Sleep dysfunction following neonatal ischemic seizures are differential by neonatal age of insult as determined by qEEG in a mouse model.

Neonatal seizures associated with hypoxic-ischemic encephalopathy (HIE) pose a challenge in their acute clinical management and are often followed by long-term neurological consequences. We used a newly characterized CD-1 mouse model of neonatal ischemic seizures associated with age-dependent (P7 vs. P10) seizure severity and phenobarbital efficacy (i.e.; PB-resistant vs. PB-efficacious respectively) following unilateral carotid ligation. The long-term consequences following untreated neonatal seizures in P7 vs. P10 ligated pups were investigated using neurobehavioral testing, 24 h v- quantitative EEG -EMG (qEEG, qEMG), and western blot analyses in adult mice. Significant hyperactivity emerged in a small sub-set of mice in both age-groups associated with a failure to habituate during open-field (OF) testing. 24 h continuous qEEGs detected significantly altered sleep architecture due to long-wake cycles in both age-groups. Delta power (0.5-4 Hz) quantification during slow-wave-sleep (SWS) revealed significant SWS compensation in P10 ligates following periods of increased sleep pressure which the P7 ligate group failed to show. Theta/beta ratios deemed as negative correlation markers of attentional control were significantly higher only in the P10 ligates. These results indicate that neonatal age-dependent differences in the characteristics of ischemic neonatal seizures in CD-1 pups differentially modulate long-term outcomes, when evaluated with v-qEEG/EMG as adults.

The molecular basis of the human serum paraoxonase activity polymorphism.

The organophosphate cholinesterase inhibitor paraoxon is hydrolysed by serum paraoxonase/arylesterase. A genetic polymorphism of paraoxonase (PON) activity which determines high versus low paraoxon hydrolysis in human populations, may determine sensitivity to parathion poisoning. We demonstrate that arginine at position 192 specifies high activity PON whereas a glutamine specifies the low activity variant. Allele-specific probes or restriction enzyme analysis of amplified DNA allow for the genotyping of individuals. PON maps to chromosome 7q21-22, proximal to the cystic fibrosis gene, in agreement with previous genetic linkage studies.

Different chromosomal localization of the Clcn4 gene in Mus spretus and C57BL/6J mice.

We report the unprecedented finding of a gene with a different map position in two mouse strains. The Clcn4 gene was found to map to the X chromosome in the wild Mediterrean mouse, Mus spretus but to chromosome 7 in the inbred strain of laboratory mouse C57BL/6J. These data indicate that a recent evolutionary rearrangement occurred on the mouse sex chromosomes, very close to the pseudoautosomal region. Our data provide molecular evidence for a major divergence near the pseudoautosomal region, consistent with the hypothesis that hybrid sterility in these species results from abnormal pairing of sex chromosomes during male meiosis.

The human pseudoautosomal GM-CSF receptor alpha subunit gene is autosomal in mouse.

The gene encoding the granulocyte macrophage colony stimulating factor receptor alpha subunit (CSF2RA) has previously been mapped to the pseudoautosomal region of the human sex chromosomes. In contrast, we report that the murine locus, Csf2ra, maps to an autosome in the laboratory mouse. By in situ hybridization and genetic mapping, Csf2ra maps at telomeric band D2 of mouse chromosome 19. This first instance of a pseudoautosomal locus in human being autosomal in mouse, indicates incomplete conservation between the human and mouse X chromosomes and suggests that the genetic content of the pseudoautosomal region may differ between species of eutherian mammals due to chromosomal rearrangements.

Diagnostic Accuracy of the Primary Care Screener for Affective Disorder (PC-SAD) in Primary Care.

