ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process. METHODS: This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories - very high, high, low and very low - according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. RESULTS: A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.

Daclizumab high-yield process reduced the evolution of new gadolinium-enhancing lesions to T1 black holes in patients with relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: In the SELECT study, treatment with daclizumab high-yield process (DAC HYP) versus placebo reduced the frequency of gadolinium-enhancing (Gd(+) ) lesions in patients with relapsing-remitting multiple sclerosis (RRMS). The objective of this post hoc analysis of SELECT was to evaluate the effect of DAC HYP on the evolution of new Gd(+) lesions to T1 hypointense lesions (T1 black holes). METHODS: SELECT was a randomized double-blind study of subcutaneous DAC HYP 150 or 300 mg or placebo every 4 weeks. Magnetic resonance imaging (MRI) scans were performed at baseline and weeks 24, 36 and 52 in all patients and monthly between weeks 4 and 20 in a subset of patients. MRI scans were evaluated for new Gd(+) lesions that evolved to T1 black holes at week 52. Data for the DAC HYP groups were pooled for analysis. RESULTS: Daclizumab high-yield process reduced the number of new Gd(+) lesions present at week 24 (P = 0.005) or between weeks 4 and 20 (P = 0.014) that evolved into T1 black holes at week 52 versus placebo. DAC HYP treatment also reduced the percentage of patients with Gd(+) lesions evolving to T1 black holes versus placebo. CONCLUSIONS: Treatment with DAC HYP reduced the evolution of Gd(+) lesions to T1 black holes versus placebo, suggesting that inflammatory lesions that evolved during DAC HYP treatment are less destructive than those evolving during placebo treatment.

Induction of human IL-10-producing neutrophils by LPS-stimulated Treg cells and IL-10.

Recent evidence has revealed an unsuspected suppressive role played by neutrophils during microbial infections. An especially intriguing aspect of this role is the ability of neutrophils to produce interleukin (IL)-10 following interaction with lipopolysaccharide (LPS)-stimulated regulatory T (Treg) cells. The present study demonstrates that generation of IL-10 in neutrophils induced by LPS-stimulated Treg cells required direct cell-cell contact. This effect was dependent on the binding of CD11b and intercellular adhesion molecule 1. Neither stimulation of neutrophils with LPS nor their culture with unstimulated Treg cells, CD3/CD28 monoclonal antibodies-stimulated Treg cells, or T conventional cells affected intracellular IL-10 expression. IL-10-positive neutrophils were also induced by exogenous IL-10, providing an example of a positive feedback loop. Both LPS-stimulated Treg cells and exogenous IL-10 exclusively promoted posttranslational modifications of histones, H3K4me3 and H3Ac Lys4, that activate IL-10 genomic locus in neutrophils, while the promoter of IL-10 gene was inactive in resting, LPS-stimulated neutrophils, following blocking of direct interaction with LPS-stimulated Treg cells or in LPS-preactivated neutrophils incubated with LPS-stimulated Treg cells. We additionally confirmed the presence of IL-10-producing neutrophils in vivo in patients with periodontal abscess induced by Gram-negative bacteria, as opposed to neutrophils isolated from the site of aseptic inflammation in patients with neuromyelitis optica.

CD56(bright) natural killer cells and response to daclizumab HYP in relapsing-remitting MS.

OBJECTIVE: To assess the relationship between CD56(bright) natural killer (NK) cells and multiple sclerosis (MS) disease activity in patients with relapsing-remitting MS treated with daclizumab high-yield process (DAC HYP). METHODS: Data were from patients enrolled in a 52-week randomized, double-blind, placebo-controlled study of DAC HYP and its extension study. Assessments included relationships of CD56(bright) NK cell numbers (identified using fluorescence-activated cell sorting) at weeks 4 and 8 with the numbers of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 and the annualized relapse rate. RESULTS: In DAC HYP-treated patients but not placebo-treated patients, the numbers of CD56(bright) NK cells increased over 52 weeks of treatment, and their numbers at weeks 4 and 8 predicted the number of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 of treatment (p ≤ 0.005 for each comparison). Similar but nonsignificant trends were observed between CD56(bright) NK cell counts and the annualized relapse rate in DAC HYP-treated patients. DAC HYP-treated patients who showed lower levels of expansion of CD56(bright) NK cells still developed fewer new or newly enlarging T2-hyperintense lesions than placebo-treated patients during the first year of treatment. CONCLUSIONS: CD56(bright) NK cells appear to mediate some of the treatment-related effects of DAC HYP, but their numbers do not account for the full effect of DAC HYP on MS-related outcomes.

