The Multiple Sclerosis Severity Score: fluctuations and prognostic ability in a longitudinal cohort of patients with MS.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS), combining the Expanded Disability Status Scale (EDSS) and disease duration, attempts to stratify multiple sclerosis (MS) patients based on their rate of progression. Its prognostic ability in the individual patient remains unproven. OBJECTIVES: To assess the stability of MSSS within individual persons with MS in a longitudinal cohort, to evaluate whether certain factors influence MSSS variability, and to explore the ability of MSSS to predict future ambulatory function. METHODS: A single-center retrospective review was performed of patients following a single provider for at least 8 years. Mixed model regression modeled MSSS over time. A Kaplan-Meier survival plot was fitted, using change of baseline MSSS by at least one decile as the event. Cox modeling assessed the influence of baseline clinical and demographic factors on the hazard of changing MSSS by at least one decile. Linear models evaluated the impact of baseline EDSS, baseline MSSS, and other factors on the Timed 25-Foot Walk (T25FW). RESULTS: Out of 122 patients, 68 (55.7%) deviated from baseline MSSS by at least one decile. Final T25FW had slightly weaker correlation to baseline MSSS than to baseline EDSS, which was moderately strongly correlated with future log T25FW. CONCLUSION: Individual MSSS scores often vary over time. Clinicians should exercise caution when using MSSS to prognosticate.

A randomized trial of teriflunomide added to glatiramer acetate in relapsing multiple sclerosis.

BACKGROUND: Teriflunomide is a once-daily oral immunomodulator for the treatment of relapsing-remitting MS. OBJECTIVE: To evaluate the safety and tolerability of teriflunomide as add-on therapy to a stable dose of glatiramer acetate (GA) in patients with relapsing forms of MS (RMS). METHODS: Phase II, randomized, double-blind, add-on, placebo-controlled study. The primary objective was to assess safety and tolerability; secondary objectives were to evaluate effects of treatment on disease activity assessed by MRI and relapse. RESULTS: Patients with RMS on GA (N = 123) were randomized 1:1:1 to receive teriflunomide 14 mg (n = 40), 7 mg (n = 42), or placebo (n = 41) for 24 weeks; 96 patients entered the 24-week extension, remaining on original treatment allocation. Teriflunomide was well tolerated over 48 weeks. The frequency of adverse events (AEs) was low across all groups; 5 (12.2%), 3 (7.1%), and 2 (5.0%) patients in the 14 mg, 7 mg, and placebo groups, respectively, discontinued treatment due to AEs. Teriflunomide reduced the number of T1-Gd lesions vs placebo (14 mg: 46.6% relative reduction, p = 0.1931; 7 mg: 64.0%: relative reduction, p = 0.0306). CONCLUSIONS: Teriflunomide added to stable-dose GA had acceptable safety and tolerability, and reduced some MRI markers of disease activity compared with GA alone. NCT00475865 (core study); NCT00811395 (extension).

Clinical course in multiple sclerosis patients presenting with a history of progressive disease.

OBJECTIVES: Determine the likelihood of worsening clinical status in the near-term course of progressive MS and evaluate the predictive validity of our diagnostic impression of progressive forms of MS. METHODS: Retrospective review of charts from 175 patients seen between 2000 and 2007 who were diagnosed with either primary or secondary progressive multiple sclerosis. Data extracted included demographic factors, neurological examination findings to determine EDSS, timed 25 foot walk (T25FW) when available, duration of symptoms, clinical course as documented on initial visit, and history of disease-modifying agent (DMA) use. Significant change in EDSS was defined as a change of one point or more from initial to final clinical evaluation. Significant change in T25FW was defined as a ±20% difference from baseline. RESULTS: Of the 175 charts reviewed, 35 patients met criteria and had sufficient documentation to allow for EDSS abstraction. Twenty-four patients (68.6%) showed no significant change in EDSS from baseline while eleven patients (31.4%) worsened and none improved. For those patients that had T25FW data available, 6 out of 20 (30%) patients worsened while 11 (55%) showed no change. Three patients (15%) improved. CONCLUSION: In this observational study at a tertiary care MS center, patients classified as progressive MS did not progress as often, or as rapidly, as previous studies have suggested. Greater than two-thirds of patients in this cohort, did not increase 1 step on the EDSS.

