The effect of scheduled antibody testing on treatment patterns in interferon-treated patients with multiple sclerosis.

BACKGROUND: Many patients with relapsing-remitting multiple sclerosis (MS) treated with high-dose interferon-ß (IFNß) develop serum binding antibodies (BAb) and neutralizing antibodies (NAb). NAb reduces the biological activity of IFNß, which contributes to clinical failure in these patients. We investigated whether access to antibody (Ab) test results would alter usual care of (IFNß)-treated patients and whether BAb could predict NAb. METHODS: This was a randomized, controlled, open-label, parallel-group, multicenter study in patients with multiple sclerosis. Subjects (n = 1358) were randomly assigned to Ab testing or usual care. BAb and NAb titres were measured using standard assays. Primary and secondary outcomes were the proportion of patients whose IFNß therapy changed and the type of and reasons for therapy changes. RESULTS: Therapy changes differed between the Ab testing and usual care arms (19.6% and 14.0%, respectively; p = 0 · 004). Results from Ab testing were more frequently reported as the reason for therapy change in the Ab testing arm than in the usual care arm (p < 0.0001). NAb and BAb positivity significantly increased the likelihood of therapy change and reduced IFNß-associated adverse events. BAb titres were a significant predictor of NAb positivity (p = 0.0012). Initial BAb-positive and NAb-positive status in both study arms had a significant impact on the overall number of patients with a therapy change (p < 0.05). CONCLUSION: Access to Ab test results impacted therapy management. BAb titres can predict NAb positivity in patients on high-dose IFNß.

On-line mass spectrometry: membrane inlet sampling.

Significant insights into plant photosynthesis and respiration have been achieved using membrane inlet mass spectrometry (MIMS) for the analysis of stable isotope distribution of gases. The MIMS approach is based on using a gas permeable membrane to enable the entry of gas molecules into the mass spectrometer source. This is a simple yet durable approach for the analysis of volatile gases, particularly atmospheric gases. The MIMS technique strongly lends itself to the study of reaction flux where isotopic labeling is employed to differentiate two competing processes; i.e., O(2) evolution versus O(2) uptake reactions from PSII or terminal oxidase/rubisco reactions. Such investigations have been used for in vitro studies of whole leaves and isolated cells. The MIMS approach is also able to follow rates of isotopic exchange, which is useful for obtaining chemical exchange rates. These types of measurements have been employed for oxygen ligand exchange in PSII and to discern reaction rates of the carbonic anhydrase reactions. Recent developments have also engaged MIMS for online isotopic fractionation and for the study of reactions in inorganic systems that are capable of water splitting or H(2) generation. The simplicity of the sampling approach coupled to the high sensitivity of modern instrumentation is a reason for the growing applicability of this technique for a range of problems in plant photosynthesis and respiration. This review offers some insights into the sampling approaches and and the experiments that have been conducted with MIMS.

Multiple Rubisco forms in proteobacteria: their functional significance in relation to CO2 acquisition by the CBB cycle.

Rubisco is the predominant enzymatic mechanism in the biosphere by which autotrophic bacteria, algae, and terrestrial plants fix CO(2) into organic biomass via the Calvin-Benson-Basham reductive pentose phosphate pathway. Rubisco is not a perfect catalyst, suffering from low turnover rates, a low affinity for its CO(2) substrate, and a competitive inhibition by O(2) as an alternative substrate. As a consequence of changing environmental conditions over the past 3.5 billion years, with decreasing CO(2) and increasing O(2) in the atmosphere, Rubisco has evolved into multiple enzymatic forms with a range of kinetic properties, as well as co-evolving with CO(2)-concentrating mechanisms to cope with the different environmental contexts in which it must operate. The most dramatic evidence of this is the occurrence of multiple forms of Rubisco within autotrophic proteobacteria, where Forms II, IC, IBc, IAc, and IAq can be found either singly or in multiple combinations within a particular bacterial genome. Over the past few years there has been increasing availability of genomic sequence data for bacteria and this has allowed us to gain more extensive insights into the functional significance of this diversification. This paper is focused on summarizing what is known about the diversity of Rubisco forms, their kinetic properties, development of bacterial CO(2)-concentrating mechanisms, and correlations with metabolic flexibility and inorganic carbon environments in which proteobacteria perform various types of obligate and facultative chemo- and photoautotrophic CO(2) fixation.

Anti-LINGO-1 has no detectable immunomodulatory effects in preclinical and phase 1 studies.

