Client Socio-Demographic and Service Receipt Inventory--European Version: development of an instrument for international research. EPSILON Study 5. European Psychiatric Services: Inputs Linked to Outcome Domains and Needs.

BACKGROUND: Cross-cultural comparison of mental health service utilisation and costs is complicated by the heterogeneity of service systems. For data to be locally meaningful yet internationally comparable, a carefully constructed approach to its collection is required. AIMS: To develop a research method and instrument for the collection of data on the service utilisation and related characteristics of people with mental disorders, as the basis for calculating the costs of care. METHOD: Various approaches to the collection of service use data and key stages of instrument development were identified in order to select the most appropriate methods. RESULTS: Based on previous work, and following translation and cross-cultural validation, an instrument was developed: the Client Socio-Demographic and Service Receipt Inventory--European Version (CSSRI-EU). This was subsequently administered to 404 people with schizophrenia across five countries. CONCLUSION: The CSSRI-EU provides a standardised yet adaptable method for collating service receipt and associated data alongside assessment of patient outcomes.

Measuring the economic benefit of treatment with atypical antipsychotics.

Schizophrenia has a major impact on the quality of life of sufferers, and its broader impact on families and on society are well known, although less thoroughly documented. The majority of sufferers require long-term treatment and support, and there are depressingly frequent media stories about violent incidents involving people with the illness. Consequently the costs of schizophrenia, broadly defined, loom large, not just from the perspective of health care decision-makers and governments, but also from that of sufferers and their families, to many other people with only indirect experience of the disease.

Issues in the design of studies for the economic evaluation of new atypical antipsychotics: the ESTO study.

BACKGROUND: Increasing attention is being focused on the costs of healthcare and the need for cost-effective treatments. Drugs for schizophrenia have not escaped this scrutiny, especially now that several new agents are available, with acquisition costs substantially higher than for established therapies. However, most of the existing evaluations of new drugs for schizophrenia have weak designs, either comparing health care costs before and after introduction of the new drug, or being based on modelling approaches incorporating numerous assumptions. AIM OF THE STUDY: The aim of the study was to discuss and resolve the key design issues in the planning of a prospective randomized trial to assess the socio-economic impact of a new atypical antipsychotic (quetiapine). METHODS: Key methodological issues were identified and discussed in the context of the economic evaluation being planned. These were patient recruitment and entry criteria, selection of comparator drug, blinding of doctor and patient, range of socio-economic outcomes, length of follow-up and sample size. RESULT: The resulting economic evaluation, the ESTO study, was an international multi-centre randomized controlled trial, with concurrent data collection for a wide range of clinical, economic and quality of life outcomes. The trial had a pragmatic design, enrolling patients experiencing an acute exacerbation on existing therapy. In addition to the presenting exacerbation, patients must have had at least one hospitalization or documented evidence of exacerbation within the previous three years. On admission to the study, existing psychotic medication was withdrawn prior to randomization to quetiapine or haloperidol. Doses of both drugs were titrated up to an optional dose, with flexibility for additional increases if required. Both patients and doctors were blinded to treatment allocations, on the grounds that, since quetiapine was still in development, unblinded assessments of efficacy would not be credible. Patients were followed for 1 year, irrespective of whether they withdrew from study medication. A wide range of socio-economic outcomes was assessed, including costs falling on the healthcare sector, other agencies and the family. In addition data were collected on patients' earnings and quality of life, measured by the Short-Form 36 health profile. Data were also collected on a range of clinical measures, such as the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI), the AIMS neurological rating scale and the neurological rating scale of Simpson and Angus. This was to assess whether changes in socio-economic end points were indeed matched by changes in the patient's clinical condition. CONCLUSIONS: The design of studies such as ESTO is inevitably a compromise between control and pragmatism. For example, whilst blinding of doctor and patient may reduce potential bias, this may cause difficulty with compliance owing to the use of additional dummy medications. Despite these compromises, the ESTO study should provide a more reliable assessment of the socio-economic outcomes of a new anti-psychotic and has attracted the widespread support of analysts and investigators. It has already served as a template for other studies and, if the methodology is successful, will have implications for the assessment of similar drugs in the future

The mental health residential care study: predicting costs from resident characteristics.

BACKGROUND: Little information is available on the costs of residential care for people with mental health problems, and there are very few research data on how or why the costs of provision vary. METHOD: As part of a broader study based on data collected from across the residential care sectors in eight districts and using multiple regression analysis, research has examined whether and which resident characteristics are associated with higher or lower costs. RESULTS: Resident characteristics account for approximately 21% of the observed variation in inter-resident costs. Separate analyses were conducted for people in the London and non-London districts. The resident characteristics that were found to be significant predictors of cost include: age, gender, ethnic group, history of psychiatric admissions, diagnosis, emotional lability, daily living skills, social interaction and network, aggression, suicidal tendencies, drug abuse and legal status. Examination of the residual ('unexplained') costs found significant differences between facility types, sectors (private and voluntary being less costly than public, other things being equal) and districts. CONCLUSIONS: The associations uncovered by these analyses can inform commissioners' planning and purchasing activities, at both the macro and micro levels, by revealing those resident needs and circumstances that are associated with higher costs.

Genetic Bit Analysis: a solid phase method for typing single nucleotide polymorphisms.