Assessing disability progression with the Multiple Sclerosis Functional Composite.

BACKGROUND: The initial Multiple Sclerosis Functional Composite (MSFC) proposal was a three-part composite of quantitative measures of ambulation, upper extremity function, and cognitive function expressed as a single composite Z-score. However, the clinical meaning of an MSFC Z-score change is not obvious. This study instead used MSFC component data to define a patient-specific disease progression event. OBJECTIVE: Evaluate a new method for analyzing disability progression using the MSFC. METHODS: MSFC progression was defined as worsening from baseline on scores of at least one MSFC component by 20% (MSFC Progression-20) or 15% (MSFC Progression-15), sustained for >or=3 months. Progression rates were determined using data from natalizumab clinical studies (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]). Correlations between MSFC progression and other clinical measures were determined, as was sensitivity to treatment effects. RESULTS: Substantial numbers of patients met MSFC progression criteria, with MSFC Progression-15 being more sensitive than MSFC Progression-20, at both 1 and 2 years. MSFC Progression-20 and MSFC Progression-15 were related significantly to Expanded Disability Status Scale (EDSS) score change, relapse rate, and the SF-36 Physical Component Summary (PCS) score change. MSFC Progression-20 and MSFC Progression-15 at 1 year were predictive of EDSS progression at 2 years. Both MSFC progression end points demonstrated treatment effects in AFFIRM, and results were replicated in SENTINEL. CONCLUSION: MSFC Progression-20 and MSFC Progression-15 are sensitive measures of disability progression; correlate with EDSS, relapse rates, and SF-36 PCS; and are capable of demonstrating therapeutic effects in randomized, controlled clinical studies.

Microbial activity and diversity during extreme freeze-thaw cycles in periglacial soils, 5400 m elevation, Cordillera Vilcanota, Perú.

High-elevation periglacial soils are among the most extreme soil systems on Earth and may be good analogs for the polar regions of Mars where oligotrophic mineral soils abut with polar ice caps. Here we report on preliminary studies carried out during an expedition to an area where recent glacial retreat has exposed porous mineral soils to extreme, daily freeze-thaw cycles and high UV fluxes. We used in situ methods to show that inorganic nitrogen (NO(3) (-) and NH(4) (+)) was being actively cycled even during a period when diurnal soil temperatures (5 cm depth) ranged from -12 to 27 degrees C and when sub-zero, soil cooling rates reached 1.8 degrees C h(-1) (the most rapid soil cooling rates recorded to date). Furthermore, phylogenetic analyses of microbial phylotypes present at our highest sites (5410 m above sea level) showed the presence of nitrifying bacteria of the genus Nitrospira and newly discovered nitrite-oxidizing Betaproteobacteria. These soils were overwhelmingly dominated (>70% of phylotypes) by photosynthetic bacteria that were related to novel cyanobacteria previously found almost exclusively in other plant-free, high-elevation soils. We also demonstrated that soils from our highest sites had higher potential for mineralizing glutamate and higher microbial biomass than lower elevation soils that had been more recently covered by ice. Overall, our findings indicate that a diverse and robustly functioning microbial ecosystem is present in these previously unstudied high-elevation soils.

Nitrogen preferences and plant-soil feedbacks as influenced by neighbors in the alpine tundra.