BACKGROUND: Depression goes often unrecognised and untreated in non-psychiatric medical settings. Screening has recently gained acceptance as a first step towards improving depression recognition and management. The Primary Care Screener for Affective Disorders (PC-SAD) is a self-administered questionnaire to screen for Major Depressive Disorder (MDD) and Dysthymic Disorder (Dys) which has a sophisticated scoring algorithm that confers several advantages. This study tested its performance against a 'gold standard' diagnostic interview in primary care. METHODS: A total of 416 adults attending 13 urban general internal medicine primary care practices completed the PC-SAD. Of 409 who returned a valid PC-SAD, all those scoring positive (N=151) and a random sample (N=106) of those scoring negative were selected for a 3-month telephone follow-up assessment including the administration of the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) by a psychiatrist who was masked to PC-SAD results. RESULTS: Most selected patients (N=212) took part in the follow-up assessment. After adjustment for partial verification bias the sensitivity, specificity, positive and negative predictive value for MDD were 90%, 83%, 51%, and 98%. For Dys, the corresponding figures were 78%, 79%, 8%, and 88%. CONCLUSIONS: While some study limitations suggest caution in interpreting our results, this study corroborated the diagnostic validity of the PC-SAD, although the low PPV may limit its usefulness with regard to Dys. Given its good psychometric properties and the short average administration time, the PC-SAD might be the screening instrument of choice in settings where the technology for computer automated scoring is available.

Development and preliminary validation of the PC-SAD5, a screener-derived short depression severity measure.

BACKGROUND: The prevalence of depressive disorders is high among patients with skin disease. The PC-SAD is a 37-item self-administered depression screening questionnaire that has been validated in dermatological patients. OBJECTIVE: The aim of this study was to develop and validate a brief depression severity instrument derived from the PC-SAD that can be used to assess severity and monitor ongoing clinical course. METHODS: Two patient samples participated in the study: 72 adult dermatological inpatients and 73 adults attending six primary care practices. Psychiatric assessment included the Structured Clinical Interview for DSM-IV and an 18-item version of the PC-SAD; moreover, dermatological patients completed the Patient Health Questionnaire depression scale (PHQ-9), while primary care patients were administered the Montgomery-Asberg Depression Rating Scale (MADRS). A subset of five PC-SAD items showing the best psychometric properties were selected, and the reliability and validity of the resulting instrument (PC-SAD5) were examined. RESULTS: The PC-SAD5 showed satisfactory internal consistency in both samples. There was a high correlation between PC-SAD5 and PHQ-9 and MADRS scores. Multiple regression analysis revealed a gradient of PC-SAD5 scores from patients with no mental disorder, those with milder forms of depression, to those with Major Depressive Disorder. Similar results were observed for the 18-item version of the PC-SAD. CONCLUSION: The availability of valid and reliable continuous measures of depression severity derived from the PC-SAD extends its field of application from depression screening to use as a follow-up measure of depression severity in routine clinical practice. A validated very short instrument such as the PC-SAD5 may have substantial clinical value.

Isolation and chromosomal localization of cDNAs encoding a novel human lymphocyte cell surface molecule, LAM-1. Homology with the mouse lymphocyte homing receptor and other human adhesion proteins.

A cDNA encoding a new human lymphocyte cell surface molecule has been isolated and shown to identify a fourth member of a recently discovered family of adhesion proteins. This lymphocyte-associated molecule (LAM-1) is uniquely composed of multiple distinct domains, one domain homologous with animal lectins, one homologous with epidermal growth factor, and two short consensus repeat units similar to those found in C3/C4 binding proteins. This cDNA clone hybridized with RNAs found in B cell lines and T lymphocytes, but not with RNA from other cell types. The amino acid sequence of LAM-1 is 77% homologous with the sequence of the mouse lymphocyte homing receptor, suggesting that LAM-1 may function in human lymphocyte adhesion. The LAM-1 gene is located on chromosome 1q23-25, as is another member of this adhesion family, suggesting that this new family of proteins may be encoded by a cluster of "adhesion protein" loci.

Rescue of PB-resistant neonatal seizures with single-dose of small-molecule TrkB antagonist show long-term benefits.

