PNUTS forms a trimeric protein complex with GABA(C) receptors and protein phosphatase 1

Phosphorylation and dephosphorylation of neurotransmitter receptors represent an important mechanism to regulate synaptic signal transduction. Here, we identified PNUTS, a targeting subunit of protein phosphatase 1 (PP1) as a new binding partner of GABA_C receptors. In the mammalian retina, PNUTS is co-expressed with GABA_C receptors and PP1 in bipolar cells. PNUTS and PP1 were detected in membrane protein preparations of the retina and precipitate with GABA_C receptor specific antibodies. Furthermore, PNUTS shuttles from the nucleus to the membrane in cells co-expressing GABA_C receptors. We show simultaneous binding of PP1 and GABA_C receptors to different domains of PNUTS, demonstrating that PNUTS cross-links PP1 and GABA_C receptors. Finally, modeling studies showed that the PP1 docking motif of PNUTS fits into the binding pocket on the enzyme surface, despite a C-terminal adjacent proline. We suggest that PNUTS targets PP1 to synaptic sites, acting as a temporary bridge between the phosphatase and GABA_C receptors.     

Use of intravenous immunoglobulin and plasma exchange in neurological disease

PURPOSE OF REVIEW: The most relevant indications for the use of intravenous immunoglobulins and plasma exchange in neurological disorders are described, with special emphasis on the data from clinical trials and aspects of specific importance for clinical routine. RECENT FINDINGS: Much therapeutic success in neuromuscular and neuroimmunological diseases came with the therapeutic introduction of intravenous immunoglobulin and plasma exchange. Today, intravenous immunoglobulins and plasma exchange are preferentially used to treat acute Guillain-Barré syndrome, myasthenic crisis, acute or chronic inflammatory demyelinating polyneuropathy, or stiff person syndrome. Intravenous immunoglobulins also proved valuable for refractory dermatomyositis or multifocal motor neuropathy. Owing to their generally mild side effects, intravenous immunoglobulins have now been tested in many more indications, sometimes with surprising clinical effects as in the case of postpolio syndrome. While intravenous immunoglobulin is not the treatment of first choice in many immune-mediated disorders of the central nervous system, plasma exchange has become an integral part of escalating relapse therapy in relapsing-remitting multiple sclerosis. SUMMARY: In recent years, our knowledge on neurological disease mechanisms has broadened and more specific treatment alternatives have become available. Yet, established therapeutic options such as intravenous immunoglobulins and plasma exchange are still high on the list for many neuroimmunological disorders. Controlled trials have led to a refinement of the application of both treatment modalities, whose targets can be sometimes congruent, but in other cases also very distinct.     

Augmentation in restless legs syndrome is associated with low ferritin

BACKGROUND AND PURPOSE: Augmentation is a major problem with dopaminergic therapy for restless legs syndrome (RLS), and predictors of augmentation have not yet been identified. We aimed to analyze the relationship between baseline ferritin level and occurrence of augmentation in a retrospective analysis of a prospective double-blind trial of cabergoline versus levodopa on augmentation in RLS. PATIENTS AND METHODS: Patients who experienced augmentation were compared to patients who did not experience augmentation. RESULTS: Augmentation symptoms causing premature discontinuation from the study or which were tolerated (n=36, ferritin: 85+59 ng/ml) were associated with lower levels of serum ferritin compared to patients without augmentation (n=302, ferritin: 118+108 ng/ml, p=0.0062). CONCLUSIONS: Ferritin as a marker of iron storage may play an important role in the pathophysiology of RLS and may prove to be a biomarker for the development of augmentation under dopaminergic therapy.     

One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome

BackgroundLong-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome.MethodsEfficacy and safety of rotigotine (0.5–4 mg/24 h), formulated as a once-daily transdermal system (patch), were investigated in an open extension (SP710) of a preceding 6-week placebo-controlled trial (SP709, 341 randomized patients) in patients with idiopathic restless legs syndrome. For efficacy assessment the international RLS severity scale (IRLS), the RLS-6 scales, the clinical global impressions (CGI) and the QoL-RLS questionnaire were administered. In addition, long-term tolerability and safety were assessed.ResultsOf 310 patients who finished the controlled trial, 295 (mean age 58 ± 10 years, 66% females) with a mean IRLS score of 27.8 ± 5.9 at baseline of SP709 were included. We report results after one year of this ongoing long-term trial. Two hundred twenty patients (retention rate = 74.6%) completed the 12-month follow-up period. The mean daily dose was 2.8 ± 1.2 mg/24 h with 4 mg/24 h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0 mg/24 h. The IRLS total score improved by −17.4 ± 9.9 points between baseline and end of Year 1 (p < 0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p < 0.001 for pre-post-comparisons of all efficacy variables). The tolerability was described as “good” or “very good” by 80.3% of all patients. The most common adverse events were application site reactions (40.0%), which led to withdrawal in 13.2%. Further relatively frequent adverse events were nausea (9.5%) and fatigue (6.4%). Two drug-related serious adverse events, nausea and syncope, required hospitalization. Symptoms of augmentation were not reported by the patients.ConclusionRotigotine provided a stable, clinically relevant improvement in all efficacy measures throughout one year of maintenance therapy. The transdermal patch was safe and generally well tolerated by the majority of patients. Comparable to any transdermal therapy, application site reactions were the main treatment complication.     

