The SIGAM mobility grades: a new population-specific measure for lower limb amputees.

PURPOSE: To develop a valid measure of lower limb amputee mobility suitable for routine clinical use, including monitoring change. METHODS: The Special Interest Group in Amputee Medicine (SIGAM) described a single-item scale comprising six clinical grades (A-F) of amputee mobility. A self-report questionnaire was developed and algorithm designed to facilitate grade assignment. Reproducibility of the questionnaire and grades were assessed in 62 amputees. Concurrent validity and sensitivity to change were investigated using the timed walking test (TWT). The mobility construct was examined in 200 amputees, using item response theory, by co-calibration with the Rivermead Mobility Index (RMI) on the same patients. RESULTS: Patients included 144 males and 66 females, aged 13-90. Intraclass correlation coefficients and reproducibility kappa values were satisfactory. Observers agreed 100% in using the algorithm. TWT improved as SIGAM grade increased. Examination of psychometric properties revealed the SIGAM item fitted within the RMI mobility matrix. Average measures for the six grades were ordered correctly. There was no local dependency or differential item functioning for clinically relevant patient subgroups. The SIGAM scale showed an effect size of 10.66. CONCLUSIONS: The SIGAM mobility grades represent a novel, valid, clinically useful measure of amputee mobility which is also sensitive to change.

Is the Rivermead Mobility Index appropriate to measure mobility in lower limb amputees?

PURPOSE: Measurement of lower limb amputee mobility was investigated using the Rivermead Mobility Index (RMI). METHOD: Reliability and reproducibility were assessed in 62 patients. The timed waking test (TWT) was used to investigate concurrent validity. The RMI construct was examined in 200 established amputees. RESULTS: One hundred and forty-four males and 66 females, aged 13-90 were recruited. Intraclass correlation coefficients and kappa statistics showed good reproducibility. Spearman correlation coefficient between the RMI and TWT -0.58 (p<0.000). Psychometric properties of the RMI were tested using item response theory. Hierachical differences in RMI grades were identified in amputees compared with neurologically impaired patients for which the RMI was developed. The RMI construct was not unidimensional, with redundancy of items and local dependency. At the upper end of the scale there were insufficient items measuring high levels of mobility. Finally, differential item functioning showed items behaving differently for patient subgroups. CONCLUSIONS: Although initial impressions suggest the RMI is a useful measure of lower limb amputee mobility, further analysis shows it is not appropriate for all amputees, with a number of limitations of its psychometric properties. Its use is not recommended in this population.

Effective induction of simian immunodeficiency virus-specific cytotoxic T lymphocytes in macaques by using a multiepitope gene and DNA prime-modified vaccinia virus Ankara boost vaccination regimen.

DNA and modified vaccinia virus Ankara (MVA) are vaccine vehicles suitable and safe for use in humans. Here, by using a multicytotoxic T-lymphocyte (CTL) epitope gene and a DNA prime-MVA boost vaccination regimen, high levels of CTLs specific for a single simian immunodeficiency virus (SIV) gag-derived epitope were elicited in rhesus macaques. These vaccine-induced CTLs were capable of killing SIV-infected cells in vitro. Fluorescence-activated cell sorter analysis using soluble tetrameric major histocompatibility complex-peptide complexes showed that the vaccinated animals had 1 to 5% circulating CD8(+) lymphocytes specific for the vaccine epitope, frequencies comparable to those in SIV-infected monkeys. Upon intrarectal challenge with pathogenic SIVmac251, no evidence for protection was observed in at least two of the three vaccinated animals. This study does not attempt to define correlates of protective immunity nor design a protective vaccine against immunodeficiency viruses, but it demonstrates clearly that the DNA prime-MVA boost regimen is an effective protocol for induction of CTLs in macaques. It also shows that powerful tools for studying the role of CTLs in the control of SIV and human immunodeficiency virus infections are now available: epitope-based vaccines, a protocol for an effective induction of CTLs in primates, and a simple and sensitive method for quantitation of epitope-specific T cells. The advantages of the DNA prime-MVA boost regimen as well as the correlations of tetramer staining of peripheral blood lymphocytes with CTL killing in vitro and postchallenge control of viremia are discussed.

Effective induction of HIV-specific CTL by multi-epitope using gene gun in a combined vaccination regime.