OBJECTIVE: To evaluate whether the anti-LINGO-1 antibody has immunomodulatory effects. METHODS: Human peripheral blood mononuclear cells (hPBMCs), rat splenocytes, and rat CD4+ T cells were assessed to determine whether LINGO-1 was expressed and was inducible. Anti-LINGO-1 Li81 (0.1-30 µg/mL) effect on proliferation/cytokine production was assessed in purified rat CD4+ T cells and hPBMCs stimulated with antibodies to CD3 +/- CD28. In humans, the effect of 2 opicinumab (anti-LINGO-1/BIIB033; 30, 60, and 100 mg/kg) or placebo IV administrations was evaluated in RNA from blood and CSF samples taken before and after administration in phase 1 clinical trials; paired samples were assessed for differentially expressed genes by microarray. RNA from human CSF cell pellets was analyzed by quantitative real-time PCR for changes in transcripts representative of cell types, activation markers, and soluble proteins of the adaptive/innate immune systems. ELISA quantitated the levels of CXCL13 protein in human CSF supernatants. RESULTS: LINGO-1 is not expressed in hPBMCs, rat splenocytes, or rat CD4+ T cells; LINGO-1 blockade with Li81 did not affect T-cell proliferation or cytokine production from purified rat CD4+ T cells or hPBMCs. LINGO-1 blockade with opicinumab resulted in neither significant changes in immune system gene expression in blood and CSF, nor changes in CXCL13 CSF protein levels (clinical studies). CONCLUSIONS: These data support the hypothesis that LINGO-1 blockade does not affect immune function. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with MS, opicinumab does not have immunomodulatory effects detected by changes in immune gene transcript expression.

New roads lead to Rubisco in archaebacteria.

The discovery of the CO(2)-fixing enzyme Rubisco in the Archaebacteria has presented a conundrum in that they apparently lack the gene for phosphoribulokinase, which is required to generate Rubisco's substrate ribulose 1,5-bisphosphate (RuBP). However, two groups have now demonstrated novel RuBP synthesis pathways, demystifying Rubisco's non-autotrophic and perhaps ancient role. A new CO(2) fixing role for Rubisco, which is distinct from the globally dominant Calvin cycle, is providing important clues furthering our understanding of the evolution of autotrophy. This perspective is strengthened by the additional recognition in this commentary that some Rubisco-containing Archaea do also contain PRK and may represent an interesting autotrophic evolutionary transition. Supplementary material for this article can be found on the BioEssays website (http://www.interscience.wiley.com/jpages/0265-9247/suppmat/index.html).

A randomized controlled study of the acute and chronic effects of cooling therapy for MS.

BACKGROUND: Cooling demyelinated nerves can reduce conduction block, potentially improving symptoms of MS. The therapeutic effects of cooling in patients with MS have not been convincingly demonstrated because prior studies were limited by uncontrolled designs, unblinded evaluations, reliance on subjective outcome measures, and small sample sizes. OBJECTIVE: To determine the effects of a single acute dose of cooling therapy using objective measures of neurologic function in a controlled, double-blinded setting, and to determine whether effects are sustained during daily cooling garment use. METHODS: Patients (n = 84) with definite MS, mild to moderate disability (Expanded Disability Status Scale score < 6.0), and self-reported heat sensitivity were randomized into a multicenter, sham-treatment controlled, double-blind crossover study. Patients had the MS Functional Composite (MSFC) and measures of visual acuity/contrast sensitivity assessed before and after high-dose or low-dose cooling for 1 hour with a liquid cooling garment. One week later, patients had identical assessments before and after the alternate treatment. Patients were then re-randomized to use the cooling garment 1 hour each day for a month or to have observation only. They completed self-rated assessments of fatigue, strength, and cognition during this time, and underwent another acute cooling session at the end of the period. After 1 week of rest, they had identical assessments during the alternate treatment. RESULTS: Body temperature declined during both high-dose and low-dose cooling, but high-dose produced a greater reduction (p < 0.0001). High-dose cooling produced a small improvement in the MSFC (0.076 +/- 0.66, p = 0.007), whereas low-dose cooling produced only a trend toward improvement (0.053 +/- 0.031, p = 0.09), but the difference between conditions was not significant. Timed gait testing and visual acuity/contrast sensitivity improved in both conditions as well. When patients underwent acute cooling following a month of daily cooling, treatment effects were similar. Patients reported less fatigue during the month of daily cooling, concurrently on the Rochester Fatigue Diary and retrospectively on the Modified Fatigue Impact Scale. CONCLUSIONS: Cooling therapy was associated with objectively measurable but modest improvements in motor and visual function as well as persistent subjective benefits.