Patient education programme on immunotherapy in multiple sclerosis (PEPIMS): a controlled rater-blinded study.

OBJECTIVE: To investigate the effectiveness of a multi-component evidence-based education programme on disease modifying therapies in multiple sclerosis. DESIGN: Controlled trial with two consecutive patient cohorts and a gap of two months between cohorts. SETTING: Three neurological rehabilitation centres. SUBJECTS: Patients with multiple sclerosis within rehabilitation. INTERVENTIONS: Control group (CG) participants were recruited and received standard information. Two months later, intervention group (IG) participants were recruited and received a six-hour nurse-led interactive group education programme consisting of two parts and a comprehensive information brochure. MAIN MEASURES: Primary endpoint was "informed choice", comprising of adequate risk knowledge in combination with congruency between attitude towards immunotherapy and actual immunotherapy uptake. Further outcomes comprised risk knowledge, decision autonomy, anxiety and depression, self-efficacy, and fatigue. RESULTS: A total of 156 patients were included (IG=75, CG=81). The intervention led to significantly more participants with informed choice (IG: 47% vs. CG: 23%, P=0.004). The rate of persons with adequate risk knowledge was significantly higher in the IG two weeks after the intervention (IG: 54% vs. CG: 31%, P=0.007), but not after six months (IG: 48% vs. CG: 31%, P=0.058). No significant differences were shown for positive attitude towards disease modifying therapy (IG: 62% vs. CG: 71%, P=0.29) and for disease modifying therapy status after six months (IG: 61.5% vs CG: 68.6%, P=0.39). Also no differences were found for autonomy preferences and decisional conflict after six months. CONCLUSION: Delivering evidence-based information on multiple sclerosis disease modifying therapies within a rehabilitation setting led to a marked increase of informed choices.

Transcranial magnetic and electrical stimulation compared: does TES activate intracortical neuronal circuits?

OBJECTIVE: To determine whether, and under which conditions, transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) can activate similar neuronal structures of the human motor cortex, as indicated by electromyographic recordings. METHODS: Focal TMS was performed on three subjects inducing a postero-anterior directed current (p-a), TES with postero-anteriorly (p-a) and latero-medially (l-m) oriented electrodes. We analyzed the onset latencies and amplitudes (single-pulse) and intracortical inhibition and excitation (paired-pulse). RESULTS: TMS p-a and TES p-a produced muscle responses with the same onset latency, while TES l-m led to 1.4-1.9 ms shorter latencies. Paired-pulse TMS p-a and TES p-a induced inhibition at short inter-stimulus intervals (ISI) (maximum: 2-3 ms) and facilitation at longer ISIs (maximum: 10 ms). No inhibition but a strong facilitation was obtained from paired-pulse TES l-m (ISIs 1-5 ms). CONCLUSIONS: Our findings support the hypothesis, that current direction is the most relevant factor in determining the mode of activation for both TMS and TES: TMS p-a and TES p-a are likely to activate the corticospinal neurons indirectly. In contrast, TES l-m may preferentially activate the corticospinal fibres directly, distant of the neuronal body. SIGNIFICANCE: TES is a suitable tool to induce intracortical inhibition and excitation.

[Lymph node metastasis of glottic laryngeal carcinoma]. / Die Halslymphknotenmetastasierung des glottischen Larynxkarzinoms.

UNLABELLED: The incidence of lymph node metastases in glottic cancer is assumed to be lower than in other head and neck cancers. In a retrospective study this statement was investigated. MATERIAL AND METHODS: This analysis was based on 910 consecutive patients with glottic carcinoma treated between 1970 and 1990 by means of surgery with special interest on regional lymph node metastases. RESULTS: 8.6 % patients had clinically positive necks (N+) and 5.9 % pathohistologically positive necks (pN+). The incidence of lymph node metastases showed correlation with pT category and vocal cord mobility. Lymph node metastases were found in 5 % of pT2, in 18 % of pT3 and in 32 % of pT4 tumors. Only one patient with pT1 cancer had metastatic lymph node involvement. The incidence of occult lymph node metastases was 18 %. Lymph node involvement, extracapsular spread and lymphangiosis carcinomatosa proved to be relevant prognostic factors. The 5 year recurrent free survival rate was 86.7 % for the whole group, 81.6 % for patients with negative nodes (pN0), and 61.8 % for patients with pN+ nodes (p < 0.001 according to logrank test). CONCLUSIONS: Clinical lymph node staging plays an important prognostic role in the staging procedure also in glottic carcinoma. At least in T3 carcinomas, elective treatment of the cervical lymph nodes seems to be necessary. T2 carcinomas with impaired cord mobility have a significant higher risk for metastatic spread; therefore neck dissection should be discussed also in these cases.

