Biomedical subjects
Publications and source records attributed to J D Fisk.
[structure: see text] We report an initial step toward the development of sulfonamide-based complements for extended peptide strands. A molecule containing one secondary sulfonamide unit and one valine residue linked by a turn-forming segment was found by IR and NMR to exhibit a doubly hydrogen-bonded folding pattern in chloroform.
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The Paced Auditory Serial Addition Test (PASAT) is a commonly used procedure that combines elements of both a working memory task and a test of information processing speed. Patients with multiple sclerosis (MS) have consistently been found to be impaired on this test and it has been recommended as a core outcome measure in clinical trials. The standard score for this task is the number of correct responses at each stimulus presentation rate but a concern has been raised that subjects may ignore some test items in order to chunk the information into manageable portions and avoid performing several cognitive tasks simultaneously. To account for this strategy, one can examine the proportion of correct responses that are consecutive (termed dyads), since such responses require that the task be performed according to the instructions. We compared a group of 35 mildly to moderately disabled MS patients and matched healthy controls on the PASAT. The MS patients made significantly fewer correct responses at the 2 slowest presentation rates (2.4, 2.0 s/digit) while their scores at faster rates (1.6, 1.2 s/digit) did not discriminate them from controls as well. Nevertheless, the MS patients' percentage of dyads was significantly lower than that of the control sample across all stimulus presentation rates. While our study supports the use of the PASAT as a test that distinguishes MS patients from healthy individuals, our results also illustrate problems that lie in the interpretation of this difference in performance. It appears that a chunking strategy may be common in the PASAT, particularly as task demands increase, and that this may mask actual performance differences. If so, the total correct response score alone is limited as a measure of working memory and information processing speed. More detailed analyses of PASAT performance, coupled with other measures of information processing, may help clarify the underlying cognitive deficits of MS patients.
Patients with multiple sclerosis (MS) frequently demonstrate impairments of information-processing speed (IPS) on measures such as the Paced Auditory Serial Addition Test (PASAT; D. M. A. Gronwall, 1977). The authors have previously shown that their new PASAT scoring method (mean dyad score) is better correlated in comparison with more traditional PASAT scoring method(s), with magnetic resonance imaging measurement of the total area (mm2) of white-matter sclerotic lesions (P. J. Snyder & J. C. Cappelleri, 2001). The present study reports that the mean dyad score discriminated 20 relapsing-remitting MS (RRMS) patients from 15 secondary-progressive MS (SPMS) patients noticeably better than did the standard scoring method(s). Mean dyad scores < 4.13 classified patients as having SPMS with 73% accuracy (sensitivity), whereas scores > or = 4.13 classified patients as having RRMS with 80% accuracy (specificity).
[structure: see text]We show that a tetrapeptide with a heterogeneous backbone, i.e., with two different classes of amino acid residues, adopts a hairpin conformation in which each type of residue plays a different structural role. The alpha-residues at the ends form hydrogen bonds characteristic of antiparallel beta-sheet secondary structure, while the central di-beta-peptide segment forms a reverse turn. The configuration of the turn residues is critical to sheet formation.
OBJECTIVE: To estimate the cost-effectiveness (CE) of interferon beta-1b (IFN beta-1b) in slowing disability progression in persons with relapsing-remitting multiple sclerosis (RRMS). METHODS: Treatment program costs and health outcomes are modeled for cohorts of 1,000 females and 1,000 males followed 40 years from onset. Fifteen scenarios model MS natural history progression, treatment efficacy, direct treatment costs, and MS healthcare costs. A single randomized placebo-controlled trial of IFN beta-1b found reduced disease activity by MRI, reduced frequency and severity of exacerbations, and a tendency toward slower disability progression. Disability years avoided are modeled as the primary health outcome analyzed. A ministry of health (MOH) perspective is adopted, using Nova Scotia population-based data. Annual IFN beta-1b direct treatment costs (Can $16,685) are high relative to both MOH healthcare costs per person with MS (Can $2,000) and estimated MOH costs avoided. RESULTS: Given "reference case" assumptions for women with RRMS, treatment reduces lifetime disability years by 10%. Cost per disability year avoided before discounting is Can $189,230 (US $124,892), and Can $274,842 (US $181,395) after discounting at 5%. Estimates for alternative scenarios vary greatly, leaving main findings unchanged. CONCLUSIONS: Using the Expanded Disability Status Scale, cost per disability year avoided due to interferon beta-1b treatment in RRMS is quite high. Comparable CE estimates, using MS-specific or generic health-related quality-of-life outcome measures, are even higher. Further research is required to better measure treatment effects, modification of MS natural history, and net societal costs of IFN beta-1b in RRMS.
