Advanced multiple sclerosis and the psychosocial impact on families.

This study explores family relationships and support needs when adapting to a relative's advanced-multiple sclerosis (MS) around transition into care. A multi-site qualitative study of relatives of people with advanced-MS was conducted. A purposive sample of 25 relatives was selected and interviewed either in the care home or participants' homes. Interviews were recorded, transcribed and analysed using grounded theory methodology and Atlas.ti 5.2 software. Data quality enhancement involved: a self-report questionnaire; triangulation and member-checking. Themes derived from the data were: information, communication and understanding; family relationships, roles and responsibilities; emotions, coping and support; life outlook and reflection. Provision of information and support for families around the transition into care appears to be inconsistent despite there being a need for family members to ask questions and discuss the impact of the condition. Relatives reported that as a family and as individuals they faced significant challenges and were in great need of support at times, but reflected that they would have found it very difficult to accept. Relatives were also often unsure what type of support would have helped. For care providers, there needs to be a shift from the traditional health care professional 'patient-centred' mindset towards more proactive family-centred approaches and steps to encourage this are articulated.

The relationship between subjective fatigue and cognitive fatigue in advanced multiple sclerosis.

The present study examined the cognitive performance and ratings of subjective fatigue in people with advanced MS and matched healthy control participants. A continuous n-back task, involving attention (0-back), was performed at the beginning and end of one testing session; a task involving working memory (1-back) was performed at the beginning and end of another testing session. Subjective fatigue was rated at regular intervals during each session. Overall, there was limited evidence of objective cognitive fatigue in the MS group, as assessed by the change in n-back performance during the sessions. The MS group did report a greater increase, than the control group, in the level of subjective fatigue during the 1-back testing session, but change in subjective fatigue did not correlate significantly with change in cognitive performance. The implications of these findings for our understanding of cognitive fatigue in MS are discussed.

Modality-specific aspects of sustained and divided attentional performance in multiple sclerosis.

While the prevalence of cognitive impairment in multiple sclerosis is well documented, few studies have systematically investigated the profile of attentional abilities. In the current study, 30 MS participants were assessed on measures of sustained and divided attention and compared to a sample of 30 neurologically intact healthy controls. Performance on visual and auditory unimodal and bimodal trials were conducted for measures of both forms of attention. A three-factor mixed measures analysis of variance (groupxtaskxmodality) was conducted. MS participants were impaired relative to controls on all measures of speed and accuracy across unimodal and bimodal trials and more impaired on measures of divided attention than on sustained attention measures. Performance on the bimodal trials was also significantly compromised relative to the unimodal trials especially on the divided attention task. The theoretical and clinical implications of these findings are discussed.

Line bisection in normal adults: direction of attentional bias for near and far space.

The direction of attentional bias in forty normal adults was assessed using a computer generated line bisection task. A 4 (viewing distance)x4 (line length)x2 (cursor starting position) repeated measures factorial design was employed. As predicted, differences in bisection performance as a function of viewing distance were observed. The findings confirmed that scanning direction (contingent upon the starting position of the cursor), but not line length, significantly modulated this effect. The direction of bias across near and far space was further clarified yielding a progressive shift from a leftward bias in near space to a rightward bias in far space. A significant interaction of distance, line length and starting position revealed differential effects for left and right starting positions as a function of viewing distance and line length. More specifically, a leftward start witnessed deviations shifting progressively from left-to-right as distance and line length increased though no comparable pattern was observed for rightward starts. The results provide important behavioural support for the suggestion that dissociated neural systems may be responsible for attending and acting in near and far space and that other lateralised functions (such as scanning strategies) can influence hemispheric activation. The findings have relevant theoretical implications as well as important implications for the clinical assessment of unilateral neglect using a standard line bisection task, both of which are discussed.

Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis.

Bcl-2 family members bearing only the BH3 domain are essential inducers of apoptosis. We identified a BH3-only protein, Bmf, and show that its BH3 domain is required both for binding to prosurvival Bcl-2 proteins and for triggering apoptosis. In healthy cells, Bmf is sequestered to myosin V motors by association with dynein light chain 2. Certain damage signals, such as loss of cell attachment (anoikis), unleash Bmf, allowing it to translocate and bind prosurvival Bcl-2 proteins. Thus, at least two mammalian BH3-only proteins, Bmf and Bim, function to sense intracellular damage by their localization to distinct cytoskeletal structures.