Plant resource partitioning of chemical forms of nitrogen (N) may be an important factor promoting species coexistence in N-limited ecosystems. Since the microbial community regulates N-form transformations, plant partitioning of N may be related to plant-soil feedbacks. We conducted a (15)N tracer addition experiment to study the ability of two alpine plant species, Acomastylis rossii and Deschampsia caespitosa, to partition organic and inorganic forms of N. The species are codominant and associated with strong plant-soil feedbacks that affect N cycling. We manipulated interspecific interactions by removing Acomastylis or Deschampsia from areas where the species were codominant to test if N uptake patterns varied in the presence of the other species. We found that Deschampsia acquired organic and inorganic N more rapidly than Acomastylis, regardless of neighbor treatment. Plant N uptake-specifically ammonium uptake-increased with plant density and the presence of an interspecific neighbor. Interestingly, this change in N uptake was not in the expected direction to reduce niche overlap and instead suggested facilitation of ammonium use. To test if N acquisition patterns were consistent with plant-soil feedbacks, we also compared microbial rhizosphere extracellular enzyme activity in patches dominated by one or the other species and in areas where they grew together. The presence of both species was generally associated with increased rhizosphere extracellular enzyme activity (five of ten enzymes) and a trend towards increased foliar N concentrations. Taken together, these results suggest that feedbacks through the microbial community, either in response to increased plant density or specific plant neighbors, could facilitate coexistence. However, coexistence is promoted via enhanced resource uptake rather than reduced niche overlap. The importance of resource partitioning to reduce the intensity of competitive interactions might vary across systems, particularly as a function of plant-soil feedbacks.

Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment.

The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

A microcantilever-based pathogen detector.

The ability to detect small amounts of materials, especially bacterial organisms, is important for medical diagnostics and national security issues. Engineered micromechanical systems provide one approach for constructing multifunctional, highly sensitive, real-time, immunospecific biological detectors. We present qualitative detection of specific Salmonella enterica strains using a functionalized silicon nitride microcantilever. Detection is achieved due to a change in the surface stress on the cantilever surface in situ upon binding of a small number of bacteria. Scanning electron micrographs indicate that less than 25 adsorbed bacteria are required for detection.

Multiple sclerosis characteristics in African American patients in the New York State Multiple Sclerosis Consortium.

The objective of this study was to determine the clinical characteristics of multiple sclerosis (MS) in African American (AA) patients in the New York State Multiple Sclerosis Consortium (NYSMSC) patient registry. The NYSMSC is a group of 18 MS centers throughout New York State organized to prospectively assess clinical characteristics of MS patients. AAs comprise 6% (329) of the total NYSMSC registrants (5602). Demographics, disease course, therapy, and socioeconomic status were compared in AA registrants versus nonAfrican Americans (NAA). There was an increased female preponderance and a significantly younger age at diagnosis in the AA group. AA patients were more likely to have greater disability with increased disease duration. No differences were seen in types of MS and use of disease modifying therapies. Our findings suggest a racial influence in MS. Further genetic studies that consider race differences are warranted to elucidate mechanisms of disease susceptibility.

Effect of dissolution kinetics on feature size in dip-pen nanolithography.

We have investigated the effects of humidity, tip speed, and dwell time on feature size during dip pen nanolithography. Our results indicate a transition between two distinct deposition regimes occurs at a dwell time independent of humidity. While feature size increases with humidity, the relative increase is independent of dwell time. The results are described by a model that accounts for detachment and reattachment at the tip. The model suggests that, at short dwell times (high speed), the most important parameter controlling the feature size is the activation energy for thiol detachment.

Patient satisfaction after LASIK for myopia.

PURPOSE: To determine satisfaction among patients treated with laser-in-situ-keratomileusis (LASIK) for various degrees of myopia (-0.75 D to -16.00 D) and myopic astigmatism (+0.50 D to +4.50 D) and assess factors which may affect satisfaction. METHODS: One-hundred seventy-four consecutive patients treated with LASIK between November 1, 1997 and October 31, 1998 were surveyed. Charts were reviewed to collect refractive data. RESULTS: Eighty-three patients (163 eyes) returned surveys for a response rate of 53%. Of the responders, 55% were female, the average age was 39.6 years (range 21-59), the mean preoperative sphere was -6.36 +/- 0.23 D, cylinder +0.94 +/- 0.07 D, and spherical equivalent-5.89 +/- 0.23 D. Ninety-six percent of eyes enjoyed freedom from corrective lenses following LASIK. Twenty-nine percent reported reduced night vision clarity following LASIK and 27% noted more eye dryness following LASIK. Overall, 84.8% were at least "very pleased" with the results of the procedure and 97% indicated that they would decide again to have LASIK. Uncorrected visual acuity and lower preoperative cylinder correlated positively with satisfaction, while increased postoperative dry eyes correlated negatively with satisfaction. CONCLUSIONS: This study demonstrates a very high level of patient satisfaction following excimer laser treatment for myopia and myopic astigmatism. A great deal of literature has evaluated objective outcomes of LASIK, but this is one of few studies to examine patient satisfaction.