A recently characterized CD-1 mouse model of phenobarbital (PB)-resistant neonatal ischemic-seizures (i.e.; unilateral carotid ligation) was shown to be associated with age-dependent (P7 vs. P10) acute seizure severity and PB-efficacy (i.e.; PB-resistant vs. PB-responsive). ANA12, a novel small-molecule TrkB antagonist, rescued the PB-resistance at P7 in a dose-dependent manner and prevented the post-ischemic downregulation of KCC2, the chief Cl- extruder in neurons. The long-term consequences of this novel rescue-intervention with ANA12 + PB in P7 and P10 ligated pups was investigated and compared to the standard first-line protocol of PB-alone loading dose. The mice underwent neurobehavioral testing, 24 h video-EEG-EMG monitoring, and immunohistochemistry in ipsi- and contralateral cortices as adults following the neonatal interventions. ANA12 + PB rescued the emergence of hyperactivity in post-ischemic P7, but not in P10 pups as adults. ANA12 + PB administration at neither P7 nor P10 significantly altered 24 h macro-sleep architecture in adults when compared to PB-alone. Behavioral state-dependent gamma (35-50 Hz) power homeostasis showed the most significant between-group differences that were age-dependent. ANA12 + PB treatment, but not PB-alone, rescued the loss of gamma power homeostasis present in P7 ligate-control but absent in P10 ligate group, highlighting the age-dependence. In contrast, PB-alone treatment, but not ANA12+PB, significantly reduced the elevated delta-AUC observed in P10 ligate-controls, when PB is efficacious by itself. These results indicate that the rescue of acute PB-resistant neonatal seizures using a novel intervention positively modulates the long-term outcomes at P7 when the seizures are refractory.

The impact of national health insurance on the tasks and practice of psychiatry.

Psychiatry, like all professions, is strongly affected by changes in societal expectations and economic forces. Changes in professional priorities and patterns of patient care will undoubtedly be brought about by national health insurance. Two major types of national health insurance have been proposed: comprehensive health insurance and catastrophic insurance. We do not anticipate major impact on psychiatric tasks from some form of catastrophic insurance. Comprehensive health insurance would shape and change psychiatric practice. An examination of psychiatric tasks provides a framework for anticipating alterations in practice. We identify four major task areas in psychiatry: (1) medical tasks, (2) reparative tasks, (3) social control tasks, and (4) humanistic tasks. These tasks would be differentially influenced. Psychiatry's medical tasks will be stressed, while funding for many reparative tasks may be limited. The care of the severely ill patient may be fragmented because of problems in integrating medical and rehabilitative services.

The concept of prevention in psychiatry: a reexamination.

We examine current concepts of prevention and offer a new approach. Prevention has different meanings and functions in the four major task areas of psychiatry: (1) medical tasks, (2) rehabilitative tasks, (3) social control tasks, and (4) humanistic tasks. Constructs of primary and secondary prevention are most useful in the medical task area. However, efforts at primary prevention of mental illness can have only limited effectiveness when we know so little about etiology. Secondary prevention is central to the medical caring tasks, where early diagnosis and treatment may lead to successful outcome. Tertiary prevention of disease and primary prevention of developmental defect are the work of the rehabilitative task area. The application of models of prevention in the social control and humanistic task areas has led to serious confusion.

Chromosomal mapping and expression levels of a mouse soluble epoxide hydrolase gene.

The chromosomal location of a murine soluble epoxide hydrolase gene was determined using in situ mapping, restriction fragment length polymorphism (RFLP) and simple sequence length polymorphism (SSLP) analysis. In situ hybridization to mouse metaphase chromosomes using a soluble epoxide hydrolase cDNA probe showed that soluble epoxide hydrolase maps at band D of chromosome 14. An RFLP found between Mus castaneus (CAST) and Mus musculus (MEV) was used to map the soluble epoxide hydrolase gene in CAST x MEV intersubspecific testcross progeny to 14 cM from the Np-1 locus on mouse chromosome 14. SSLP markers were then used to confirm the location of soluble epoxide hydrolase at 14.0 +/- 3.7 cM distal to Np-1 and 19.2 +/- 4.3 cM proximal to D14Mit7. This region of mouse chromosome 14 is homologous with human chromosomes 8, 13 and 14. Enzyme assays and immunoblotting results suggest significant quantitative differences in expression of soluble epoxide hydrolase among three mouse strains. Northern blotting analysis showed that soluble epoxide hydrolase mRNA levels were correlated with the relative level of soluble epoxide hydrolase enzyme activity and soluble epoxide hydrolase protein in all three mouse strains.

Human and rabbit paraoxonases: purification, cloning, sequencing, mapping and role of polymorphism in organophosphate detoxification.