Fumarates for the treatment of multiple sclerosis: potential mechanisms of action and clinical studies

All licensed disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis (MS) only display partial efficacy and hitherto require parenteral administration. Thus, there is a high demand for innovative and at the same time orally available MS therapeutics. Fumaric acids and their esters (FAE) may represent such a new class of compounds. FAE display immunomodulatory properties and may also exert neuroprotective effects, as shown in vitro as well as in experimental models of MS. A first Phase II study with the new, modified FAE BG00012/FAG-201 (BG-12) in relapsing-remitting MS revealed significant effects on MRI parameters such as gadolinium-enhancing lesions, T1 hypointense lesions and T2 lesion load after 24 weeks of treatment. The trial also underlined the safety and good tolerability of FAE that are already in clinical use for the systemic treatment of severe psoriasis. Presently, two Phase III studies are ongoing to investigate the clinical long-term efficacy of BG-12. In summary, FAE are potential candidates that may open a new therapeutic option for relapsing-remitting MS in the near future.     

Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial

BACKGROUND: Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome. Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome. METHODS: In this randomised, double-blind, placebo-controlled trial, 458 patients with moderate-to-severe idiopathic restless legs syndrome (average baseline International Restless Legs Syndrome Study Group severity rating scale [IRLS] sum score of 28.1) were randomly assigned to receive transdermal rotigotine 1 mg over 24 h (n=115), 2 mg over 24 h (n=112), or 3 mg over 24 h (n=114), or to receive placebo (n=117). Study medication was delivered via patches, applied once a day for 6 months. Randomisation was done with a computer-generated randomisation list, stratified by centre. Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions (CGI) item 1 score, assessed by analysis of covariance in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00136045. FINDINGS: Efficacy analyses were done on 112 patients in the 1 mg group, 109 in the 2 mg group, 112 in the 3 mg group, and 114 in the placebo group. Mean change in IRLS sum score from baseline at the end of the maintenance phase was -13.7 (SE 0.9) in the 1 mg group, -16.2 (0.9) in the 2 mg group, -16.8 (0.9) in the 3 mg group, and -8.6 (0.9) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Mean change in CGI item 1 score from baseline at the end of the maintenance phase was -2.09 (0.14) in the 1 mg group, -2.41 (0.14) in the 2 mg group, -2.55 (0.14) in the 3 mg group, and -1.34 (0.14) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Skin reactions, mostly mild or moderate, were seen in 145 (43%) of 341 patients who received rotigotine and in two (2%) of 117 who received placebo. Ten patients had serious adverse event that were deemed to be related to rotigotine: elevation of liver enzymes (one patient), worsening of tinnitus (one patient), non-response to anticoagulation (one patient), electrocardiogram changes (one patient), and application-site reactions (six patients). No admissions to hospital were needed for the application-site reactions, and they all resolved within a short time of patch removal without any other therapeutic intervention. The rate of typical dopaminergic side-effects in patients who received rotigotine was low; no signs of augmentation were noted. INTERPRETATION: 24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome. FUNDING: Schwarz Biosciences.     

Etiology and VTE risk factor distribution in patients with inferior vena cava thrombosis

Introduction

Inferior vena cava (IVC) thrombosis is a rare event and data detailing the underlying etiology are scarce.

Materials and methods

Therefore, we reviewed all available cases of IVC thrombosis consecutively registered in the MAISTHRO (MAin-ISar-THROmbosis) database and described the prevalence of VTE risk factors and other conditions contributing to IVC thrombosis development.

Results

53 patients (35 F, 18 M) with IVC thrombosis aged 12 to 79 years were identified. 40 patients (75.5%) developed thrombosis under the age of 45. Local problems, such as IVC anomalies or external venous compression, contributed to the development of thrombosis in 12 cases (22.6%). Lupus anticoagulants (10.9 vs. 2.3%, p = 0.013) and malignoma (17.0 vs. 6.4%, p = 0.023) were more prevalent in IVC thrombosis patients compared to 265 age and sex matched controls with isolated lower extremity DVT. No difference was identified with regard to inherited thrombophilia or other known VTE risk factors. Symptomatic pulmonary embolism (PE) occurred in 32.1% of IVC thrombosis patients compared to 15.2% of controls (p = 0.005).

Conclusions

Local problems such as IVC anomalies and external venous compression, malignancy and the presence of lupus anticoagulants contribute to the risk of IVC thrombosis. The risk of symptomatic pulmonary embolism in the acute setting is high.