A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis.

The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNß)-1a (Avonex(®) reference arm). RRMS patients age 18-55 years with Expanded Disability Status Scale (EDSS) scores of 0-5.5 and documented pre-study relapse (≥ 1 in previous year, 2 in previous 2 years, or 1 in previous 1-2 years and ≥ 1 GdE lesion in the previous year) were randomized (1:1:1) to laquinimod 0.6 mg once-daily, matching oral placebo, or IFNß-1a IM 30 µg once-weekly (rater-blinded design), for 24 months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod (n = 434), placebo (n = 450), and IFNß-1a (n = 447). ARR was not significantly reduced with laquinimod [-18 %, risk ratio (RR) = 0.82, 95 % CI 0.66-1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p < 0.001). Confirmed disability worsening was infrequent (10 % laquinimod, 13 % placebo). The change in confirmed disability worsening with laquinimod measured using EDSS was -31 % [hazard ratio (HR) 0.69, p = 0.063], and using Multiple Sclerosis Functional Composite (MSFC) z-score was -77 % (p = 0.150), vs. placebo. IFNß-1a reduced ARR 26 % (RR = 0.74, 95 % CI 0.60-0.92, p = 0.007), showed no effect on PBVC loss (+11 %, p = 0.14), and changes in disability worsening were -26 and -66 % as measured using the EDSS (HR 0.742, p = 0.13) and MSFC (p = 0.208), respectively. Adverse events occurred in 75, 82, and 70 % of laquinimod, IFNß-1a, and placebo patients, respectively. Once-daily oral laquinimod 0.6 mg resulted in statistically nonsignificant reductions in ARR and disability progression, but significant reductions in brain atrophy vs. placebo. Laquinimod was well-tolerated.

Alemtuzumab more effective than interferon ß-1a at 5-year follow-up of CAMMS223 clinical trial.

OBJECTIVE: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon ß-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon ß-1a (IFNß-1a) through extended follow-up (up to 60 months from baseline). METHODS: Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNß-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months. RESULTS: Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNß-1a (both p < 0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNß-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNß-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNß-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNß-1a patients. Immune thrombocytopenia occurred in 3% of alemtuzumab patients and 0.9% of IFNß-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab patient developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab. CONCLUSIONS: Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNß-1a, with a safety profile consistent with previous reports. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that alemtuzumab is more effective than interferon ß-1a in reducing relapses and disability in patients with RRMS in a long-term follow-up of a rater-blinded, randomized clinical trial with 59.5% of patients participating in the extended follow-up period.

Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study.

BACKGROUND: Laquinimod, an oral novel immunomodulator, was shown to reduce MRI-measured disease activity in relapsing-remitting MS (RRMS) patients. OBJECTIVES: To determine whether the safety and efficacy profile of laquinimod, as shown in a placebo-controlled 36-week trial (LAQ/5062), is sustained and reproducible. METHODS: Two hundred and fifty seven patients entered the extension phase in which MRI was performed at the beginning and at the end of the active extension phase. Clinical assessments were performed at weeks 4, 12 and every 12 weeks thereafter. RESULTS: Two hundred and thirty nine (93%) patients completed the extension phase and 222 (86.3%) had a final scan available. Gadolinium-enhanced (GdE) T1 lesions were significantly reduced for patients switching from placebo to 0.3/ 0.6 mg doses (52%, p = 0.0006). In patients initially randomized to 0.6 mg in LAQ/5062 the reduction of MRI activity observed in the placebo-controlled phase was maintained in the extension. The proportion of GdE-free patients for those who switched from placebo increased from a baseline of 31% to 47% at the end of the extension phase (p = 0.01). The most prominent safety signal was elevations of liver enzymes, reversible in all cases. CONCLUSIONS: The good efficacy and the excellent safety and tolerability profiles of laquinimod 0.6 mg/day are confirmed in this extension study.