Human and rabbit paraoxonases/arylesterases were purified to homogeneity by chromatographic and gel electrophoretic/isofocusing procedures coupled with activity stains. N-terminal and peptide sequence analysis suggested retention of the secretion signal sequence and allowed design of oligonucleotide probes. The probes were used to isolate a 1294-bp rabbit paraoxonase cDNA clone, which, in turn, was used to isolate three human cDNA clones. Comparison of rabbit and human protein and cDNA sequences indicated a high degree of sequence conservation (approximately 85% identity) and verified that paraoxonase retains its signal sequence (except for the N-terminal Met). The rabbit cDNA encodes a protein of 359 amino acids and the human a protein of 355 amino acids. In situ hybridization demonstrated, as expected, that the paraoxonase gene maps to the long arm of human chromosome 7. Arginine at position 192 specifies high activity paraoxonase and glutamine low activity human paraoxonase. Variation in protein levels explains the variation of enzyme activity observed within a genetic class. Toxicity studies showed that raising rat plasma paraoxonase levels by i.v. administration of partially purified rabbit paraoxonase protected animals against cholinesterase inhibition by paraoxon and chlorpyrifos oxon. Protection correlated with the relative rates of hydrolysis of these two compounds.

Issues encountered in an attempt to implement a second-generation management information system.

Human service organization are beset by internal and external requests for information. As the scale and complexity of such delivery systems has increased, the use of computer-based information systems has become a necessity. The evolution of a client information system in a large, decentralized mental health center is reviewed in this paper to illustrate several critical issues that can be encountered in the application of computer-based technology to human services. An analysis of the center's existing information system and the development of the data forms and procedures necessary for a second-generation system to meet information needs revealed the unique data structure and analysis problems of human service delivery systems. These problems were complicated by regulatory agencies' imposition of external reporting requirements that frequently were unpredictable and inconsistent. Finally, planning and negotiations with the participation of all involved parties demonstrated that formal and informal administrative constraints and conflicting interests within human service organizations must be accommodated or a system may fail. All of these factors combine to highlight both the problems and the need for highly flexible multipurpose information systems.

Patient-based health status assessments in an outpatient psychiatry setting.

OBJECTIVE: The reliability, validity, and feasibility of the routine use of a generic health status instrument, the Short-Form-36 Health Survey (SF-36), were examined in a psychiatric outpatient clinic of a general hospital. METHODS: The sample comprised 411 patients referred to an outpatient psychiatry department between April 1994 and March 1995. They filled out the SF-36 along with their admission forms. Scores and reports were generated, and the results were returned to the charts and used at weekly clinical conference discussions. Feasibility was evaluated using subjective and objective data on administration of the instrument, its psychometric properties, and costs. Results from the outpatient psychiatry patients were compared with those from patients scheduled for elective surgery and a healthy normative sample. RESULTS: Routine administration of the SF-36 was successfully achieved with minimal resistance from staff and patients. The SF-36 provided reliable and valid data. As predicted, patients with emotional disorders scored lower, indicating more impairment, on scales measuring mental health than did the elective surgery patients and the normative sample. However, the psychiatric patients' scores on the physical health scale were lower than clinicians expected. Compared with the elective surgery patients, the psychiatric patients were less impaired on only the physical functioning and bodily pain scales; no difference was found between the two groups in role functioning due to physical problems. CONCLUSIONS: Routine use of the SF-36 in a general hospital psychiatric outpatient clinic was feasible, and the results were reliable, valid, and helpful to clinicians. Psychiatric patients' significantly lower scores in physical health and social and role functioning provided additional information about their difficulties.

A framework for the analysis of theoretical and therapeutic approaches to schizophrenia.