Thyroid hormone receptor-interacting protein 1 modulates cytokine and nuclear hormone signaling in erythroid cells.

Erythropoietin (Epo) and thyroid hormone (T(3)) are key molecules in the development of red blood cells. We have shown previously that the tyrosine kinase Lyn is involved in differentiation signals emanating from an activated erythropoietin receptor. Here we demonstrate that Lyn interacts with thyroid hormone receptor-interacting protein 1 (Trip-1), a transcriptional regulator associated with the T(3) receptor, providing a link between the Epo and T(3) signaling pathways. Trip-1 co-localized with Lyn and the T(3) receptor alpha in the cytoplasm/plasma membrane of erythroid cells but translocated to discrete nuclear foci shortly after Epo-induced differentiation. Our data reveal that T(3) stimulated the proliferation of immature erythroid cells, and inhibited maturation promoted by erythropoietin. Removal of T(3) reduced cell division and enhanced terminal differentiation. This was accompanied by large increases in the cell cycle inhibitor p27(Kip1) and by increasing expression of erythroid transcription factors GATA-1, EKLF, and NF-E2. Strikingly, a truncated Trip-1 inhibited both erythropoietin-induced maturation and T(3)-initiated cell division. This mutant Trip-1 acted in a dominant negative fashion by eliminating endogenous Lyn, elevating p27(Kip1), and blocking T(3) response elements. These data demonstrate that Trip-1 can simultaneously modulate responses involving both cytokine and nuclear receptors.

Quality of Life (QoL) in severely disabled multiple sclerosis patients: comparison of three QoL measures using multidimensional scaling.

This study reports a comparison of three quality of life (QoL) measures completed by patients with advanced multiple sclerosis. Multidimensional scaling analysis explored the structure of relationships amongst a general health measure (the Short Form 36--SF 36) and two person-centred measures (the Patient Generated Index--PGI; and the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting version--SEIQoL-DW). Results showed distinct differences both between the two person-centred measures, and when compared against the general health measure, reflecting the different conceptual bases of these measures. The findings suggest that PGI scores closely relate to measures of physical functioning, whereas SEIQoL-DW scores relate more closely to feelings of health and vitality. The implications of these results for selection and development of appropriate QoL scales for the target population are discussed.

Pro-apoptotic apoptosis protease-activating factor 1 (Apaf-1) has a cytoplasmic localization distinct from Bcl-2 or Bcl-x(L).

How Bcl-2 and its pro-survival relatives prevent activation of the caspases that mediate apoptosis is unknown, but they appear to act through the caspase activator apoptosis protease-activating factor 1 (Apaf-1). According to the apoptosome model, the Bcl-2-like proteins preclude Apaf-1 activity by sequestering the protein. To explore Apaf-1 function and to test this model, we generated monoclonal antibodies to Apaf-1 and used them to determine its localization within diverse cells by subcellular fractionation and confocal laser scanning microscopy. Whereas Bcl-2 and Bcl-x(L) were prominent on organelle membranes, endogenous Apaf-1 was cytosolic and did not colocalize with them, even when these pro-survival proteins were overexpressed or after apoptosis was induced. Immunogold electron microscopy confirmed that Apaf-1 was dispersed in the cytoplasm and not on mitochondria or other organelles. After the death stimuli, Bcl-2 and Bcl-x(L) precluded the release of the Apaf-1 cofactor cytochrome c from mitochondria and the formation of larger Apaf-1 complexes, which are steps that presage apoptosis. However, neither Bcl-2 nor Bcl-x(L) could prevent the in vitro activation of Apaf-1 induced by the addition of exogenous cytochrome c. Hence, rather than sequestering Apaf-1 as proposed by the apoptosome model, Bcl-2-like proteins probably regulate Apaf-1 indirectly by controlling upstream events critical for its activation.

HS1 interacts with Lyn and is critical for erythropoietin-induced differentiation of erythroid cells.

