Differential effect of R 56865 on ouabain binding to isolated sarcolemma and intact atrial tissue of guinea-pig.

1. R 56865 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl]-N-methyl- 2-benzothiazolamine) is a compound known to antagonize cardiac glycoside intoxication. Therefore, the effect of the compound on ouabain binding to intact cardiac tissue as well as cardiac membrane preparations was investigated. 2. The binding of ouabain to highly purified sarcolemmal membranes was not influenced by R 56865 1 x 10(-6) mol l-1 (ouabain: KD = 1.3 x 10(-7) mol l-1, Bmax = 160 pmol mg-1; ouabain + R 56865: KD = 1.4 x 10(-7) mol l-1, Bmax = 168 pmol mg-1). 3. In contrast to the results in purified membranes, the binding of ouabain (10(-8) mol l-1 to 5 x 10(-7) mol l-1) to intact atria was significantly reduced. 4. Ouabain, 5 x 10(-7) mol l-1, led to a transient positive inotropic effect of about 220% followed by a developing negative inotropic effect after 3 h. R 56865, 10(-7) mol l-1, led to a maximal positive inotropic effect of about 290% also followed by a delayed decline of contractile force. A tenfold higher concentration of R 56865 led to sustained positive inotropic effect of about 250% in the same time interval. 5. The different effects of R 56865 on ouabain binding in subcellular preparations and intact tissue do not support the view that R 56865 interferes directly with the action of ouabain on Na/K-ATPase. An indirect effect, which may be mediated by a lowered intracellular sodium load is discussed.     

Update on rheuma-orthopedics - role and therapeutic options

Orthopaedic treatment options for rheumatological patients have been further developed over recent years. For orthopaedic treatment, a range of different interventions are offered: orthoses and special technical aids as well as injections for joints and tendons, or surgery. Surgical interventions cover joint preservation, restitution and arthrodeses. Improvements in equipment and surgical procedures also make minimally invasive interactions possible for rheumatoid diseases. Thus, postoperative morbidity has been reduced significantly. Improvement in function, reduction of pain and prevention of recurrent local inflammation are primary. Considering these aims, arthrodeses are restricted to special indications. Joint preservation and restitution are the predominant measures used. The various procedures are discussed.     

MEG-based identification of the epileptogenic zone in occult peri-insular epilepsy

IntroductionPresurgical work-ups of patients with pharmacoresistant epileptic seizures can require multiple diagnostic methods if magnetic resonance imaging (MRI) combined with video-EEG monitoring fails to show an epileptogenic lesion. Yet, the added value of available methods is not clear. In particular, only a minority of epilepsy centres apply magnetoencephalography (MEG). This study explores the potential of MEG for patients whose previous sophisticated work-ups missed deep-seated, peri-insular epileptogenic lesions.Patients and methodsThree patients with well documented, frequent, stereotypical hypermotor seizures without clear focus hypotheses after repeated presurgical work-ups including video-EEG-monitoring, 3 Tesla (3 T) magnetic resonance imaging (MRI), morphometric MRI analysis, PET and SPECT were referred to MEG source localisation.ResultsIn two out of three patients, MEG source localisation identified very subtle morphological abnormalities formerly missed in MRI or classified as questionable pathology. In the third patient, MEG was not reliable due to insufficient detection of epileptic patterns. Here, a 1 mm × 1 mm × 1 mm 3 T fluid-attenuated inversion recovery (FLAIR) MRI revealed a potential epileptogenic lesion. A minimal invasive work-up via lesion-focused depth electrodes confirmed the intralesional seizure onset in all patients, and histology revealed dysplastic lesions. Seizure outcomes were Engel 1a in two patients, and Engel 1d in the third.DiscussionMEG can contribute to the identification of epileptogenic lesions even when multiple previous methods failed, and when the lesions are located in deep anatomical structures such as peri-insular cortex. For epilepsy centres without MEG capability, referral of patients with cryptogenic focal epilepsies to centres with MEG systems may be indicated.     

