Usability of Geographic Information: current challenges and future directions.

The use of Geographic Information or GI, has grown rapidly in recent years. Previous research has identified the importance of usability and user centred design in enabling the proliferation and exploitation of GI. However, the design and development of usable GI is not simply a matter of applying the tried and tested usability methods that have been developed for software and web design. Dealing with data and specifically GI brings with it a number of issues that change the way usability and user centred design can be applied. This paper describes the outcomes of a workshop held in March 2010 exploring the core issues relating to GI usability. The workshop brought together an international group of twenty experts in both human factors and GI, from a wide range of academic and industrial backgrounds. These experts considered three key issues, the stakeholders in GI, key challenges applying usability to GI and the usability methods that can be successfully applied to GI. The result of this workshop was to identify some areas for future research, such as the production of meaningful metadata and the implications of blurring of the line between data producers and data consumers.

A multicentre randomized controlled trial of leisure therapy and conventional occupational therapy after stroke. TOTAL Study Group. Trial of Occupational Therapy and Leisure.

OBJECTIVE: To evaluate the effects of leisure therapy and conventional occupational therapy (OT) on the mood, leisure participation and independence in activities of daily living (ADL) of stroke patients 6 and 12 months after hospital discharge. DESIGN: Multicentre randomized controlled trial. SETTING AND PARTICIPANTS: Four hundred and sixty-six stroke patients from five UK centres. MAIN OUTCOME MEASURES: The General Health Questionnaire (12 item), the Nottingham Extended ADL Scale and the Nottingham Leisure Questionnaire, assessed by post, with telephone clarification. RESULTS: Four hundred and forty (94%) and 426 (91%) subjects were alive at 6 and 12 months, respectively. Three hundred and seventy-four (85% of survivors) and 311 (78% of survivors) responded at 6 and 12 month follow-up respectively. At six months and compared to the control group, those allocated to leisure therapy had nonsignificantly better GHQ scores (-1.2: 95% CI -2.9, +0.5), leisure scores (+0.7, 95% CI -1.1, +2.5) and Extended ADL scores (+0.4: 95% CI -3.8, +4.5): the ADL group had nonsignificantly better GHQ scores (-0.1: 95% CI -1.8, +1.7) and Extended ADL scores (+1.4: 95% CI -2.9, +5.6) and nonsignificantly worse leisure scores (-0.3: 95% CI -2.1, +1.6). The results at 12 months were similar. CONCLUSION: In contrast to the findings of previous smaller trials, neither of the additional OT treatments showed a clear beneficial effect on mood, leisure activity or independence in ADL measured at 6 or 12 months.

Development and validation of the Nottingham Leisure Questionnaire (NLQ).

OBJECTIVES: To reduce the length of the Nottingham Leisure Questionnaire (NLQ) in order to make it more suitable for postal use, and to evaluate its test-retest reliability, sensitivity, stability and validity in relation to other measures of activities of daily living (ADL), mood and handicap. METHOD: The NLQ was shortened and the response categories collapsed. Results from a previous trial which had used the NLQ were reanalysed to establish if significant group differences were maintained. The new version of the NLQ was subsequently tested for test-retest reliability on a new group of patients from the Nottingham stroke register who were asked to complete it twice. The new NLQ and other measures were sent to patients in a multicentre rehabilitation trial (TOTAL) six and twelve months after recruitment for postal completion. SUBJECTS: One hundred and thirty-seven consecutive patients from the Nottingham stroke register and 466 patients with a stroke in a multicentre rehabilitation trial. RESULTS: The original NLQ was reduced from 37 to 30 items and from five to three response categories. Data from an earlier study were reanalysed and differences between treatment groups remained. The results of a test-retest analysis using kappa showed that six items had excellent agreement, 15 good and nine fair, suggesting acceptable test-retest reliability. Results from the rehabilitation trial showed that the subjects performed all items and few additional activities were suggested. Higher NLQ scores were associated with higher subscores on the Nottingham Extended Activities of Daily Living Scale (NEADL) and lower NLQ scores with living alone and worse emotional health. CONCLUSION: The NLQ has been successfully modified for postal self-administration but there is potential for further development.