Altered innate immune response of plasmacytoid dendritic cells in multiple sclerosis.

Plasmacytoid dendritic cells (pDCs) are of crucial importance in immune regulation and response to microbial factors. In multiple sclerosis (MS), pDCs from peripheral blood showed an immature phenotype, but its role in susceptibility to MS is not determined. Because infectious diseases are established triggers of exacerbations in MS, in this study we have characterized the expression of Toll-like receptors (TLR) and the maturation and functional properties of peripheral blood pDCs from clinically stable, untreated MS patients in response to signals of innate immunity. After stimulation of TLR-9, interferon (IFN)-alpha production by pDCs was significantly lower in MS (n = 12) compared to healthy controls (n = 9). In an allogenic two-step co-culture assay we found an impaired effect of TLR-9 stimulation on IFN-gamma expression of autologous naive T cells in MS patients (n = 4). In peripheral blood mononuclear cells, TLR-9 stimulation with type A CpG ODN resulted in a higher expression of TLR-1, -2, -4, -5 and -8 in MS patients (n = 7) compared with healthy controls (n = 11). These findings suggest an altered innate immune response to microbial stimuli in MS patients and may help understanding of why common infectious agents trigger MS attacks.

Patients with multiple sclerosis resisted to glucocorticoid therapy: abnormal expression of heat-shock protein 90 in glucocorticoid receptor complex.

OBJECTIVE: The majority of patients with multiple sclerosis (MS) respond favorably to glucocorticoids (GS) for their relapse treatment (steroid-sensitive multiple sclerosis). Unfortunately, a small subset of patients with multiple-sclerosis fails to adequately respond even to high dose of GS (steroid-resistant multiple sclerosis). Mechanism of GS therapeutic unresponsiveness is not resolved. METHODS: Transcripts for glucocorticoid receptor (GR) was assessed in peripheral blood mononuclear cells by real-time polymerase chain reaction in patients with steroid-sensitive and steroid-resistant multiple sclerosis. GR expression was assessed by Western blotting. The amount of heat-shock protein 90 (hsp90) in GR cytoplasmic complex was assessed by immunoprecipitation. Hsp90 was shown to stabilize the GR complex, to prevent its translocation to nucleus, and to inhibit GR transcription. RESULTS: Peripheral blood mononuclear cells of steroid-resistant multiple sclerosis transcripts for all three isoforms of GR, alpha, beta, and gamma, were reduced by about two-folds compared with patients with steroid-sensitive multiple sclerosis. We have not found an increase in the beta and gamma transcripts of GR, which might serve as a dominant negative mutants, over GR alpha in steroid-resistant multiple sclerosis. The amount of hsp90 in the GR complex in cytoplasm was significantly higher in steroid-resistant multiple sclerosis compared with steroid-sensitive multiple sclerosis. CONCLUSIONS: Molecular mechanism of GS unresponsiveness in some patients with multiple sclerosis might be related to increased presence of hsp90 in the GR cytoplasmic complex, leading to the inhibition of GR translocation to nucleus and reduction in its transcription.

Proton magnetic resonance spectroscopy of normal appearing white matter in asymptomatic relatives of multiple sclerosis patients.

Proton magnetic resonance spectroscopy of normal appearing white matter (NAWM) was performed in 25 first-degree relatives of patients with multiple sclerosis (MS). In relatives of MS patients, insignificant trends in the NAA/Cho ratio (to be lower) and in the Cho/Cr ratio (to be higher) were found when compared with healthy controls. These results demonstrated that there are only minimal, insignificant changes in commonly identified metabolite concentrations in NAWM of relatives of MS patients when compared with healthy subjects.

EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses.