IN previous work we have begun to articulate a conception of psychiatry as a profession and to show how this conception may be useful in examining specific controversial issues such as national health insurance and the concept of prevention in psychiatry (Astrachan, Levinson, and Adler 1976; Adler, Levinson, and Astrachan 1978). We define a profession not in terms of its varied theories or forms of practice, but in terms of the major tasks it must perform and the perspectives it takes regarding these tasks. Historically, psychiatry has been committed to four major tasks. These interconnected tasks have been sanctioned by society, and all must be addressed if psychiatry is to retain its credibility and legitimacy. In practice, the tasks frequently are intertwined, yet they are conceptually distinct. In the present paper, we use this conception of psychiatry as a framework for the analysis of the many approaches that have been taken to the understanding and treatment of schizophrenia. Each task is defined in terms of a problematic condition to be controlled or eliminated: illness, defect, deviance, impeded growth. The rationale for work on each task is given by a corresponding theoretical perspective. There is marked disagreement, and often bitter controversy, about the validity of different theories, the value of different treatments, and even the legitimacy of various approaches. Let it be clear, then, that our goal is not to evaluate specific concepts and techniques, nor to argue that one task or perspective is more legitimate than any other. Our goal, rather, is to clarify the nature of the disagreement and to present a comprehensive framework within which different approaches to schizophrenia can be understood and compared and then reconnected in practice.

Perspectives on rehabilitative and educative-developmental psychotherapy.

Two approaches to psychotherapy from two different perspectives are explored: the rehabilitative and the educative-developmental. The goals of treatment, the therapist/patient role relationship and treatment techniques are delineated and illustrated by use of case material. Whether the focus is on self-image, specific learning, social interpersonal deficits, or on a spectrum of maturational arrests, if the focus of treatment is on disturbed functioning with the goals of reducing the impact of the defect than the work is more often rehabilitative than educative-developmental. A wide range of psychotherapeutic activities can be rehabilitative in nature whether the techniques used are exploratory or supportive. If the focus is on self-exploration with the goals of self-understanding leading to conflict resolution then the work is educative-developmental in nature. The significant differences between a therapeutic relationship based on an impairment model and an educative one are delineated. Other differences in approach between these two perspectives are also discussed.

Circadian cycle-dependent EEG biomarkers of pathogenicity in adult mice following prenatal exposure to in utero inflammation.

Intrauterine infection or inflammation in preterm neonates is a known risk for adverse neurological outcomes, including cognitive, motor and behavioral disabilities. Our previous data suggest that there is acute fetal brain inflammation in a mouse model of intrauterine exposure to lipopolysaccharides (LPS). We hypothesized that the in utero inflammation induced by LPS produces long-term electroencephalogram (EEG) biomarkers of neurodegeneration in the exposed mice that could be determined by using continuous quantitative video/EEG/electromyogram (EMG) analyses. A single LPS injection at E17 was performed in pregnant CD1 dams. Control dams were injected with same volumes of saline (LPS n=10, Control n=8). At postnatal age of P90-100, 24-h synchronous video/EEG/EMG recordings were done using a tethered recording system and implanted subdural electrodes. Behavioral state scoring was performed blind to treatment group, on each 10s EEG epoch using synchronous video, EMG and EEG trace signatures to generate individual hypnograms. Automated EEG power spectrums were analyzed for delta and theta-beta power ratios during wake vs. sleep cycles. Both control and LPS hypnograms showed an ultradian wake/sleep cycling. Since rodents are nocturnal animals, control mice showed the expected diurnal variation with significantly longer time spent in wake states during the dark cycle phase. In contrast, the LPS-treated mice lost this circadian rhythm. Sleep microstructure also showed significant alteration in the LPS mice specifically during the dark cycle, caused by significantly longer average non-rapid eye movement (NREM) cycle durations. No significance was found between treatment groups for the delta power data; however, significant activity-dependent changes in theta-beta power ratios seen in controls were absent in the LPS-exposed mice. In conclusion, exposure to in utero inflammation in CD1 mice resulted in significantly altered sleep architecture as adults that were circadian cycle and activity state dependent.

A framework for the analysis of psychotherapeutic approaches to schizophrenia.

A conceptual framework is articulated which clarifies the importance of psychotherapy as part of the treatment armamentarium in working with individuals carrying schizophrenic diagnoses. The author looks at the goals and appropriate role relationships for understanding and treating schizophrenic individuals from multiple psychotherapeutic perspectives. The goal is to present an overview within which different psychotherapeutic approaches to schizophrenia can be understood and compared and then reconnected in actual practice.

Personality disorders: theory and psychotherapy.

A framework for the psychotherapeutic treatment of individuals with personality disorders is presented utilizing psychodynamic concepts. The therapeutic process is illustrated by clinical examples that show how the issue of interactive fit applies to each phase of treatment.