From primed to learn: the saturation of repetition priming and the induction of long-term memory.

Although practice can make perfect, it is not clear how much practice is needed to trigger long-lasting performance gains on a given task. Here, using a letter enumeration task, we show that the transition of experience dependent performance gains to a relatively stable form, as well as the triggering of delayed, long-lasting, between session gains (both effects are considered manifestations of consolidation processes) is amount-of-practice dependent. We then show (a) that consolidation processes, once triggered, can proceed without further practice as a function of time and (b) that the triggering of consolidation processes is related to repetition priming effects--performance gains in processing a previously experienced item. However, we show that repetition priming effects saturate after a limited number of consecutive repetitions and reflect an initial, but potentially reversible, response to the repeated experience. Moreover, we show that one critical parameter determining the occurrence of repetition priming (but not skill learning) is the presence of interference (by a somewhat different set of items) prior to the primer presentation. Thus, our results suggest that the saturation of repetition priming effects, rather than priming per se, may be critical to the induction of slow learning processes and consolidation.

Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson's disease.

Levodopa is administered with dopa decarboxylase inhibitors (DDI) to prevent its peripheral degradation. This increases conversion of levodopa to 3-O-methyldopa (3-OMD) by catechol-O-methyltransferase (COMT). S-adenosylmethionine (SAM), which is synthesized from adenosine triphosphate and methionine (MET), serves as methyl donor for this O-metabolisation of levodopa with resulting conversion of SAM to total homocysteine (tHcy) via S-adenosylhomocysteine (SAH). Previous studies showed augmented plasma levels of tHcy in long-term levodopa/DDI-treated patients with Parkinson's disease (PP). Objective of this study was to compare MET, SAM, levodopa, 3-OMD, tHcy and SAH in plasma of 20 levodopa/DDI treated PP and corresponding controls. A significant decrease of MET respectively SAM and an increase of tHcy appeared in PP. SAH with its short half-life did not differ. Levodopa/DDI long-term treatment contributes to altered levels of substrates of the O-methylation cycle in PP.

Facilitation of motor evoked potentials after repetitive voluntary hand movements depends on the type of motor activity.

Recent neurophysiological studies suggest that repetitive execution of identical movements is crucial for motor learning. During and after repetitive motor action, changes in motor cortical excitability have been demonstrated by means of transcranial magnetic stimulation. Nevertheless, the frequency and intensity of movement repetition that are necessary to achieve an optimal improvement in motor function are unknown. Fourteen healthy volunteers participated in the present study, which deals with the post-exercise facilitatory and/or inhibitory effects of 5 different motor conditions, including repetitive isotonic contractions at the wrist at two different velocities and two different forearm positions, a sustained isometric hand extension and repetitive hand extensions at the wrist induced by means of transcutaneous electrical muscle stimulation. The modification of muscular response potentials in the extensor carpi radialis muscle was measured following the various motor tasks and the electrical muscle stimulation. The only statistically significant facilitatory effect was observed following an extension-relaxation task at low frequency. Furthermore, the duration of transcranially induced silent periods showed a significant reduction after this motor task.

Facilitation of motor evoked potentials in hand extensor muscles of stroke patients: correlation to the level of voluntary contraction.

