In 2005, the EU launched the European Emission Trading Scheme (EU ETS) to reduce CO2 emissions and spur low carbon investments. There is only little empirical evidence regarding its actual effects on corporate investment decisions. We investigate these effects in case studies in the German electricity sector. We find that companies in the sector integrate costs for CO2 in their investment decisions. The EU ETS constitutes a main driver for small-scale investments with short amortization times. Its impact on large-scale investments in power plants or in R&D efforts is limited. To overcome this weakness, policy makers should reflect their long-term reduction intentions in the scarcity of allowances, provide more incentives to increase efficiency, and reduce regulatory uncertainty.

The effects of regulatory pressure on environmental strategy have long been investigated in the context of environmental policy and effects of innovation and technological change. However, there is...

We describe four patients with relapsing remitting multiple sclerosis (RRMS) who experienced a relapse with acute onset of painful sensations. Pain sensations disappeared in two of them and markedly reduced in the other ones after repeat application of intrathecal triamcinolone acetonide (TCA) following a prior unsuccessful treatment with intravenous steroids. TCA administration was well tolerated and no serious side effects occurred. Repeated intrathecal TCA injection may provide a substantial benefit in RRMS patients with acute onset of pain due to an inflammatory lesion within the spinal cord.

Available immunomodulatory and conventional steroid treatment regimens provide a limited symptomatic benefit for patients with progressive multiple sclerosis (MS). We performed an open trial on the short-term efficacy of repeated intrathecal application of the sustained release steroid triamcinolone acetonide (TCA) in 27 progressive MS patients. Six TCA administrations, performed every third day, reduced the Expanded Disability Status Scale (EDSS) score [initial: 5.4+/-1.3, 3-7.5 (mean+/-SD, range); end: 4.9+/-1.1; 2.5-6.5; P<0.001] and significantly increased the walking distance and speed in particular after the fourth TCA injection. Concomitantly serially determined cerebrospinal fluid (CSF) markers of cell injury, neuron-specific enolase, total tau-protein, S-100, and beta-amyloid did not significantly change within the interval of TCA treatment. No serious side effects appeared. We conclude that repeat intrathecal injection of 40 mg TCA provides a substantial benefit in progressive MS patients with predominant spinal symptoms and does not alter CSF markers of neuronal cell injury.

An exploratory, prospective, open-label study of fumaric acid esters (FAE, Fumaderm (R)) was conducted in patients with relapsing-remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6-week baseline, 18-week treatment (target dose of 720 mg/day), 4-week washout, and a second 48-week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0-6.0 and at least one gadolinium-enhancing (Gd+) lesion on T1-weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine-hole peg test (9-HPT). Effects of FAE on intracellular cytokine profiles, T-cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non-compliance, and follow-up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4-week washout period. EDSS scores, AI, and 9-HPT remained stable or slightly improved from baseline in all patients. Measures of T-cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Glatiramer acetate (GA), a mixture of synthetic polypeptides, has beneficial effects on the clinical course and the MRI-defined disease activity of patients with multiple sclerosis (MS). In MS, evidence has been provided that the apoptosis of disease-relevant T cells is dysregulated. In this study, we investigated the effect of GA on T cell apoptosis, T cell activation, and cytokine profile of lymphocytes derived from 19 relapsing-remitting MS patients during the first year of GA therapy. Analysis of blood samples obtained every 6 weeks showed an increase in apoptotic T helper cells after 30 weeks of therapy. This effect remained until the end of the study and was accompanied by an increase in activated T cells and interleukin-4-producing lymphocytes. Thus, in addition to the established effect of GA on the cytokine network, GA-mediated immunomodulation might involve the apoptotic elimination of T helper cells.