Reduced information processing efficiency, consequent to impaired neural transmission, has been proposed as underlying various cognitive problems in patients with Multiple Sclerosis (MS). This study employed two measures developed from experimental psychology that control for the potential confound of perceptual-motor abnormalities (Salthouse, Babcock, & Shaw, 1991; Sternberg, 1966, 1969) to assess the speed of information processing and working memory capacity in patients with mild to moderate MS. Although patients had significantly more cognitive complaints than neurologically intact matched controls, their performance on standard tests of immediate memory span did not differ from control participants and their word list learning was within normal limits. On the experimental measures, both relapsing-remitting and secondary-progressive patients exhibited significantly slowed information processing speed relative to controls. However, only the secondary-progressive patients had an additional decrement in working memory capacity. Depression, fatigue, or neurologic disability did not account for performance differences on these measures. While speed of information processing may be slowed early in the disease process, deficits in working memory capacity may appear only as there is progression of MS. It is these latter deficits, however, that may underlie the impairment of new learning that patients with MS demonstrate.
OBJECTIVE: To prospectively analyze the association between changes in cognitive function and circulating anticardiolipin antibodies (aCL) over a period of 5 years in patients with systemic lupus erythematosus (SLE). METHODS: Cognitive function was assessed in 51 unselected female SLE patients at baseline and after a mean followup of 64.5 months (range 52-71 months), using standardized tests of cognitive function, i.e., the Wechsler Adult Intelligence Scale-Revised, the Wechsler Memory Scale-Revised, and the California Verbal Learning Test. Circulating IgG, IgA, and IgM aCL and anti-double-stranded DNA (anti-dsDNA) antibody levels were determined by enzyme-linked immunosorbent assay on 4-7 occasions over the same time period. Persistent antibody reactivity was defined as levels more than 2 standard deviations (moderately positive) and more than 5 standard deviations (highly positive) above the mean for normal controls over the duration of the study. Changes in overall cognitive performance and in raw scores on individual cognitive tests were compared in patients who were persistently positive or negative for aCL. RESULTS: At baseline 11 patients (22%) were cognitively impaired, compared with 7 (14%) at followup. Between 16% and 37% of patients had persistently elevated aCL levels of different isotypes. There was no significant difference in the prevalence of overall cognitive impairment in patients who were persistently positive for aCL compared with those who were not. In contrast, over the period of study, patients who had persistent IgG aCL positivity had a reduction in psychomotor speed, and patients who had persistent IgA aCL positivity had a reduction in conceptual reasoning and executive ability. Similar associations with anti-dsDNA antibodies were not found. CONCLUSION: These results suggest that IgG and IgA aCL may be responsible for long-term subtle deterioration in cognitive function in patients with SLE.
The activities of daily living (ADL) functioning of 26 subjects with Alzheimer's disease was measured using the Assessment of Motor and Process Skills (AMPS) and family informants' Older Americans Resources and Services (OARS) Activities of Daily Living (ADL) reports. Concordance with a clinician's ratings of subjects' level of ADL functioning was achieved for 77% of the subjects based on their AMPS ADL process ability measures and for 54% for the subjects based on their family informants' OARS ADL ratings. In cases of discordance, subjects' AMPS ADL process ability measures were just as likely to overestimate (11.5%) as to underestimate (11.5%) subjects' ADL functioning. In contrast, 46% of the informants overestimated their family members' ADL functioning, and this was more likely to occur when subjects' cognitive impairment was mild.
Alzheimer's disease raises numerous ethical issues which vary and evolve over the course of the illness. In recognition of the need for ongoing discussion of these issues, the Alzheimer Society of Canada established a Task Force on Ethics in 1995. Through a process of "discourse ethics" and consultation on a national scale, the Task Force produced a series of guidelines dealing with the issues of: communicating the diagnosis, driving, respecting individual choice, quality of life, participation in research, genetic testing, the use of restraints, and end-of-life care. This manuscript presents a summary of these guidelines as well as a summary of the ideas on which they were based. It was the hope of the Society that the publication of these guidelines will serve to facilitate discussion of the ethics of care of those with Alzheimer's disease.
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Despite their limitations, mental status tests and self/proxy reports of instrumental activities of daily living (IADL) are often used to predict functional competence. In contrast, the Assessment of Motor and Process Skills (AMPS) is a direct observational assessment of IADL competence. Sixty-four community-dwelling elderly (20 Alzheimer's disease [AD] patients and 44 nondemented) were assessed with the AMPS, the Mini-Mental State Examination (MMSE), and the Older Americans Resources and Services (OARS)-IADL. Performance on all three assessments was significantly lower for the AD sample. The MMSE did not correlate significantly with the AMPS motor ability measures but it correlated modestly with the AMPS process ability measures. The OARS-IADL correlated significantly with the AMPS motor ability measure for the nondemented sample alone. Although mental status and self/proxy assessments provide some insight into individuals' IADL competence, direct observation of IADL task performance provides additional information regarding the subtle process and motor skills changes that occur in progressive dementing conditions.