Reliable and effective induction of cytotoxic T-lymphocytes (CTL) is one of the prime objectives of vaccine research. Previously, novel HIV vaccine candidates were constructed as a string of CTL epitopes (20 human, 3 macaque and 1 mouse) delivered using a DNA vector [Hanke T, Schneider J, Gilbert SG, Hill AVS, McMichael A. DNA multi-CTL epitope vaccines for HIV and Plasmodium falciparum: immunogenicity in mice. Vaccine 1998;16:426-435.] or modified vaccinia Ankara (MVA [Hanke T, Blanchard TJ, Schneider J, Ogg GS, Tan R, Becker MSC, Gilbert SG, Hill AVS, Smith GL, McMichael A. Immunogenicities of intravenous and intramuscular administrations of MVA-based multi-CTL epitope vaccine for HIV in mice. J Gen Virol 1998;79:83-90.]), i.e. vaccine vehicles acceptable for use in humans. In mice, a single intramuscular (i.m.) needle injection of either vaccine alone elicited good CTL responses. Here, it is demonstrated that the multi-epitope DNA also induced CTL when delivered intradermally using the Accell gene gun. The CTL responses increased after re-immunization and after three deliveries were comparable to those induced by a single i.m. injection. Recent evidence indicates that combining routes and vaccine vehicles enhances the immunogenicity of vaccine-delivered or -encoded antigens. Here, it is shown that administration of DNA by an i.m. priming/gene gun boosting more efficiently induced CTL than gene gun priming/i.m. boosting. A similar increment was obtained by sequential vaccinations using a gene gun-delivered DNA followed by recombinant MVA. Thus particular sequences of routes or vaccine vehicles rather than simple prime-boost delivery of a single vaccine is critical for an effective elicitation of CTL.

The influence of prior stroke on the prosthetic rehabilitation of lower limb amputees.

Concurrent stroke is believed to have an adverse influence on the process and outcome of prosthetic rehabilitation, but there is limited published evidence for this. The aim of this study was to establish a clearer picture in order to assist decision making for both patients and professionals. Demographic and clinical data were collected from all lower limb amputees referred from North and West Yorkshire for prosthetic rehabilitation. Additional data were collected from all new lower limb amputees in three of the referring health districts, irrespective of prosthetic referral. Patients with prior stroke were less likely to be referred for prosthetic rehabilitation. Improved mobility and independence were seen following prosthetic rehabilitation irrespective of prior stroke. The group with prior stroke compared well with the non-stroke group in terms of walking aid usage, but a smaller proportion of the stroke group were able to walk 30 m without stopping and there were trends for smaller gains in independence in the stroke group. Nevertheless, this study demonstrates that prosthetic rehabilitation can be successful in a selected amputee population with prior stroke. In those who continue prosthetic use for one year, outcome is similar to that in patients without stroke.

Sequential study of bacterial antibody levels and faecal flora in rheumatoid arthritis patients taking sulphasalazine.

Faecal and serum samples were collected from 31 patients with active RA during treatment with DMARD sulphasalazine (SASP). These were examined for changes in faecal flora and antibodies to bacterial antigens respectively. Faecal counts of Clostridium perfrigens but not Escherichia coli or total aerobic or anaerobic counts fell significantly after 2 weeks of treatment, this decrease being maintained throughout the treatment period. There was, however, no relationship between changes in the faecal carriage of this micro-organism and response to drug treatment, as assessed using clinical and biochemical indicators of disease activity. Changes in antibody levels to antigen preparations of this organism were also unrelated to response to drug treatment. These results suggest that the anti-rheumatic properties of SASP are independent of its antibacterial effect on bacteria in the bowel and also that neither faecal carriage of, nor antibody responses to this bacterium are involved in disease pathogenesis. Antibody levels to an antigen preparation of Cl. perfringens were found to be significantly lower in those patients who respond well to SASP than those patients who show poor response; this may prove useful as a clinical marker for predicting those patients likely to respond to SASP therapy.

Extracellular proteolytic activation of bacteriolytic peptidoglycan hydrolases of Staphylococcus simulans biovar staphylolyticus.

Staphylococcus simulans biovar staphylolyticus secreted two bacteriolytic peptidoglycan hydrolases as proproteins that were activated as they were processed by an extracellular sulphydryl protease. This processing resulted in the production of multiple molecular-mass forms of each enzyme. Cells from early exponential phase cultures were susceptible to lysis by the mature forms of each of the peptidoglycan hydrolases whereas stationary phase cells were resistant. Thus secretion of these bacteriolytic enzymes during early exponential growth as precursors that are activated later by the protease would provide time for the cells to become resistant.

Comparison of faecal florae in patients with rheumatoid arthritis and controls.