The influence of ongoing voluntary isometric contractions (ranging from 2.5% to 100% of maximum force production) on motor evoked potentials in the extensor carpi radialis muscle was investigated in 20 healthy subjects and 25 hemiparetic stroke patients using transcranial magnetic stimulation at threshold and at 90% of maximum stimulus intensity. In healthy subjects and in stroke patients, an initial sharp decay in response latencies was observed at low contraction levels. In hemiparetic patients, however, no significant further reduction of response latencies with increasing contraction levels was observed irrespective of whether threshold or 90% stimulus intensities were applied. The continuous decrease in latency in the healthy subjects is supposed to result from an enhanced involvement of rapidly conducting corticospinal neurones that are preferentially damaged in the patient group. In healthy subjects and in hemiparetic patients, however, the increase in response amplitudes runs in parallel with increasing force production, at least with threshold stimulus intensity. Contrary to response latencies, amplitude facilitation appears to be less dependent on the involved corticospinal fibre spectrum but to be predominantly based on temporal and spatial summation effects. The relevance of the latency and amplitude data obtained in healthy subjects and in stroke patients for physiology and localization of facilitatory processes, i.e. whether cortical or spinal, is discussed. For the rehabilitation of stroke patients it is concluded that the effect of slight voluntary contractions is indeed superior to most other facilitatory approaches. The functional relevance is discussed.

Influence of physiotherapeutic facilitation techniques on motor evoked potentials in centrally paretic hand extensor muscles.

In the rehabilitation of stroke patients, various facilitation techniques are applied to reduce weakness in centrally paretic muscles and to improve functional motor capacity. The present investigation compared the facilitatory effect of 5 different physiotherapeutic approaches onto the centrally paretic extensor carpi radialis muscle in 30 stroke patients classified into 3 groups according to the individual degree of paresis. In order to quantify the influence of the respective facilitation manoeuvre, single transcranial magnetic stimuli were applied before and during the application of cutaneous/proprioceptive stimuli, a weight bearing task, contraction of the affected and the non-affected extensor carpi radialis muscle and during proximal preinnervation on the affected side. All procedures, indeed, enhanced the frequency of occurrence of muscular response potentials and their amplitudes while diminishing their response latencies. The most prominent effects were observed when the muscle itself was voluntarily activated. A similarly strong facilitation was obtained in the most severely affected patients with cutaneous and proprioceptive stimuli, but such stimuli had inhibitory effects in the healthy control group. The present study illustrates the interaction of cortically evoked motor potentials with peripherally or centrally generated inputs, contributes to the understanding of the neurophysiological mechanisms underlying physiotherapeutic facilitation techniques and helps in providing rational criteria to decide about the most appropriate facilitation method.

[Radioimmunoscintimetry for intraoperative lymph node diagnosis in colorectal cancer]. / Die Radioimmunszintimetrie zur intraoperativen Lymphknotendiagnostik beim colorektalen Karzinom.

In a prospective study 32 patients with primary colorectal carcinomas were studied by means of radioimmunoscintigraphy with the anti-carcinoembryonic antigen monoclonal antibody BW 431/26 labelled with either 131I (group 1, n = 17) or 99Tc (group 2, n = 15). Scintigraphy of the resected specimen was used as a model for intraoperative radioimmunoscintimetry, and all positive lymph nodes were marked during the investigation. The results were compared with the data yielded by preoperative investigations (CT, MR, endosonography) and checked by histology and immunohistochemistry. The analysis (sensitivity, specificity) included: type of investigation, time interval from antigen application, type of radionuclide, size of lymph nodes investigated, and serum level of CEA. 131I-Scintigraphy of the resected specimen gave the best results in the detection of lymph node metastases (sensitivity 1, specificity 0.57) and was superior to all other diagnostic procedures. When the investigation was performed 6-8 days after administration of the antibody the specificity improved to 1. The best results (sensitivity 1, specificity 0.91) were achieved in small (< 1 cm) lymph node metastases. A good correlation between scintigraphic diagnosis and immunohistochemical CEA detection was confirmed. Serum levels of CEA had no influence on the scintigraphic results. We conclude that intraoperative radioimmunodetection of lymph node metastases may improve the radicality in the resection of colorectal tumors. The best results are achieved with 131I-labelling and with application of the antibody 6-8 days before the operation.