Relapses, exacerbations or attacks of multiple sclerosis are the dominating feature of relapsing-remitting multiple sclerosis (MS), but are also observed in patients with secondary progressive MS. High-dose methylprednisolone is the routine therapy for relapses at present, but other treatments are also in current use. The objective of the task force was to review the literature on treatment of MS relapses to provide evidence-based treatment recommendations. Review was carried out on the literature with classification of evidence according to the EFNS guidelines for scientific task forces. Short-term, high-dose methylprednisolone treatment should be considered for the treatment of relapses of MS (level A recommendation). The optimal glucocorticoid treatment regimen, in terms of clinical efficacy and adverse events, remains to be established. A more intense, interdisciplinary rehabilitation programme should be considered as this probably further improves recovery after treatment with methylprednisolone (level B recommendation). Plasma exchange is probably efficacious in a subgroup of patients with severe relapses not responding to methylprednisolone therapy, and should be considered in this patient subgroup (level B recommendation). There is a need for further randomized, controlled trials in order to establish the optimal treatment regimen for relapses of MS.

Multiple Sclerosis Severity Score: using disability and disease duration to rate disease severity.

BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

Guidance for the preparation of neurological management guidelines by EFNS scientific task forces--revised recommendations 2004.

Since the publication of the first EFNS task force reports in 1997, a total of 20 evidence-based guidelines for the treatment and management of neurological diseases have been published by the EFNS (http://www.efns.org/guidelines). In 2001, recommendations for the preparation of neurological guidelines were issued by the EFNS Scientific Committee (Eur J Neurol 2001; 8: 549-550). These have now been updated and revised. More unified criteria for standards of reporting are set up which include classes of scientific evidence and predefined levels of recommendation. These criteria as well as others listed below should be used for all working groups that aim at recommending treatment, diagnostic procedures or other interventions within the framework of the EFNS.

No difference in efficacy of two different doses of intravenous immunoglobulins in MS: clinical and MRI assessment.

We performed a double-blind, placebo-controlled study to evaluate the efficacy of low and high dose of intravenous immunoglobulins (IVIG) in relapsing/remitting (RR) multiple sclerosis (MS). Patients (n = 49) with clinical definite RR MS were randomly allocated to three groups and treated with 0.2 g/kg (n = 17) or 0.4 g/kg (n = 15) once a month of IVIG and placebo (n = 17) for 12 months. Clinical data were assessed monthly and magnetic resonance imaging (MRI) was performed every 3 months during the study period. Annual relapse rate (ARR) and change of the mean Expanded Disability Status Scale (EDSS) and Neurological Rating Scale Score (NRSS) from baseline to study conclusion were used as the clinical end-points. For MRI activity total lesion volume on T2-weighted image (T2WI), new lesions and gadolinium (Gd)-enhanced lesions on T1WI were analysed. ARR in both IVIG groups (0.88 for 0.2 g/kg and 0.86 for 0.4 g/kg) was reduced compared with placebo (1.24) during treatment period. Neurological disability measured with EDSS decreased slightly in both the IVIG groups (0.029 and 0.066, respectively) and increased by 0.29 in placebo (P = 0.0117). The neurologic impairment measured by NRSS showed similar trend. The total lesion volume on T2WI increased by 13.56% in placebo whereas in the 0.4 g/kg IVIG group decreased by -3.95% and in the 0.2 g/kg IVIG group increased by 3.6%. The cumulative numbers of Gd-enhancing lesions and new T2WI lesions in the IVIG groups were reduced in comparison with the placebo group. Our findings suggest that the dose 0.2 g/kg of IVIG is equally effective as 0.4 g/kg in reducing MS activity.

Magnetisation transfer ratio analysis of normal appearing white matter in patients with familial and sporadic multiple sclerosis.

OBJECTIVES: To assess differences in magnetisation transfer ratio (MTR) analysis of normal appearing white matter (NAWM) in patients with familial multiple sclerosis (MS) and those with sporadic MS. METHODS: 10 patients with familial MS, 10 patients with sporadic MS, and 10 healthy subjects were included in the study. Groups were matched according to the sex, age, disease duration, type of disease, EDSS, and MRI T1 and T2 lesion load. Magnetisation transfer imaging (MTI) with and without saturation pulse were performed. On the MTR map 16 different regions of interest of normal appearing white matter were analyzed. RESULTS: The mean MTR value of normal appearing white matter was significantly lower both in familial patients and those with sporadic MS compared with healthy subjects (33.8% v 46.4%; 38.6% v 46.4% respectively, p< 0.05). Additionally, patients with familial MS showed significantly lower mean MTR value than patients with sporadic MS (33.8% v 38.6%, p<0.05). There was also significant regional variation of MTR values between these two groups of patients. CONCLUSIONS: Lower and more widespread MTR abnormalities in patients with familial MS might indicate differences in the extent and nature of white matter pathology between familial and sporadic MS.