Available immunomodulatory and conventional steroid treatment options for patients with progressive multiple sclerosis (MS) only provide limited symptomatic benefit. We performed an open trial on the short-term and long-term efficacy and safety of repeated intrathecal application of the sustained release steroid triamcinolone acetonide (TCA) in 36 progressive MS patients. Six TCA administrations, performed every third day, reduced the EDSS score (initial: 5.6+/-0.93 [mean+/-S.D.]; end: 4.9+/-1.0; p<0.001) and increased the walking distance (WD) (initial: 294+/-314 m; end: 604+/-540 m; p<0.001). Twenty MS patients continued intrathecal TCA treatment with one TCA injection performed with a variable frequency ranging from 6 to 12 weeks. Both EDSS and walking distance remained stable in these patients until the end of the follow-up investigation period. No serious side effects occurred. We conclude that repeated intrathecal TCA injection provides substantial benefit for progressive MS patients with predominantly spinal symptoms.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Impaired remyelination and axonal degeneration may account for progressive disability in MS patients. As ciliary neurotrophic factor (CNTF) takes part in myelogenesis, we examined the frequency of a CNTF-null mutation in 349 MS patients with respect to their clinical presentation and in comparison with 434 healthy controls. Similar genotype frequencies for the CNTF mutation were obtained in MS patients (genotype 0101=74.8%, 0102=22.3%, 0202=2.9%) and controls (genotype 0101=71.7%, 0102=26.5%, 0202=1.8%) even after stratification for the HLA-DRB1*15 allele. In addition, there was no significant correlation of CNTF genotypes to age at onset, course or severity of the disease. We therefore conclude, that the requirement for CNTF in myelogenesis or cell survival may be bypassed by a second ligand or redundancy of functional activity of other neurotrophic factors.

OBJECTIVES:We investigated whether therapy of multiple sclerosis (MS) with glatiramer acetate (GA) involves the modulation of programmed cell death (apoptosis) in disease-relevant T-helper lymphocytes.MATERIAL AND METHODS:Blood was drawn from 15 relapsing-remitting MS patients both before (baseline) as well as 6, 12, and 18 weeks after GA therapy and from 15 healthy controls. Detection of apoptosis was performed in response to in vitro stimulation with GA, myelin basic protein or medium alone.RESULTS:T-helper lymphocytes from untreated MS patients displayed an overall increased apoptosis susceptibility in vitro, compared to controls. During subsequent GA therapy, apoptosis vulnerability of these T cells in MS patients significantly declined under the initial baseline before treatment, and was finally equal in treated patients and controls. GA itself had no direct apoptosis-modulatory properties in vitro.CONCLUSION:Our findings indicate that therapy of multiple sclerosis with glatiramer acetate presumably involves the compensation of altered apoptosis in T-helper lymphocytes.

Background and Objectives: Immunoadsorption (IA) is an established procedure to remove Igs and immune complexes from peripheral blood. Since Igs reportedly bind to human leucocyte antigen (HLA) molecules, we were interested to know whether removal of Ig will also influence the plasma concentration of soluble HLA (sHLA). Patients and Methods: Nine patients suffering from severe autoimmune disease and undergoing 17 single courses of IA treatment were monitored for their sHLA class I (sHLA–I) and sHLA–DR plasma levels. Plasma was separated by a hollow–fiber–type separator. Plasma samples were taken before therapy, after 15 min of recirculation (without operating the adsorber), after 1 and 2 liters of plasma adsorption, and 24 and 48 h after the end of IA. Results: Before treatment the mean levels of sHLA–I and sHLA–DR were 0.37 (±0.06 SEM) and 0.32±0.05 μg/ml, respectively. After 2 liters of plasma filtration, an increase in sHLA–DR (0.80±0.10 μg/ml) was observed (p<0.001), whereas sHLA–I was only slightly affected (mean: 0.45±0.06 μg/ml). sHLA concentrations returned to initial levels after 24 h. Conclusion: The significant increase in sHLA–DR may contribute to the immunomodulatory effect of IA.

