration were dependent on sinusoidal frequency and pulse duration. Pulse duration-dependent effects were also seen when comparing bipolar, monopolar, and common-ground configurations. Bipolar and monopolar stimulation were compared in Nucleus subjects using pulse trains at 50 microseconds per phase. For bipolar stimulation, thresholds decreased as a function of electrode separation, reaching a level near that for monopolar stimulation at separations of 3.5 to 6.5 mm in most cases. These results may be interpreted in terms of effects of current configuration on the magnitude and shape of electrical-potential fields produced in the cochlea, although more central factors also play a role in determining psychophysical detection thresholds.
Animals↗