Are quantitative functional measures more sensitive to worsening MS than traditional measures?

The authors used data collected prospectively during a multicenter trial in 133 patients with secondary progressive MS to assess the relative sensitivity of quantitative functional tests and traditional measures, including the Expanded Disability Status Scale (EDSS) and Ambulation Index. Quantitative functional measures worsened in 69% of patients during an average of 6 months of observation, whereas the Clinical Global Impression of Change worsened in 33% and the EDSS worsened in 25% of patients. These changes should be interpreted in the context of the test-retest reliability for each measure.

A profile of multiple sclerosis: the New York State Multiple Sclerosis Consortium.

We have obtained a current profile of multiple sclerosis York State through a centralized patient registry and standardized data collection instrument associated with the New York State Multiple Sclerosis Consortium of 12 MS centers located throughout the state. Data from the first 3019 patients with clinically definite MS revealed a clear relationship between MS disease type, duration of disease, and severity of physical disability. Patients with relapsing disease had disease durations approximately half as long as those with progressive forms of the disease (means approximately 6 years versus 11 years). The majority of patients with relapsing disease had Expanded Disability Status Scale (EDSS) scores of 4.0 or less (self-sustained, fully ambulatory), whereas the majority of patients with progressive disease types had EDSS scores of 6.0 or greater (at least unilateral assist for walking). These findings emphasize the importance of early intervention in patients with relapsing disease to slow or prevent the accumulation of physical disability associated with progressive types of disease. Progressive disease was associated with lack of full-time employment and being disabled before the age of 60 years. Patients with relapsing disease were more likely to be employed and have private forms of insurance, whereas patients with progressive types of disease were more likely to have government-supported insurance to cover medical expenses.

Development of a multiple sclerosis functional composite as a clinical trial outcome measure.

The primary clinical outcome measure for evaluating multiple sclerosis in clinical trials has been Kurtzke's expanded disability status scale (EDSS). New therapies appear to favourably impact the course of multiple sclerosis and render continued use of placebo control groups more difficult. Consequently, future trials are likely to compare active treatment groups which will most probably require increased sample sizes in order to detect therapeutic efficacy. Because more responsive outcome measures will be needed for active arm comparison studies, the National Multiple Sclerosis Society's Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis appointed a Task Force that was charged with developing improved clinical outcome measures. This Task Force acquired contemporary clinical trial and historical multiple sclerosis data for meta-analyses of primary and secondary outcome assessments to provide a basis for recommending a new outcome measure. A composite measure encompassing the major clinical dimensions of arm, leg and cognitive function was identified and termed the multiple sclerosis functional composite (MSFC). The MSFC consists of three objective quantitative tests of neurological function which are easy to administer. Change in this MSFC over the first year of observation predicted subsequent change in the EDSS, suggesting that the MSFC is more sensitive to change than the EDSS. This paper provides details concerning the development and testing of the MSFC.

Evaluation of recommendations for replication-competent retrovirus testing associated with use of retroviral vectors.