In this ‘double-blind’, randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing–remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

ing tests yielded normal or negative results: serum chemistry profile, complement levels, antinuclear antibodies and antineutrophil cytoplasmatic antibodies; serology for hepatitis B and C viruses and syphilis, and chest X-ray. The patient was treated with dapsone, 100 mg once daily, zidovudine, 250 mg twice daily, zalcitabine, 750 three times a day, and saquinavir, 600 mg three times a day. The lesions quickly started to resolve and completely disappeared in 3 weeks. Together with the clinical improvement of her lesions a rise in her CD4 count to 205 cells/mm and a diminution in the serum level of P24 antigen, 30 pg/mL, was demonstrated 2 months later. She continues with the same treatment as maintenance therapy. EED is believed to have an immune complex-mediated pathogenesis and both antibodies to HIV in a patient with leucocytoclastic vasculitis, and HIV-antigens in patients with glomerulonephritis and polyarteritis nodosa-like necrotizing vasculitis have been shown to be implicated in the formation of immune complexes in HIV-infected patients with these vasculitic disorders. We could not demonstrate the presence of P24 antigen nor antibodies to HIV in the skin lesions of our patient. However, she did not present signs of other causes of EED such as malignancies, monoclonal gammopathies, bacterial or viral infections other than HIV infection, and the outgrowth of the skin lesions ran simultaneously with a rise in her P24 antigen serum level and the development of a polyclonal hypergammaglobulinaemia. Both serum results and skin lesions improved quickly with dapsone and antiretroviral therapy. The four patients of Leboit and Cokerell did not respond to dapsone because fibrosis had supposedly developed. Only seven patients with EED associated with HIV-1 and another one with HIV-2 infection have been reported. Our patient is the first reported female with such an association. Furthermore, although discrete nodules are seen in non-HIVinfected patients with EED, the presence of bulky masses like those in our patient are exceptional. However, they were present in most patients (five of nine) with EED and HIV infection. We believe that a therapeutical approach to patients with EED associated with HIV infection should focus on reducing circulating P24 antigen with an adequate antiretroviral therapy in addition to conventional dapsone treatment.

Zusammenfassung Bei der multiplen Sklerose als chronisch demyelinisierender Erkrankung des Zentralnervensystems (ZNS) werden derzeit 3 Verfahren zur Remyelinisierungsförderung untersucht: Die Gabe von Wachstumsfaktoren, die Transplantation myelinbildender Zellen und die Applikation von intravenösen Immunglobulinen (IVIg). Im Tiermodell führen diese Prinzipien zu Remyelinisierungen in experimentell akut demyelinisierten Arealen des ZNS und verbessern z.T. die Leitfähigkeit der Axone. Die systemische Therapie mit Wachstumsfaktoren könnte v.a. durch Wirkungen auf gesunde Gewebe limitiert sein. Bei Transplantationen stellt sich das Problem der Immunogenität von homologen Zellen, da noch keine nicht immunogenen Zellinien zur Verfügung stehen. Auch ist die zur Kultivierung und Vermehrung von humanen Oligodendrozyten und deren Vorläuferzellen benötigte Kombination von Wachstumsfaktoren nicht bekannt. Beim Menschen gibt es wachsende Evidenzen für eine remyelinisierungsfördernde Potenz von IVIg. Zum Beweis dieser Wirkung sind weitere kontrollierte Studien nötig und werden momentan durchgeführt.

Multiple sclerosis (MS),the most common neurological autoimmune disorder diagnosed in young adults, is characterised by the repeated occurrence of demyelinating lesions within the central nervous system (CNS). Promotion of remyelination in the brain and spinal cord constitutes a potential strategy for therapeutic intervention in MS and other demyelinating diseases. Three different principles are known to promote remyelination in the CNS of different animal models: Application of growth factors, transplantation of myelin-forming cells and intravenous immunoglobulin (IVIg) therapy. However, the systemic application of growth factors could be limited by effects on unaffected tissue. For successful transplantation we still have the problem of homologous cells not tolerated by a immunological different organism. Currently the required combination of growth factors needed to cultivate human homologous cells is not known,so that cells suitable for transplantation are still not available. Nevertheless, there is increasing evidence for beneficial effects of IVIg therapy on the promotion of remyelination in humans. In this review we summarise recent findings on the regulation of myelin sheath development and oligodendrocyte differentiation,and discuss the presented strategies in the context of possible clinical application for the therapy of MS.