The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels

We hypothesized that lacosamide modulates voltage-gated sodium channels (VGSCs) at clinical concentrations (32-100 muM). Lacosamide reduced spiking evoked in cultured rat cortical neurons by 30-s depolarizing ramps but not by 1-s ramps. Carbamazepine and phenytoin reduced spike-firing induced by both ramps. Lacosamide inhibited sustained repetitive firing during a 10-s burst but not within the first second. Tetrodotoxin-sensitive VGSC currents in N1E-115 cells were reduced by 100 muM lacosamide, carbamazepine, lamotrigine, and phenytoin from V(h) of -60 mV. Hyperpolarization (500 ms) to -100 mV removed the block by carbamazepine, lamotrigine, and phenytoin but not by lacosamide. The voltage-dependence of activation was not changed by lacosamide. The inactive S-stereoisomer did not inhibit VGSCs. Steady-state fast inactivation curves were shifted in the hyperpolarizing direction by carbamazepine, lamotrigine, and phenytoin but not at all by lacosamide. Lacosamide did not retard recovery from fast inactivation in contrast to carbamazepine. Carbamazepine, lamotrigine, and phenytoin but not lacosamide all produced frequency-dependent facilitation of block of a 3-s, 10-Hz pulse train. Lacosamide shifted the slow inactivation voltage curve in the hyperpolarizing direction and significantly promoted the entry of channels into the slow inactivated state (carbamazepine weakly impaired entry into the slow inactivated state) without altering the rate of recovery. Lacosamide is the only analgesic/anticonvulsant drug that reduces VGSC availability by selective enhancement of slow inactivation but without apparent interaction with fast inactivation gating. The implications of this unique profile are being explored in phase III clinical trials for epilepsy and neuropathic pain.     

Localization Accuracy of Distributed Inverse Solutions for Electric and Magnetic Source Imaging of Interictal Epileptic Discharges in Patients with Focal Epilepsy

Distributed inverse solutions aim to realistically reconstruct the origin of interictal epileptic discharges (IEDs) from noninvasively recorded electroencephalography (EEG) and magnetoencephalography (MEG) signals. Our aim was to compare the performance of different distributed inverse solutions in localizing IEDs: coherent maximum entropy on the mean (cMEM), hierarchical Bayesian implementations of independent identically distributed sources (IID, minimum norm prior) and spatially coherent sources (COH, spatial smoothness prior). Source maxima (i.e., the vertex with the maximum source amplitude) of IEDs in 14 EEG and 19 MEG studies from 15 patients with focal epilepsy were analyzed. We visually compared their concordance with intracranial EEG (iEEG) based on 17 cortical regions of interest and their spatial dispersion around source maxima. Magnetic source imaging (MSI) maxima from cMEM were most often confirmed by iEEG (cMEM: 14/19, COH: 9/19, IID: 8/19 studies). COH electric source imaging (ESI) maxima co-localized best with iEEG (cMEM: 8/14, COH: 11/14, IID: 10/14 studies). In addition, cMEM was less spatially spread than COH and IID for ESI and MSI (p < 0.001 Bonferroni-corrected post hoc t test). Highest positive predictive values for cortical regions with IEDs in iEEG could be obtained with cMEM for MSI and with COH for ESI. Additional realistic EEG/MEG simulations confirmed our findings. Accurate spatially extended sources, as found in cMEM (ESI and MSI) and COH (ESI) are desirable for source imaging of IEDs because this might influence surgical decision. Our simulations suggest that COH and IID overestimate the spatial extent of the generators compared to cMEM.     

Aktivierung epileptischer Aktivit?t durch Etomidat?

Objective

Pharmacological activation of focal epileptic discharges is employed during presurgical evaluation to increase the yield of epileptic activity. Administration of etomidate has been shown to increase focal epileptic activity recorded by foramen ovale electrodes and by magnetoencephalography (MEG). However, results from simultaneous MEG and electroencephalography (MEG/EEG) recordings suggest that sensitivity of surface EEG for epileptic spikes might be diminished due to generalized theta/delta activity caused by etomidate. This project aimed to show differences between epilepsy patients and a control group with respect to clinical and EEG changes after administration of etomidate.

Methods

A total of 11 patients with focal epilepsy underwent activation with etomidate with simultaneous video EEG monitoring during presurgical evaluation. In addition activation with etomidate was performed in a control group of four patients without epilepsy under surveillance with simultaneous video EEG monitoring during anesthetization for spinal surgery.