The faecal flora of 25 out-patients with active rheumatoid arthritis (RA) was compared with that of 25 age- and sex-matched controls. A comprehensive survey revealed a significantly higher carriage rate of Clostridium perfringens in the RA population (88%) than controls (48%) (p less than 0.01). Coliform counts also tended to be higher, but there were no other significant differences between patients and controls. When the study was enlarged to include a further 113 RA patients with variable disease activity and a further 38 controls, clostridia were again more frequently carried by those with RA (70%) than controls (45%) (p less than 0.01) and clostridial counts were significantly higher in the patient group (p = 0.006). Moreover, counts in patients with active or moderately active disease were significantly higher than in those with inactive disease (p less than 0.001). These data are consistent with the hypothesis that Cl. perfringens plays a role in triggering or is otherwise associated with disease activity in RA. The findings may be alternatively an effect of the disease or its treatment with, for example, anti-inflammatory drugs.

Effects of sulphasalazine on faecal flora in patients with rheumatoid arthritis: a comparison with penicillamine.

Twenty-six out-patients with active rheumatoid arthritis (RA) were randomly allocated to treatment with sulphasalazine (SASP) or D-penicillamine (DPA). Faecal samples were collected from all patients at 4-weekly intervals and examined for changes in faecal flora during treatment. Both treatment groups showed substantial clinical improvement. In the SASP-treated group this was accompanied by significant falls in counts of Cl. perfringens and E. coli. No such changes were seen in the DPA-treated group. These results suggest that SASP's efficacy in RA may be related to its antibacterial properties.

A study to determine the active moiety of sulphasalazine in rheumatoid arthritis.

Thirty patients with active rheumatoid arthritis (RA) participated in an open study of 6 months' treatment with either 5-aminosalicylic acid (5-ASA) or sulphapyridine (SP), the two moieties of sulphasalazine (SASP). Patients were assessed at regular intervals using clinical and biochemical tests designed to detect specific antirheumatic activity. Patients taking SP showed significant improvement in disease activity, but those taking 5-ASA did not improve, despite the fact that high serum concentrations of 5-ASA and acetyl 5-ASA were achieved. These results suggest that SP is the active moiety of SASP. Its possible mode of action is discussed. Nausea was a frequent problem in patients taking SP. Unless this can be overcome, SP is unlikely to offer any therapeutic advantages over SASP in the treatment of RA.

5-Aminosalicylic acid or sulphapyridine. Which is the active moiety of sulphasalazine in rheumatoid arthritis?

Thirty patients with active rheumatoid arthritis participated in an open study of 6 months' treatment with either 5-aminosalicylic acid or sulphapyridine, the two moieties of sulphasalazine. Patients were assessed at regular intervals using a number of clinical and biochemical tests designed to detect specific antirheumatic activity. Patients taking sulphasalazine showed significant improvement in most parameters of disease activity, but those taking 5-aminosalicylic acid did not improve despite the fact that high serum concentrations of 5-aminosalicylic acid and acetyl 5-aminosalicylic acid were achieved. These results suggest that sulphapyridine is the active moiety of sulphasalazine. Its possible mode of action is discussed. Nausea was a frequent problem in patients taking sulphapyridine. Unless this problem can be overcome, sulphapyridine is unlikely to offer any therapeutic advantages over sulphasalazine in the treatment of rheumatoid arthritis.

Comparison between penicillamine and sulphasalazine in rheumatoid arthritis: Leeds-Birmingham trial.

Sulphasalazine was first formulated by Svartz in the early 1940s, specifically for use as a remission inducing drug in rheumatoid arthritis. After the publication of an unfavourable trial, however, the drug was restricted to patients with ulcerative colitis. In the late 1970s sulphasalazine was re-examined in rheumatoid arthritis and favourable results reported in "open" trials. A double blind controlled trial was therefore conducted comparing enteric coated sulphasalazine and D-penicillamine in patients with active rheumatoid arthritis. A total of 63 patients were recruited in two centres; 31 were treated with sulphasalazine and 32 received penicillamine. After 16 weeks' treatment both drugs had produced significant improvements in clinical score, pain score measured on a visual analogue scale, grip strength, Ritchie articular index, erythrocyte sedimentation rate, and serum C reactive protein concentration. Nausea was the major side effect in the sulphasalazine treated group. No potentially dangerous effects of sulphasalazine were encountered in contrast with those seen in the penicillamine group. The results suggest that sulphasalazine is an effective and safe drug capable of producing remissions in active rheumatoid arthritis. They also lend confidence to the use of preliminary "open" trials as a means of screening for remission inducing drugs in rheumatoid arthritis.