A new method for typing single nucleotide polymorphisms in DNA is described. In this method, specific fragments of genomic DNA containing the polymorphic site(s) are first amplified by the polymerase chain reaction (PCR) using one regular and one phosphorothioate-modified primer. The double-stranded PCR product is rendered single-stranded by treatment with the enzyme T7 gene 6 exonuclease, and captured onto individual wells of a 96 well polystyrene plate by hybridization to an immobilized oligonucleotide primer. This primer is designed to hybridize to the single-stranded target DNA immediately adjacent from the polymorphic site of interest. Using the Klenow fragment of E. coli DNA polymerase I or the modified T7 DNA polymerase (Sequenase), the 3' end of the capture oligonucleotide is extended by one base using a mixture of one biotin-labeled, one fluorescein-labeled, and two unlabeled dideoxynucleoside triphosphates. Antibody conjugates of alkaline phosphatase and horseradish peroxidase are then used to determine the nature of the extended base in an ELISA format. This paper describes biochemical features of this method in detail. A semi-automated version of the method, which we call Genetic Bit Analysis (GBA), is being used on a large scale for the parentage verification of thoroughbred horses using a predetermined set of 26 diallelic polymorphisms in the equine genome.

Molecular approaches to the study of long-term sensitization in Aplysia californica.

In order to gain insight into the molecular mechanisms underlying the establishment and maintenance of long-term sensitization in Aplysia new tools are being used to study the synaptic facilitation in the sensory-motor connection which mediates the gill-and-siphon withdrawal reflex. The supposition that long-term changes in neuronal properties share molecular pathways with other cells during development and differentiation points towards specific candidate genes as well as towards a general experimental strategy designed to find proteins which might mediate these changes. The unique properties of Aplysia cell biology may, in addition, provide a means to examine their specific roles in the triggering of the changes, as well as the nature of the changes themselves.

Simultaneous expression of immunoglobulin mu and delta heavy chains by a cloned B-cell lymphoma: a single copy of the VH gene is shared by two adjacent CH genes.

The cloned murine B-cell lymphoma line (BCL1) that expresses surface IgM and IgD is considered to be a model for the immunoglobulin gene expression of the mature virgin B cell. Of particular interest is the mechanism by which a single VH gene is shared by two CH genes. We examined the organization of the immunoglobulin heavy chain genes in BCL1 DNA. A single arrangement of CH genes was found with the expressed VHDJH gene complex just 5' to the Cmu gene. The complete DNA sequence of the VH gene was determined. No rearrangement occurred in the intervening DNA between the JH and C mu genes or between the C mu and C delta genes. We conclude that dual expression of mu and delta heavy chains using a single VH gene is accomplished by alternate processing of a primary transcript that encompasses the the VHDJH complex and both CH genes.

Characterization of a spontaneous murine B cell leukemia (BCL1). I. Cell surface expression of IgM, IgD, Ia, and FcR.

The surface marker expression of a spontaneous B lymphocyte leukemia discovered in a BALB/c mouse (BCL1) was examined and found to include a subset of markers known to occur on normal B lymphocytes. The tumor cells bore surface Ig that included both mu- and delta-chains associated with the lambda light chain. Alloantigens coded for within the murine MHC, including H-2D, H-2K, and I-region products, were identified on the tumor cells. Although normal B lymphocytes are thought to express products coded for within both the I-A and I-E subregions, the BCL1 expressed only normal amounts of I-E subregion products. In addition, the H-2 and Ia antigens revealed by 2-dimensional gel electrophoresis exhibited an abnormal pattern of post-translational modifications. The Fc, but not the complement-receptor, was present on the surface of tumor cells. The presence of IgD, Ia antigens, and the responsiveness to lipopolysaccharide (see subsequent paper) have led us to postulate that the BCL1 tumor represents a later differentiative stage than murine B lymphocyte tumors previously described.

Characterization of a spontaneous murine B cell leukemia (BCL1). II. Tumor cell proliferation and IgM secretion after stimulation by LPS.

A spontaneous BALB/c B lymphocyte leukemia could be stimulated in vitro by the polyclonal B cell activator lipopolysaccharide (LPS) and the conditions for activation were studied. Spleen cells or peripheral blood lymphocytes from tumor-bearing animals responded by increased DNA synthesis and the peak of activation occurred earlier than with normal mouse spleen cells. Tumor cells harvested from the spleen, but not from the peripheral blood, could be induced by LPS to secrete IgM. Direct demonstration that the response was due to tumor cell activation and not that of contaminating normal B lymphocytes was provided by karyotype analysis and by immunoprecipitation, which showed the restriction of light chains on secreted IgM molecules to the lambda isotype.

The pathology and homing of a transplantable murine B cell leukemia (BCL1).

The pathology and homing characteristics of a murine B cell leukemia are described. Experiments utilizing autoradiography to determine the early homing pattern of the leukemic cells revealed a pronounced localization of the labeled cells to the spleen. The cells that were seen in the white pulp showed preferential localization to the follicles or B cell domains. Tissue section immunofluorescence with antibodies to kappa- and lambda-light chains was used to study the initial mouse with this disease as well as to study the mice that were injected with in vivo passaged cells. These mice also showed predominant involvement of the spleen. Although the initial mouse with this disease had 200,000 lambda-bearing B lymphocytes per mm3 in the peripheral blood and closely resembled a human chronic lymphocytic leukemia patient, the studies described suggest that this murine B cell neoplasm is a lymphoma with a striking predilection for splenic involvement. The other organs including the bone marrow as well as the peripheral blood appeared to be involved secondarily. This unusual spontaneously occurring murine B cell disease provides a useful model for the investigation of certain commonly occurring human lymphomas and leukemias.