Naked DNA vaccination differentially modulates autoimmune responses in experimental autoimmune encephalomyelitis.

Vaccination with naked DNA represents a therapeutic strategy currently under consideration in multiple sclerosis (MS). In this study, we tested the potential therapeutic effect of vaccination with a naked DNA construct encoding proteolipid protein (pRc/CMV-PLP) upon the outcome of subsequent sensitization for experimental autoimmune encephalomyelitis (EAE) actively-induced in SJL mice with PLP139-151 peptide in adjuvant. Intramuscular vaccination with the naked DNA pRc/CMV-PLP construct led to PLP expression in local muscle tissue that persisted for about 8 weeks. Early sensitization for EAE (4 weeks after DNA vaccination) caused recipient mice to develop a severe, exacerbated form of disease (in comparison to control mice), while late sensitization (>10 weeks) resulted in a milder, ameliorated form. In the groups sensitized <10 weeks post-DNA vaccination with pRc/CMV-PLP induction of a Th1-type cytokine response was noted. In contrast, sensitization >10 weeks post-DNA vaccination led to peripheral tolerance as evidenced by a decrease in T cell proliferation and cytotoxic T cell response, no Th2 response, and no increase in apoptosis. These data are novel in that they demonstrate a differential effect of DNA vaccination and have important implications for its use as a mechanism to enhance or modulate immune reactivity.

[Cerebral adrenomyeloneuropathy as a late type of adrenoleukodystrophy: case report]. / Mózgowa odmiana adrenomyeloneuropatii jako pózna postac adrenoleukodystrofii. Opis przypadku.

Adrenoleukodystrophy (ALD) is a hereditary disease related to abnormalities in the structure and function of peroxisomes. The nature of disorder arises from defective process of beta-oxidation of very-long-chain fatty acids and their accumulation in various organs. ALD may present as a few phenotypes urologic symptomatology of which depends on proportions of the brain, spinal cord and peripheral nerves affection. Below, we present a case (and its family) of a cerebral type of adrenomyeloneuropathy--a rare form of adrenoleukodystrophy, and discuss its clinical manifestation as well as biochemical, hormonal, electrophysiological, neuropsychological and magnetic resonance imaging (MRI) diagnostics.

Inhibitory and stimulatory effects of lactacystin on expression of nitric oxide synthase type 2 in brain glial cells. The role of Ikappa B-beta.

Expression of inflammatory nitric oxide synthase (NOS2) is mediated by transcription factor NFkappaB. By using the specific proteasome inhibitor lactacystin to examine IkappaB degradation, we observed a paradoxical increase in lipopolysaccharide- and cytokine-dependent NOS2 expression at low concentrations or when lactacystin was added subsequent to cytokines. Lactacystin reduced the initial accumulation of NOS2 mRNA but reduced its subsequent decrease. Lactacystin increased NOS2 promoter activation after 24 h, but not after 4 h, and similarly prevented initial NFkappaB activation and at later times caused NFkappaB reactivation. Lactacystin reduced initial degradation of IkappaB-alpha and IkappaB-beta, however, at later times selectively increased IkappaB-beta, which was predominantly non-phosphorylated. Expression of full-length rat IkappaB-beta, but not a carboxyl-terminal truncated form, inhibited NOS2 induction and potentiation by lactacystin. Lactacystin increased IkappaB-beta expression in the absence of NOS2 inducers, as well as expression of heat shock protein 70, and the heat shock response due to hyperthermia increased IkappaB-beta expression. These results suggest that IkappaB-beta contributes to persistent NFkappaB activation and NOS2 expression in glial cells, that IkappaB-beta is a stress protein inducible by hyperthermia or proteasome inhibitors, and that delayed addition of proteasome inhibitors can have stimulatory rather than inhibitory actions.