Relationship of the functional recovery after hip arthroplasty to the neuroendocrine and inflammatory responses.

We studied the relationship between the neuroendocrine and inflammatory responses to hip arthroplasty and functional recovery in 102 patients undergoing elective arthroplasty for osteoarthritis. Blood samples were collected for up to 7 days after surgery and analysed for concentrations of norepinephrine, epinephrine, cortisol, interleukin-6 and C-reactive protein. The primary outcome measures were milestones in hospital, times to walk 10 and 25 m, pain on discharge from hospital, and function 1 and 6 months after surgery. Walking distances in hospital were significantly delayed in patients with greater interleukin 6 and C-reactive protein concentrations, but few neuroendocrine measures had significant correlations with functional recovery in hospital. Multivariate analysis showed that the interleukin 6 concentration on day 1 was the unique predictor of time to walk 10 and 25 m, and that the day 2 concentration of C-reactive protein was the unique predictor of pain on discharge from hospital. No significant correlations were found between the inflammatory and neuroendocrine variables and recovery at 1 and 6 months. We conclude that the inflammatory response affects immediate functional recovery after hip arthroplasty.

Hip and knee arthroplasty: a comparison and the endocrine, metabolic and inflammatory responses.

Changes in circulating levels of catecholamines, cortisol, glucose, interleukin-6 and C-reactive protein and in the leucocyte count were investigated for 7 days after surgery in 158 patients undergoing hip or knee arthroplasty. We compared the responses to the two operations, and also examined the effects of pathology (osteoarthritis and rheumatoid arthritis) on the changes associated with knee arthroplasty. Exploratory factor analysis was applied to the data to identify the variables and sampling times that could be used in future to provide a concise description of the response. Patients undergoing knee arthroplasty showed significantly greater changes in noradrenaline, adrenaline and glucose levels, but not in cortisol levels, compared with those undergoing hip arthroplasty. Interleukin-6 and C-reactive protein concentrations were also significantly greater in knee patients than hip patients; however, when corrected for pathology, many of these differences were not significant. Minimal effects of pathology (chronic inflammation with rheumatoid arthritis) were found on the hormonal changes in knee patients. In particular, there was little evidence to support the inference from animal data that the hypothalamic-pituitary-adrenal axis is impaired. The expected increases in interleukin-6 and C-reactive protein concentrations were found in the rheumatoid arthritis patients. Exploratory factor analysis showed that the response could be separated into six components, accounting for 60% of the total variance, and identified the variables and sampling times indicative of each. In conclusion, there are differences in the hormonal, but not inflammatory, responses to hip and knee arthroplasty. Little evidence was found for an important effect of pathology on the changes associated with knee surgery. Factor analysis provided a useful summary of the data.

Paroxysmal nocturnal hemoglobinuria: analysis of the effects of mutant PIG-A on gene expression.

Compelling evidence indicates that mutations in PIG-A are necessary for the development of paroxysmal nocturnal hemaglobinuria (PNH), however, it is unclear why mutant PIG-A stem cells have a selective advantage. Further, multiple, discrete PIG-A mutations have been detected in the peripheral blood and bone marrow of patients with PNH, but the contribution of the different mutant clones to hematopoiesis is variable. This observation implies that factors in addition to mutant PIG-A influence the proliferative properties of the abnormal cells. To investigate the etiology of the selective advantage and the clonal dominance in PNH, gene expression in cells with mutant PIG-A was analyzed. Representational difference analysis was used to compare the pattern of cDNA expression between a human lymphoblastoid cell line with mutant PIG-A and its wild-type counterpart. These experiments demonstrated that the pattern of gene expression was different between the two cells lines in that the PIG-A mutant cells failed to express antiquitin mRNA. Transfection of the mutant cells with normal PIG-A restored expression of glycosyl phosphatidylinositol anchored proteins but not antiquitin. These experiments demonstrate that differences in the pattern of gene expression can occur independent of the PIG-A mutation. Depending upon the functional properties of the involved genes, these differences could influence the proliferative properties of PIG-A mutant cells and contribute to the selective advantage and clonal dominance that characterize PNH.