Erythroid cells terminally differentiate in response to erythropoietin binding its cognate receptor. Previously we have shown that the tyrosine kinase Lyn associates with the erythropoietin receptor and is essential for hemoglobin synthesis in three erythroleukemic cell lines. To understand Lyn signaling events in erythroid cells, the yeast two-hybrid system was used to analyze interactions with other proteins. Here we show that the hemopoietic-specific protein HS1 interacted directly with the SH3 domain of Lyn, via its proline-rich region. A truncated HS1, bearing the Lyn-binding domain, was introduced into J2E erythroleukemic cells to determine the impact upon responsiveness to erythropoietin. Truncated HS1 had a striking effect on the phenotype of the J2E line-the cells were smaller, more basophilic than the parental proerythoblastoid cells and had fewer surface erythropoietin receptors. Moreover, basal and erythropoietin-induced proliferation and differentiation were markedly suppressed. The inability of cells containing the truncated HS1 to differentiate may be a consequence of markedly reduced levels of Lyn and GATA-1. In addition, erythropoietin stimulation of these cells resulted in rapid, endosome-mediated degradation of endogenous HS1. The truncated HS1 also suppressed the development of erythroid colonies from fetal liver cells. These data show that disrupting HS1 has profoundly influenced the ability of erythroid cells to terminally differentiate.

A novel ADP-ribosylation like factor (ARL-6), interacts with the protein-conducting channel SEC61beta subunit.

We report here the isolation of a new member of the ADP-ribosylation factor (ARF)-like family (ARL-6) present in the J2E erythroleukemic cell line, but not its myeloid variants. Consistent with this lineage-restricted expression, ARL-6 mRNA increased with erythropoietin-induced maturation of J2E cells, and decreased with interleukin 6-induced differentiation of M1 monoblastoid cells. In tissues, ARL-6 mRNA was most abundant in brain and kidney. While ARL-6 protein was predominantly cytosolic, its membrane association increased following exposure to GTP-gammaS, like many members of the ARF/ARL family. Using the yeast two-hybrid system, six molecules which interact with ARL-6 were identified including SEC61beta, a subunit of the heterotrimeric protein conducting channel SEC61p. Co-immunoprecipitation of ARL-6 confirmed a stable association between ARL-6 and SEC61beta in COS cells. These results demonstrate that ARL-6, a novel member of the ADP-ribosylation factor-like family, interacts with the SEC61beta subunit.

HLS7, a hemopoietic lineage switch gene homologous to the leukemia-inducing gene MLF1.

Hemopoietic lineage switching occurs when leukemic cells, apparently committed to one lineage, change and display the phenotype of another pathway. cDNA representational difference analysis was used to identify myeloid-specific genes that may be associated with an erythroid to myeloid lineage switch involving the murine J2E erythroleukemic cell line. One of the genes isolated (HLS7) is homologous to the novel human oncogene myeloid leukemia factor 1 (MLF1) involved in the t(3;5)(q25.1;q34) translocation associated with acute myeloid leukemia. Enforced expression of HLS7 in J2E cells induced a monoblastoid phenotype, thereby recapitulating the spontaneous erythroid to myeloid lineage switch. HLS7 also inhibited erythropoietin- or chemically-induced differentiation of erythroleukemic cell lines and suppressed development of erythropoietin-responsive colonies in semi-solid culture. However, intracellular signaling activated by erythropoietin was not impeded by ectopic expression of HLS7. In contrast, HLS7 promoted maturation of M1 monoblastoid cells and increased myeloid colony formation in vitro. These data show that HLS7 can influence erythroid/myeloid lineage switching and the development of normal hemopoietic cells.

A screening test of auditory comprehension for individuals with severe physical disability (PACST).

Tests of auditory comprehension are frequently unsuitable for patients with physically disabling conditions as they require abilities such as good vision or physical manipulation of test materials. A suitable test is required to assess patients who can only indicate 'yes' or 'no'. This has implications for enabling patients to make decisions about their care. A test consisting of 60 Yes-No questions was developed from a larger set tested on normals. A clinical trial was completed and the test found to be a useful tool. It allocates patients to three groups: normal, impaired and chance performance.

Assessing auditory comprehension in the context of severe physical disability: the PACST.