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A number of intercorrelated factors, including level of neurologic impairment, age, and conceptual reasoning, appear to be related to memory performance among patients with Multiple Sclerosis (MS). A battery of neuropsychological tests was administered to 131 patients with MS ranging in age from 19 to 76 years, with a mean symptom duration of 12.3 years and an overall mild level of MS-related neurologic impairment. Regression analyses indicated that neurologic impairment and age each contributed uniquely to the prediction of delayed free recall of a word list. Furthermore, when the effect of conceptual reasoning was accounted for, neither neurologic impairment nor age were significantly related to recall. Thus, a mediated relation was confirmed, supporting the idea that a significant portion of neurologic-impairment-related and age-related differences in recall are due to differences in conceptual reasoning that are important for optimal performance on tests of recall. Additional analyses failed to support a similar mediated relation using recognition rather than recall as the measure of memory performance.
The Assessment of Motor and Process Skills (AMPS) is an observational measure of functional competence in instrumental activities of daily living (IADL) that was designed to overcome the limitations of self reports and proxy reports. The AMPS allows simultaneous evaluation of the underlying motor and process (organizational/adaptive) skills necessary for competent task performance. We examined the IADL performance of 22 community-dwelling patients with mild to moderate MS in comparison to nondisabled subjects matched for age and gender. Functional competence of the MS subjects, as measured by the AMPS, was poorer than that of the control group. Many MS subjects who would not have been expected to have IADL difficulties on the basis of ratings of neurologic impairment were impaired in their IADL performance. For some patients, IADL impairment reflected deficits in their motor and process skills, whereas for others, process skill impairments alone were responsible for deficient task performance.
Previous studies have reported variable prevalence of pain in multiple sclerosis (MS) and have not documented the impact of pain on daily living. In this consecutive series, we report on data collected from structured interviews with 85 patients seen within a 16-month period at a regional referral clinic. The prevalence of pain for the month preceding assessment was 53%. There were no significant differences between patients who did and those who did not report pain on the basis of patient demographics (age, gender) and disease characteristics (disease subtype, duration and neurologic symptom severity). Disease duration and neurologic symptom severity were significantly correlated with the number of hours of pain per week but were not correlated with pain severity, the number of pain sites or pain-related distress. There was wide variability in the number of pain hours/week reported with 17.6% of the sample reporting continuous pain for the month preceding assessment. Sixty-five percent of patients with pain reported taking medications for pain and 90% of these patients evaluated their medication(s) as 50% effective or better. Nevertheless, patients with pain reported poorer mental health and more social-role handicap. Discussion focuses on the need for routine assessment of pain and the comprehensive evaluation of the effectiveness of pain interventions in the therapeutic management of patients with MS.
The fatigue impact scale (FIS) was developed to improve our understanding of the effects of fatigue on quality of life. The FIS examines patients' perceptions of the functional limitations that fatigue has caused over the past month. FIS items reflect perceived impact on cognitive, physical, and psychosocial functioning. This study compared 145 patients referred for investigation of chronic fatigue (ChF) with 105 patients with multiple sclerosis (MS) and 34 patients with mild hypertension (HT). Internal consistency for the FIS and its three subscales was > .87 for all analyses. Fatigue impact was highest for the ChF group although the MS group's reported fatigue also exceeded that of the HT group. Discriminant function analysis correctly classified 80.0% of the ChF group and 78.1% of the MS group when these groups were compared. This initial validation study indicates that the FIS has considerable merit as a measure of patient's attribution of functional limitations to symptoms of fatigue.
Nervous system involvement in SLE encompasses a wide array of clinical manifestations which may reflect multiple etiologic factors including autoantibodies to nervous tissue antigens. The aim of the present study was to examine the association between autoantibodies to a wide range of brain antigens and cognitive abnormalities in an unselected population of 70 SLE patients. Using a battery of standardized neuropsychological tests, cognitive impairment was identified in 15/70 (21%) SLE patients compared with 1/25 (4%) patients with rheumatoid arthritis and 1/23 (4%) healthy subjects (P = 0.04). Integral membrane proteins were isolated from dissociated brain cells by temperature-induced phase separation with Triton X-114. Synaptosomes were isolated by differential centrifugation and membrane enriched fractions were prepared by lectin affinity chromatography. Western blotting identified IgG reactivity to a wide range of proteins (MW 22-52 K) in SLE patients. The proteins identified were distinct from well-characterized intracellular antigens including ribosomal P proteins. There was no significant difference in the prevalence of anti-brain antibodies between SLE patients who were cognitively impaired and those who were not impaired. Furthermore, there was no association between the presence of autoantibodies and subsets of cognitive dysfunction. These results suggest that circulating autoantibodies to brain antigens are not responsible for the abnormalities in cognitive function in SLE patients.