Human immunodeficiency virus type 1 incorporates both glycosyl phosphatidylinositol-anchored CD55 and CD59 and integral membrane CD46 at levels that protect from complement-mediated destruction.

Human immunodeficiency virus type 1 (HIV-1) can be either resistant or sensitive to complement-mediated destruction depending on the host cells. Incorporation of different levels of host cell CD46, CD55 and CD59 may account for this differential sensitivity to complement. However, it has not been determined whether CD46, CD55 and CD59 can all be incorporated at levels which protect virions. To determine whether each of these proteins can protect HIV-1, virions were derived from CHO cells expressing either human CD46, CD55 or CD59. Virions were shown to incorporate both glycosyl phosphatidylinositol (GPI)-anchored CD55 and CD59 as well as transmembrane CD46. Importantly, all three virus preparations were significantly more resistant to complement lysis than control virus. This study demonstrates that HIV-1 incorporates both transmembrane and GPI-anchored complement control proteins from host cells and that both types of protein increase complement resistance of virus.

The pharmacokinetics and pharmacodynamics of rocuronium in patients with hepatic cirrhosis.

AIMS: To determine the effects of hepatic cirrhosis on the pharmacodynamics and pharmacokinetics of rocuronium bromide. METHODS: We studied 21 healthy patients and 17 patients with mild or moderate cirrhosis (Child-Pugh Class A and B). Patients were premedicated with diazepam orally; anaesthesia was induced with fentanyl and thiopentone, and maintained with isoflurane 0.6% (end-tidal) and nitrous oxide 66% in oxygen. The compound action potential of the adductor pollicis muscle in response to supramaximal stimulation of the ulnar nerve was recorded using the train-of-four (TOF) twitch technique. A bolus dose of rocuronium 0.6 mg kg(-1) was then given. Venous blood samples were taken for up to 8 h, and plasma rocuronium concentrations determined by h.p.l.c. RESULTS: The time to onset of neuromuscular block and maximal block achieved did not differ between the two groups. The mean (s.d.) recovery times were prolonged in the cirrhotic compared with the healthy group: 25% recovery T1:T0, 53.7 (18.1) vs 42.3 (14.2) min; 50% recovery T1:T0, 73.9 (33.9) vs 52.6 (19.8) min; 75% recovery T1:T0, 84.2 (24.5) vs 66.8 (27.2) min (all P<0.05); recovery of T4:T1 to 70%, 114.9 (31.7) vs 76.1 (28.8) min (P<0.01). A pharmacokinetic and pharmacodynamic model was fitted to the data for each patient. Three compartments were used to model the pharmacokinetic data; an effect compartment was added to model the pharmacodynamic data. Plasma clearance was significantly reduced in the cirrhotic group (2.66 (0.60) vs 3.70 (1.03) ml kg(-1) min (-1); P<0.005). The central (V1) and steady state volumes of distribution (V(ss)) did not differ significantly between the groups. The slow redistribution (t1/2,lambda1) and elimination (t1/2,z) half-lives were both significantly prolonged in cirrhosis (28.3 (12.1) vs 16.8 (4.6) min, P < 0.005; and 143 (80) vs 92 (40) min, P < 0.05 respectively). The exit rate constant for the effect compartment k(eo) was significantly increased in the cirrhotic group (0.25 (0.18) vs 0.16 (0.06) min(-1); P < 0.05), but cirrhosis had no significant effect on the parameters of the concentration-effect relationship Cp(ss)(50) and gamma. CONCLUSIONS: Hepatic elimination is an important pathway in the clearance of rocuronium, and delayed disposition causes the effect to be prolonged.

A role for C5 and C5a-ase in the acute neutrophil response to group B streptococcal infections.