Inhibition of tumour necrosis factor alpha (TNF-alpha)-induced neutrophil respiratory burst by a TNF inhibitor.

Tumour necrosis factor alpha (TNF-alpha) plays an important role in microbial defence and tissue damage by activating neutrophils. Therefore the ability of natural molecules to regulate the activity of TNF-alpha is likely to be of major importance in our understanding of the mechanisms of inflammation. We have examined the effects of a highly purified urine-derived TNF inhibitor (TNF inh) on the TNF-alpha-induced respiratory burst in human neutrophils. TNF-alpha inh-treated TNF-alpha was unable to stimulate a neutrophil lucigenin-dependent chemiluminescence response and superoxide formation. Treatment of TNF with the inhibitor also significantly reduced the priming ability of TNF-alpha for a response to the peptide f-met-leu-phe. These results show that the ability of TNF-alpha to induce a key neutrophil response is amenable to regulation by the TNF-alpha inh.

Modulation of IL-1 inflammatory and immunomodulatory properties by IL-6.

Among the major cytokines present in inflammatory lesions interleukin-1 (IL-1), tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) share many biological activities. Since IL-1 alpha, IL-1 beta and TNF alpha have been previously demonstrated to play an important role in connective tissue destruction by stimulating the production of prostaglandin E2 (PGE2) and collagenase, these functions were investigated in the presence or absence of natural human IL-6 (nhIL-6) or recombinant human IL-6 (rhIL-6). IL-6 was found 1 degree to stimulate immunoglobulin A production by the CESS B cell line up to 19 fold without being affected by the presence of IL-1 beta and 2 degrees to stimulate murine thymocytes proliferation up to 2-4 fold, with an increase up to 60-fold in costimulation with either IL-1 alpha or beta. IL-6 alone, even at very high concentrations (up to 200 U/ml and 50 ng/ml), did not induce PGE2 production by fibroblasts and synovial cells. However, IL-1 alpha or beta induced PGE2 production by human dermal fibroblasts and by human synovial cells was inhibited (in 5/8 experiments) up to 62% by addition of IL-6. On the contrary in 2/4 experiments TNF alpha-induced PGE2 production was increased (approximately 2 fold) by the addition of IL-6. IL-1 and TNF alpha-induced collagenase production in synovial cells remained unchanged in the presence of IL-6.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of a tumor necrosis factor alpha (TNF-alpha) inhibitor: evidence of immunological cross-reactivity with the TNF receptor.

Previous studies have shown that urine of febrile patients contains a tumor necrosis factor alpha inhibiting activity (TNF-alpha Inh) when tested in a cytotoxicity assay using the tumor necrosis factor alpha (TNF-alpha)-susceptible cell line L929. In the present study, we investigated the relationship between the TNF-alpha Inh and a potential soluble form of the receptor, as the former has been shown to block TNF-alpha activities by binding to the ligand. We demonstrate that human TNF-alpha is affected to a greater extent than is murine TNF-alpha. This species specificity of the inhibitor correlates with the binding studies of TNF receptor interactions already reported. We raised a polyclonal antibody to TNF-alpha Inh that neutralizes its activity and does not recognize TNF-alpha. Solubilized cross-linked 125I-labeled TNF-alpha receptor complex could be immunoprecipitated by using either anti-TNF-alpha or anti-TNF-alpha Inh antibody, suggesting immunological cross-reactivity between the receptor and the inhibitor. By using fluorescein isothiocyanate-coupled TNF-alpha, it was possible to visualize by fluorescence-activated cell sorter analysis the TNF-alpha receptor on phytohemagglutinin/interleukin 2-activated T cells. A similar increase of immunofluorescence intensity of the activated T cells was observed by using anti-TNF-alpha Inh antibody revealed with a fluorescein isothiocyanate-coupled goat anti-rabbit IgG1 conjugate, suggesting that the TNF-alpha Inh is also expressed as a membrane protein. Taken together, our results suggest that the TNF-alpha Inh originally described might be a soluble form of the TNF receptor itself.