Balancing the perfect scorecard. Inquiry as intervention in physician practice management.

We describe how inquiry into several operational aspects of health care delivery in the Division of Medicine at the Cleveland Clinic Foundation improved clinical and administrative functions, demonstrating the principle that inquiry is intervention. The process of inquiry displays data on a "performance wheel" that summarizes several indicators, allowing easy comprehension of performance in various operational aspects and a visual appreciation of the interaction among these operational aspects.

Sampling hard to reach populations.

Studies on 'hidden populations', such as homeless people, prostitutes and drug addicts, raise a number of specific methodological questions usually absent from research involving known populations and less sensitive subjects. This paper examines the advantages and limitations of nonrandom methods of data collection such as snowball sampling. It reviews the currently available literature on sampling hard to reach populations and highlights the dearth of material currently available on this subject. The paper also assesses the potential for using these methods in nursing research. The sampling methodology used by Faugier (1996) in her study of prostitutes, HIV and drugs is used as a current example within this context.

Systematic search for major genes in schizophrenia: methodological issues and results from chromosome 12.

We describe a method of systematically searching for major genes in disorders of unknown mode of inheritance, using linkage analysis. Our method is designed to minimize the probability of missing linkage due to inadequate exploration of data. We illustrate this method with the results of a search for a locus for schizophrenia on chromosome 12 using 22 highly polymorphic markers in 23 high density pedigrees. The markers span approximately 85-90% of the chromosome and are on average 9.35 cM apart. We have analysed the data using the most plausible current genetic models and allowing for the presence of genetic heterogeneity. None of the markers was supportive of linkage and the distribution of the heterogeneity statistics was in accordance with the null hypothesis.

Imprinting and anticipation. Are they relevant to genetic studies of schizophrenia?

Among 29 multiply affected pedigrees, age of onset among parents and offspring was examined for evidence of both anticipation and genomic imprinting. The results do not suggest that either mechanism is operating in schizophrenia, but only very large effects can be confidently excluded.

The lymphoblast beta-adrenergic receptor in bipolar depressed patients: effect of chronic incubation with lithium chloride.

We have recently reported a study of beta-adrenergic receptor binding characteristics in lymphoblast cell lines derived from patients with bipolar disorder (BD) and healthy, matched control subjects. In the present study we have investigated the effects of incubating cells from the same subjects with lithium chloride (1 mM) for 7 days prior to assay. There was no difference in beta-adrenergic receptor number between control and BD cell lines and incubation with lithium had no effect on receptor number in either group. Exposure of the cells to isoprenaline (1 nM) for 24 h immediately prior to assay caused significantly less down-regulation in BD cells (15 +/- 5%) than control cells (39 +/- 4%), as described previously. Incubation with lithium significantly increased the down-regulation response to isoprenaline in BD cells (39 +/- 6%) but not in control cells (30 +/- 7%). After lithium, the agonist-induced decrease in beta-AR number in BD cells was no longer significantly different from that in control cells. We conclude that lithium selectively enhanced the agonist down-regulation of beta-adrenergic receptors in cells derived from patients with bipolar disorder. The functional significance of this result and the potential biochemical mechanisms responsible for this effect are discussed.

Failure to find linkage between schizophrenia and genetic markers on chromosome 21.

We sought evidence for the involvement of mutations in the amyloid precursor protein gene (APP) in the pathogenesis of schizophrenia in two ways. First, linkage analysis was performed in a sample of 24 families multiply affected with schizophrenia. The genotypes were studied for GT12 (D21S210), a highly polymorphic microsatellite marker at the APP locus. Second, we used single strand conformation analysis (SSCA) to screen for mutations in exon 17 of APP in one affected member from each family and in a sample of 44 unrelated patients. In addition, we looked for linkage between schizophrenia and a series of highly polymorphic markers situated at approximately 20cM intervals along the long arm of chromosome 21. We were unable to find evidence for linkage to GT12 or the other markers studied. SSCA did not reveal any mutations in exon 17 of AP. We conclude that mutations within APP are an unlikely cause of schizophrenia. Moreover, this study provides no evidence for a major gene for schizophrenia on chromosome 21, and linkage can be excluded from much of this region under some genetic models.

The lymphoblast beta-adrenergic receptor in bipolar depressed patients: characterization and down-regulation.

beta-Adrenergic receptor binding and adenylyl cyclase activity were examined in lymphoblast cell lines established from 12 patients with bipolar disorder and 10 unrelated healthy control subjects. No significant differences were found in [125I]iodocyanopindolol binding affinity or capacity or in isoprenaline-stimulated cAMP response. Incubation of lymphoblasts with isoprenaline (1 nM) for 24 h prior to assay reduced both receptor number and adenylyl cyclase activity. The extent of receptor down-regulation was significantly less in cells of bipolar disorder patients (20 +/- 5%) compared to controls (40 +/- 4%). Desensitization of adenylyl cyclase, however, was reduced to a similar degree in bipolar (65 +/- 14%) and control (68 +/- 20%) subjects. We conclude that basal beta-adrenergic receptor characteristics are not altered in bipolar disorder but that agonist down-regulation of receptor number may be less efficient than in control cells. The functional implications of this effect are discussed.

A SCAN-SADS comparison study of psychotic subjects and their first-degree relatives.

Two diagnostic interviews, the Schedule for Affective Disorders and Schizophrenia (lifetime version) (SADS-LA) and the Schedule for the Clinical Assessment of Neuropsychiatry (SCAN) were compared for main diagnoses and for their acceptibility to psychotic subjects and their psychiatrically well relatives. Broad agreement for DSM-III, DSM-III-R and draft ICD-10 diagnoses was good, although there were areas of disagreement between the two interviews which are discussed.