Congenic C5-deficient and C5-sufficient mice were infected with group B streptococci (GBS) to determine if the polymorphonuclear leukocyte (PMNL) chemoattractant C5a contributes to PMNL recruitment in GBS infection and if GBS C5a-ase reduces C5a-induced PMNL recruitment in vivo. PMNL accumulation was greater in the peritoneum and air spaces of C5-sufficient mice than in C5-deficient mice. Administration of human C5 to C5-deficient mice caused a significant increase in PMNL recruitment following infection with C5a-ase-negative GBS. GBS C5a-ase did not reduce PMNL accumulation in C5-sufficient mice but reduced PMNL recruitment in C5-deficient mice reconstituted with human C5. These data indicate that C5a is important for rapid PMNL recruitment to sites of GBS infection and that GBS C5a-ase inactivates human, but not murine, C5a in vivo. Reduction of the acute inflammatory response by C5a-ase likely contributes to GBS virulence in human neonates.

Biochemical characterization of procoagulant albumin.

Procoagulant albumin (Pro-Alb) is an anionic form of albumin isolated from normal human plasma that regulates vascular endothelial cell hemostatic properties, including induction of tissue factor activity. We investigated the biochemical modification of Pro-Alb that was associated with procoagulant-inducing activity. Tryptic digestion of Pro-Alb identified greatest bioactivity in the carboxy-terminus of the molecule, a region associated with lipid binding sites. Activated charcoal treatment and phopholipase C digestion reduced the procoagulant-inducing activity of Pro-Alb, and Pro-Alb contained 2.3-fold more phosphorus than inactive albumin. We conclude that modification of albumin by phospholipid imparts tissue factor-inducing activity to Pro-Alb.

The role of leisure in stroke rehabilitation.

Stroke patients often fail to resume full lives, even if they make a good physical recovery, and social and leisure pursuits show a particular decline. The usual goals of rehabilitation are mobility and independence in self-care, but recovery in a broader sense may be impeded if health professionals concentrate exclusively on these. Leisure has been shown to be closely associated with life satisfaction and would be a worthwhile, and now measurable, goal of rehabilitation. Elderly people show a decline in leisure activity which has been studied extensively and may provide a useful model for the more rapid decline seen in stroke patients. Further research is needed to confirm the finding that specialized occupational therapy can be effective in raising leisure activity, and to show whether this will translate into improved psychological well-being.

A comparison of the infusion pharmacokinetics and pharmacodynamics of cisatracurium, the 1R-cis 1'R-cis isomer of atracurium, with atracurium besylate in healthy patients.

We have compared the pharmacokinetics of cisatracurium with atracurium when given by bolus dose followed by continuous infusion. Twenty healthy patients were anaesthetised with thiopentone, midazolam, fentanyl and 70% nitrous oxide in oxygen. Ten patients (Group C) were randomly allocated to receive cisatracurium 0.1 mg.kg-1 and 10 patients (Group A) were given atracurium 0.5 mg.kg-1. Neuromuscular block was monitored using a mechanomyograph. When the first twitch of the train-of-four had recovered to 5% of control, an infusion of cisatracurium 3 micrograms.kg-1.min-1 was started in Group C and an infusion of atracurium 10 micrograms.kg-1.min-1 was started in Group A. The infusion rates were adjusted to maintain the first twitch of the train-of-four at 5% of control. The times to 90% and maximum depression of the first twitch of the train-of-four were significantly longer after cisatracurium than atracurium (2.2 and 3.4 min compared with 1.3 and 1.8 min, respectively; p < 0.01 in each instance). No significant differences were found in recovery parameters between the two groups. Blood samples were taken at regular intervals following the bolus, during the infusion and for 8 h thereafter. The plasma samples were analysed using high-performance liquid chromatography for cisatracurium and atracurium (using a method which distinguishes between the three geometric isomer groups), laudanosine and monoquaternary alcohol. The results were analysed using the Non-linear Mixed Effects Model program. A two-compartment model was fitted to the data. The different isomer groups of atracurium have different pharmacokinetics, the trans-trans group having the highest clearance (1440 ml.min-1) and the cis-cis group the lowest (499 ml.min-1). The clearance of cisatracurium (425 ml.min-1) is less than that of cis-cis atracurium and its elimination half-life is longer (34.9 min and 21.9 min, respectively). The plasma concentration of laudanosine after cisatracurium was one-fifth of that after atracurium.