With input from the gene therapy community, CBER is actively examining the recommendations for RCR testing during retroviral vector production, production of ex vivo-transduced cells, and in patients who receive such material. Our initial recommendations were made at a time when our experience with RCR detection assays and clinical use of retroviral vectors was limited. As the gene therapy field has matured, there is an increasing amount of data available on RCR detection assays and from monitoring of patients in clinical trials. The cumulative data give assurance that RCR detection assays in use are of sufficient sensitivity to provide a margin of safety to patients: no patients to date have evidence of RCR infection. However, CBER encourages members of the gene therapy community to continue to submit data to the FDA or to publish data that will enhance the cumulative data base on RCR testing assays, experience with different VPC, and patient monitoring. Based on the analysis of data accumulated to data, and ongoing discussions with members of the gene therapy community, CBER is proposing to discuss changes to the current RCR testing recommendations, as summarized below. RCR testing during production of retroviral vector and ex vivo-transduced cells. Development of characterized standards for RCR testing of supernatant and cells should allow comparison of assay sensitivity. One proposal under consideration is to apply statistical methods to determine how much material needs to be tested independent of the size of the production lot. Data and discussion are still needed to define a limit concentration and a value for probability of detection for RCR testing, while maintaining an appropriate margin of safety. These modifications of RCR testing strategies could lead to improvements in assay sensitivity. Additional discussion and data are also needed to evaluate the current recommendations of the testing for ex vivo-transduced cells: should both cells and supernatant be tested in all cases? RCR testing during patient follow-up. The time points required for RCR testing during patient follow-up need examination. One proposal under consideration is to sample and assay at three time points during the first year of treatment (e.g., 4-6 weeks, 3 months, and 1 year post-treatment). Further discussion is needed to define appropriate additional follow-up. Choice of assays to detect surrogate markers for RCR infection (i.e., serologic or PCR-based assays) should consider mode of vector administration and the patient population. Positive results with such assays should be pursued by direct culture assay to obtain and characterize the infectious viral isolate. These proposals will be the focal point for the discussion at the Retroviral Vector Breakout Session at the 1997 FDA/NIH Gene Therapy Conference. After the 1997 FDA/NIH Gene Therapy Conference, CBR plans to propose revised recommendations for RCR testing for public comment.

A multicenter, randomized, double-blind, placebo-controlled trial of influenza immunization in multiple sclerosis.

We determined the effect of influenza vaccine in patients with relapsing/remitting MS. Considerable controversy surrounds the question of whether to administer influenza vaccines to MS patients. Prevention of a febrile viral illness is clearly desirable in MS, and previous studies suggest that immunization is safe. Despite this, many clinicians avoid vaccination because they fear precipitating an MS exacerbation. We conducted a multicenter, prospective, randomized, double-blind trial of influenza immunization in patients with relapsing/remitting MS. In the autumn of 1993, 104 patients at five MS centers received either standard influenza vaccine or placebo. Patients were followed for 6 months for evaluation of neurologic status and the occurrence of influenza. Influenza was operationally defined as fever > or = 38 degrees C in the presence of coryza, cough, or sore throat at a time when the disease was present in the community. Attacks were defined in the standard manner, requiring objective change in the examination. Patients were examined at 4 weeks and 6 months after inoculation and were contacted by telephone at 1 week and 3 months. They were also examined at times of possible attacks but not when they were sick with flu-like illness. Three vaccine patients and two placebo patients experienced attacks within 28 days of vaccine (no significant difference). Exacerbation rates in the first month for both groups were equal to or less than expected from published series. The two groups showed no difference in attack rate or disease progression over 6 months. Influenza immunization in MS patients is neither associated with an increased exacerbation rate in the postvaccination period nor a change in disease course over the subsequent 6 months.

Characterization of cell cultures derived from Fugu, the Japanese pufferfish.

The Japanese pufferfish (genus Fugu), which possesses a highly compact genome, is becoming a popular model among those interested in sequencing and mapping the genomes of higher vertebrates. Although genomic libraries have been derived and used to study the molecular biology of Fugu, biological material derived from the living organism is difficult to obtain for laboratories distant from the Asian Pacific. We have established cell cultures from two Fugu species: kusafugu, Fugu niphobles, and torafugu, F. rubripes. Cultures derived from F. niphobles fry and F. rubripes eye have been passaged more than 60 times over the course of one year, representing approximately 180 population doublings. Proliferating cultures were also initiated from F. rubripes brain, liver, fin, spleen, kidney, swimbladder, and muscle. Karyotype analyses indicated that F. rubripes eye-derived cells possessed a chromosome number in the diploid range; F. niphobles fry cells were slightly hyperploid. Flow cytometry confirmed that the relative amounts of DNA present in cultured cells from both Fugu species were similar to that measured in blood cells collected from F. rubripes, and approximately one-seventh of that measured in diploid human cells. Telomerase activity was easily detectable in lysates prepared from F. niphobles fry cells and F. rubripes eye cells, consistent with the notion that these cultures are capable of indefinite proliferation.