Life stress, social support, and locus of control during early adolescence: interactive effects.

Examined the relationships between negative events, locus of control, social support, and psychological adjustment in an early adolescent sample. Of interest were the potential stress-buffering effects of social support and the conjunctive effects of social support and locus of control upon adjustment. Family support was positively related to adjustment in several domains, whereas school support was only related to school competence. Peer support was positively related to peer competence and anxiety, and negatively related to school competence. Examination of the buffering hypothesis suggested that both family and school support served to moderate the relationship between negative events and school competence. Conjunctive effects were also detected in that school support buffered number of negative events best for those individuals with an internal locus of control for successes.

No evidence for a pseudoautosomal locus for schizophrenia. Linkage analysis of multiply affected families.

Evidence for a pseudoautosomal locus for a schizophrenia susceptibility gene was sought by two forms of analysis of 25 multiply affected families. Firstly, in the sample as a whole there was an excess of same-sex over mixed-sex siblings compared with that expected. Secondly, linkage analysis was performed in six of the families. The genotypes were studied for DXYS14, a highly polymorphic marker in the telomeric pseudoautosomal region. No evidence for positive linkage was found with two-point analysis under eight different genetic models for the mode of transmission. A non-parametric, sibling-pair analysis also failed to detect linkage. Our findings provide no evidence for linkage within the pseudoautosomal region; same-sex concordance must arise from some other mechanism.

Exclusion of a schizophrenia susceptibility gene from the chromosome 5q11-q13 region: new data and a reanalysis of previous reports.

The report of a putative schizophrenia susceptibility gene linked to markers in the chromosome 5q11-q13 region and subsequent failures of replication have provoked considerable controversy. We here report six Welsh families multiply affected with schizophrenia in which there is no evidence for linkage between a dominant-like schizophrenia gene and 5q11-q13 markers. It is argued that our new results together with a combined reanalysis of previous studies suggest that a schizophrenia susceptibility gene can be excluded from the 5q11-q13 region. The apparent disparities between published results are most likely to reflect a chance finding in the one positive study and probably should not be interpreted as resulting from true linkage heterogeneity.

The significance of ragged-red fibres in neuromuscular disease.

The pathological significance of ragged-red fibres is uncertain. We have studied ragged-red fibres in the muscle biopsies of 3 adults; one with polymyositis and two with progressive external ophthalmoplegia. All the ragged-red fibres were Type 1 fibres. In two patients the mean diameter of the ragged-red fibres was significantly smaller than the unaffected Type 1 fibres. Some of these fibres showed features of regeneration, and others of degeneration. In the patient with polymyositis the mitochondria were proliferated and contained osmiophilic dense bodies; in the other two patients paracrystalline mitochondrial inclusions were prominent. These findings suggest that ragged-red fibres do not represent a single pathological process.

Pathogenesis of longitudinal splitting of muscle fibres in neurogenic disorders and in polymyositis.

Longitudinal splitting of muscle fibres has been studied in the biopsies of eighteen patients with neurogenic disorders, and of twenty with polymyositis. In neurogenic disorders splitting predominantly affects hypertrophied fibres, and is probably due to mechanical overload induced by normal loads imposed on a weakened muscle. A similar phenomenon occurs in hypertrophied fibres in chronic polymyositis. However, in acute, or active polymyositis an appearance resembling fibre splitting can result from sequestration of necrotic segments within a fibre and also from regeneration occurring within intact sarcolemmal tubes after segmental sub-endomysial necrosis. These different processes, which can be distinguished by light and ultrastructural criteria, are important compensatory factors in neuromuscular disorders.

Neostigmine-induced end-plate proliferation in the rat. A study using supra-vital methylene blue.

The supra-vital methylene blue technique was used to study motor end-plate morphology in 21 BD-1X rats, treated for 7 to 16 weeks with oral neostigmine bromide, and in five control animals. Motor endings of treated animals showed preterminal, terminal, and ultraterminal sprouting and an increase in mean end-plate length (p less than 0.001). These changes were most prominent after 14 weeks of treatment. After 16 weeks of therapy, mean end-plate length decreased and the proliferative abnormality became less evident. The adverse effect of neostigmine on motor end-plates may have clinical relevance in the management of myasthenia gravis and may be partly responsible for the end-plate abnormalities previously reported in this disease.

Longitudinal fibre splitting in neurogenic muscular disorders--its relation to the pathogenesis of "myopathic" change.

In 15 patients with neurogenic muscular disorders, including cases of motor neuron disease, Wohlfart-Kugelberg-Welander disease, Davidenkow's scapuloperoneal syndrome, peripheral neuropathy and traumatic neuropathies, muscle biopsies were carried out, usually after EMG or single fibre EMG investigation. Enzyme histochemical and electronmicroscopic techniques were used to study longitudinal fibre splitting and its quantitative relation to the general changes in the biopsies. In 9 cases serial sections were used to study the longitudinal extent and character of fibre splitting. Longitudinal fibre splitting was found in 14 cases. It was prominent in Type 1 fibres, and in those biopsies in which hypertrophy was most marked. It was often associated with central migration of sarcolemmal nuclei. Ultrastructurally there was evidence that splitting consisted of mechanical disruption of the myofibrillar pattern, followed by an active process of membrane formation. We suggest that longitudinal splitting of muscle fibres, induced by overload of poorly innervated, hypertrophied fibres, can account for many of the "myopathic" changes found in neurogenic muscular disorders.