Physical illness and disability among elderly people in England and Wales: the Medical Research Council Cognitive Function and Ageing Study. The Analysis Group.

STUDY OBJECTIVE: This study was conducted as part of the MRC cognitive function and ageing study. It aimed to estimate the lifetime prevalence of self reported physical illnesses and other health related events, and the prevalence of limiting disability in people over 65 in six areas of England and Wales. DESIGN: Screening phase of a two stage prevalence study. SETTING: Geographically delimited areas in four urban and two rural areas including institutions. PARTICIPANTS: Random population samples of people in their 65th year and above on the sample definition date, interviewed between 1989 and 1994. In Newcastle, Nottingham, and Oxford (urban) and in Cambridgeshire and Gwynedd(rural), the sample was stratified to provide equal numbers in the 65-74 and 75 years and over age groups. In Liverpool (urban), equal numbers in the five year age groups were taken. MAIN RESULTS: Age standardised prevalences were calculated for each geographical area, sex, and age group (65-74, 75+). Many conditions were more prevalent in the older age group including stroke, Parkinson's disease, arthritis, diabetes, and shingles but hypertension was more common in the younger age group. Conditions that were more prevalent in men included angina, heart attack, stroke, head injury, and peptic ulcers while hypertension, shingles, pernicious anaemia, and thyroid disease were more common in women. There was a complex pattern of area differences for individual conditions. Cambridgeshire had generally low prevalences for many diseases, including vascular problems, Gwynedd and Newcastle had less healthy elderly populations, and Nottingham and Newcastle had the highest percentages of housebound. CONCLUSIONS: This study provides the most robust available estimates for life-time prevalence of a variety of health conditions on a regional and national basis. It shows the greatly increased prevalence of disability in the very old population, particularly women.

Analysis of the gene that encodes the complement regulatory protein, membrane inhibitor of reactive lysis (CD59). Identification of an alternatively spliced exon and characterization of the transcriptional regulatory regions of the promoter.

Membrane inhibitor of reactive lysis (MIRL, CD59) is an 18-kDa glycosylphosphatidylinositol-anchored protein that regulates formation of the membrane attack complex of complement. The purpose of these studies was to characterize the gene that encodes CD59. Our experiments redefined the structural organization of the gene by identifying a previously unrecognized alternatively spliced exon. Analysis by PCR of cDNA derived from a variety of cultured human cell lines and from PBMC showed that transcripts containing the alternatively spliced exon sequence were expressed concordantly with transcripts lacking that sequence. Primer extension studies demonstrated that the transcriptional start site of alternatively spliced CD59 mRNA is the same as that of transcripts without the alternatively spliced exon sequence, suggesting that expression of both forms of CD59 mRNA is regulated similarly. Analysis of the promoter region showed that the first 70 nucleotides immediately 5' of the transcriptional start site of the CD59 gene are essential for both constitutive and PMA-responsive transcription; however, responsiveness to PMA is cell line specific. Together, these studies have redefined the organization of the CD59 gene and identified regions of the promoter involved in constitutive and PMA-inducible transcription.

Molecular basis of paroxysmal nocturnal hemoglobinuria.

The purpose of this review is to summarize recent studies that have led to a more complete understanding of the molecular basis of paroxysmal nocturnal hemoglobinuria (PNH). Somatic mutations of PIG-A arising in pluripotent hematopoietic stem cells are necessary for the development of PNH. PIG-A is an X-linked gene that is essential for synthesis of the glycosyl phosphatidylinositol (GPI) moiety that serves as a membrane anchor for a functionally diverse group of cell surface proteins. Consequently, the progeny of stem cells with mutant PIG-A are deficient in all GPI-anchored proteins (GPI-AP). Among the GPI-AP that are expressed on hematopoietic cells are two important regulators of the complement system, decay-accelerating factor, (CD55) and membrane inhibitor of reactive lysis, (CD59). It is the deficiency of erythrocyte CD55 and CD59 that accounts for the intravascular hemolysis and hemoglobinuria that are the clinical hallmarks of PNH. A remarkable feature of PNH is that the peripheral blood is a mosaic composed of variable proportions of GPI-AP+ and GPI-AP- cells and that, in an individual patient, the GPI-AP- cells can be derived from multiple mutant stem cells. Currently, however, there is no evidence that the PIG-A mutation per se provides a proliferative advantage. Thus, PNH is not a monoclonal disease with a malignant phenotype. Rather, the mutant stem cells appear to dominate hematopoiesis because under some pathological conditions, GPI-AP deficiency is advantageous. The close association of PNH with aplastic anemia suggests that the selection pressure arises as a consequence of a specific type of bone marrow injury.