Existing tests of auditory comprehension are frequently unsuitable for patients with physically disabling conditions as tests require skills such as physical manipulation of materials. A suitable test is required to assess the reliability and validity of responses in patients who can only indicate 'yes' and 'no'. This has implications for enabling patients to participate, for example, in decision making over their care. In the construction of the Putney Auditory Comprehension Screening Test (PACST) 200 normal participants were tested with 258 yes/no questions. From their results a test consisting of 60 unambiguous questions, varying in difficulty, type, syntactic complexity and length were selected. A clinical trial was completed with 112 patients from the Royal Hospital for Neuro-disability. The 60 item test was found to be reliable and valid. Results were also compared with independent ratings by ward managers and speech and language therapists. Effects of demographic variables were as expected. A 60 question test was developed which was shown by the clinical trial to be a useful tool. Questions vary in difficulty, but not enough to establish a difficulty gradient. On the basis of performance on the test, patients can be allocated to three groups: normal, impaired, and chance performance.

Future research directions in laterality.

This paper considers the current conceptual state of research into neuropsychological laterality and considers some issues which might appropriately be considered for the forward development of the field. It considers the biological context which has been adopted for these studies and the psychological significance of performance asymmetries. A principal emphasis of the paper is the degree to which inferences, rather than direct methodological deductions, can be drawn from the research undertaken. The status of the dichotomies which have been proposed, the role of interhemispheric transfer, and stages of processing models are considered. The degree to which cerebral asymmetries may be inferred to reflect normal processes of the brain is questioned, and some prospects of the future discussed.

A clinical study of the automated assessment of intelligence by the Mill Hill Vocabulary test and the Standard Progressive Matrices test.

As part of the Leicester/DHSS project on microcomputer-aided assessment, 274 patients at five clinical sites were assessed with either a computerized version or the standard version of the Mill Hill Vocabulary (Synonyms) test. Of this group, 178 were retested on the alternative version of the test. Similarly, 184 patients were tested with either a computerized version or the standard version of the Standard Progressive Matrices test, of whom 129 were retested on the alternative test form. High correlations were found between the standard and computerized versions for both tests. For the Mill Hill Vocabulary test, no significant difference was found between test versions for first administration, and the vast majority of retested subjects had very similar scores on each version. On the Standard Progressive Matrices, however, subjects obtained significantly lower scores on the computerized test. It is concluded that whereas the computerized Mill Hill Vocabulary test could be used in place of the standard version of clinical settings, the computerized Standard Progressive Matrices test could not be used.

Mixed-list presentation and visual field asymmetry: attempts to differentially activate the hemispheres.

Mixed lists of abstract nouns and random forms were presented in an attempt to induce differential activation of the two hemispheres. For Expt. 1, nine probability levels, from P = 0.1 to P = 0.9 for both nouns and forms were examined. Prior to the presentation of each trial a cue was presented which gave the probability of that trial being either a noun or a form. For Expts. 2 and 3, eleven mixed blocks were presented, each containing a different proportion of nouns and forms. The activational model predicts right visual field (RVF) advantages for both stimulus types when nouns are more probable or more frequent than forms, and left visual field (LVF) advantages for both stimulus types when forms are more probable than nouns. The structural model predicts RVF and LVF advantages for nouns and forms respectively, regardless of their probability of occurrence. It was found that the more probable or frequent the stimulus type the faster the response. However, all 3 experiments offered some support for the structural model and no support for the activational model.

The reaction of psychiatric patients to computerized assessment.

A questionnaire was given following test administration in either a standard or computerized form, to 367 psychiatric patients who completed up to eight psychometric tests. Patients responded in the computerized versions by using either a keyboard or a touch-screen. In general, the evaluation of both test forms was positive and fewer differences were detected than had been expected. Where differences existed, the computerized forms were found more enjoyable, especially in the case of the simpler tests, but were also reported to be less comprehensible and less clear in the case of some of the more complex ones. Subjective estimates of attainment and willingness to undergo further testing were largely unaffected by test form. The touch-screen was preferred to the keyboard in the simpler tests, but in other cases there was evidence that prior experience of the standard form of the test facilitated performance. The findings support the feasibility of creating computerized tests which are essentially parallel to standard original forms, but point to the need to understand the complex factors which govern the users' evaluation of human-computer interaction. However, computerized assessment seems to be entirely acceptable to clinical psychiatric patients.