Syngeneic bone marrow transplantation without conditioning in a patient with paroxysmal nocturnal hemoglobinuria: in vivo evidence that the mutant stem cells have a survival advantage.

A 10-year-old girl with paroxysmal nocturnal hemoglobinuria (PNH) received an infusion of syngeneic bone marrow without preparative marrow ablation or immunosuppression. Following transplant, the patient became asymptomatic in concordance with an increase in the percentage of peripheral blood cells with normal expression of glycosyl phosphatidylinositol-anchored proteins (GPI-AP). However, molecular analysis suggested engraftment of a relatively small number of donor stem cells and persistence of an abnormal stem cell with mutant PIG-A. During 17 months of observation, the percentage of cells with normal GPI-AP expression gradually decreased, while intravascular hemolysis progressively increased. Approximately 16.5 months post-transplant, the patient once again became symptomatic. Together, these results indicate that syngeneic marrow infusion provided a clinical benefit by increasing the proportion of erythrocytes with normal expression of GPI-anchored complement regulatory proteins without supplanting the abnormal stem cells. However, evidence of insidious disease progression following the marrow infusion implies that the abnormal stem cells have a survival advantage relative to the transplanted stem cells. Thus, these studies contribute in vivo data in support of the hypothesis that PNH arises as a consequence of a pathological process that selects for hematopoietic stem cells that are GPI-AP-deficient.

Identification and characterization of an inherited mutation of PIG-A in a patient with paroxysmal nocturnal haemoglobinuria.

Analysis of the X-linked gene PIG-A from haemopoietic cells of a female PNH patient showed a homozygous C-55-T substitution that caused replacement of arginine with tryptophan at codon 19. Aval restriction analysis of PIG-A cDNA demonstrated that the patient was homozygous for this mutation, whereas her mother was heterozygous and her father was hemizygous. Flow cytometry, however, showed normal expression of glycosyl phosphatidylinositol anchored proteins on blood cells of the patient's mother and father. Therefore the C-55-T mutation is an inherited sequence variant that does not account for the PNH phenotype of this patient.

Increased lipase inhibition in uremia: identification of pre-beta-HDL as a major inhibitor in normal and uremic plasma.

The hypertriglyceridemia commonly observed in uremia has been attributed to an abnormally high inhibitor activity in plasma for lipoprotein lipase (LPL) and hepatic lipase (HL), both of which have a key role in lipoprotein metabolism. The purpose of this investigation was to establish a relationship between plasma lipase inhibitor activity and hypertriglyceridemia, identify the main plasma lipase inhibitor, and determine the basis for the greater inhibitor activity in uremia. In a mixed population of normal (N = 8) and uremic subjects (N = 12), log-transformed plasma triglycerides correlated with both inhibitor activity and uremic status. However, inhibitor activity was the only retained predictor variable for triglycerides in a multiple linear regression model (r = 0.91; P < 0.0001). An inhibitor isolated from normal plasma was identified as a particle containing apolipoprotein A-I (apo A-I) and 3% phospholipid. This particle, which has pre-beta electrophoretic mobility and a Stokes' radius of 54 A, therefore corresponds to a form of the previously described pre-beta-HDL (free apo A-I) in the non-lipoprotein fraction of plasma. Comparison of normal and uremic plasma indicated that the greater lipase inhibitor activity in the latter could be attributed to an increased concentration of apo A-I in the non-lipoprotein fraction of plasma (pre-beta-HDL), as well as to increased inhibition by the uremic lipoproteins. The increased plasma lipase inhibitor activity may be important in the pathogenesis of hypertriglyceridemia in chronic renal failure.