Results

All patients except three epilepsy patients became unconscious after administration of etomidate. Motor symptoms of the eyes, the face and the limbs unrelated to the semiology of their habitual seizures occurred in the epilepsy patients. No clinical symptoms beyond sedation were observed in patients of the control group. In epilepsy patients no epileptic activity was recorded after injection of etomidate, however, generalized delta/theta activity occurred in all epilepsy patients several seconds after injection similar to patients in the control group.

Conclusion

General anesthesia with etomidate is a safe procedure. In contrast to epilepsy patients, patients in the control group did not show any clinical symptoms. However, in this study no epileptic activity could be recorded with surface EEG after administration of etomidate. These results were in contrast to prior invasive EEG and MEG studies. Future studies should evaluate the differences in recordings from surface EEG, MEG and invasive EEG using etomidate activation.     

Operative Therapie bei rheumatoider Arthritis der Hand

The need for operative treatment of severe rheumatic deformities of the hand and wrist is decreasing due to the increased use of disease-modifying drugs; however, some patients do not tolerate or do not sufficiently respond to these drugs, which often results in the hands being affected and in advanced stages to severe deformity and loss of function. In these cases operative surgery can help to slow the progression of rheumatic destruction and restore the function of the patient’s hand. This article describes the principles of surgery for rheumatoid arthritis of the hand. A meticulous synovectomy or tenosynovectomy is the first stage of treatment. With progression of rheumatic destruction various salvage procedures are necessary to preserve the best possible functional state.     

Detection of epileptic spikes by magnetoencephalography and electroencephalography after sleep deprivation

IntroductionIn diagnosis of epilepsies electrophysiological findings play a key role. While spontaneous electroencephalography (EEG) and EEG with sleep deprivation (EEGsd) are widely evaluated and used, application of magnetoencephalography (MEG) in this field is primarily limited to presurgical assessment of focal epilepsies.MethodsIn this study we retrospectively compared MEG (M/EEG) and EEGsd in 63 (55) patients with focal and generalized epilepsy with regard to occurrence of epileptic spikes.ResultsMEG could record epileptic spikes in 38 patients (60%), while EEGsd recorded spikes in only 32 patients (51%). In a group of 55 patients simultaneous MEG/EEG (M/EEG) was able to record spikes in 38 patients (71%) compared to epileptic spikes in 28 patients (51%) recorded by EEGsd. In a subgroup of 17 MR-negative patients simultaneous M/EEG could record epileptic spikes in all patients, while EEGsd was successful in only 11 (64%) of them.ConclusionIn this study, MEG showed a tendency to record epileptic spikes in more patients than EEGsd. Furthermore, simultaneous M/EEG has been shown to be especially successful in detection of epileptic spikes in patients with MR-negative epilepsy. This might at least in parts be explained by neocortical predominance of MR-negative epilepsy. Thus, this study motivates prospective studies to evaluate the substitutability of EEGsd by MEG more extensively.     

Evaluation of healthy and diseased muscle with magnetic resonance elastography

OBJECTIVE: To investigate whether a new tissue-imaging technique, magnetic resonance elastography (MRE), offers a viable, noninvasive way to study healthy and diseased muscle. DESIGN: Convenience sample. SETTING: A magnetic resonance imaging (MRI) laboratory. PARTICIPANTS: Eight control subjects (4 men, 4 women), between the ages of 24 and 41 years, with normal neuromuscular examinations and histories, and 6 subjects (3 men, 3 women), ages 17 to 63 years, with lower-extremity neuromuscular dysfunction (1 with childhood poliomyelitis, 2 with flaccid, 3 with spastic paraplegia). INTERVENTIONS: Subjects lay supine with their legs within the coils of a 1.5T MRI machine, with their feet strapped to a footplate positioned so that the axes of rotation of their ankles coincided with the apparatus. All subjects were tested in a no-load (0 torque) condition. Control subjects were also evaluated as they isometrically resisted ankle dorsi- (20.2Nm, 40.5Nm) and plantar- (8.2Nm, 16.4Nm) flexion moments. Subjects with neuromuscular dysfunction were evaluated in the same manner, except 1 individual with residual lower-extremity strength who could only be tested in the resting and passive ankle dorsiflexion modes. Shear waves were induced with a 150-Hz electromechanic transducer located over the belly tibialis anterior. MRE images were collected with a gradient-echo technique gated to the transducer's motion. Wave-phase propagation was visualized with 8 equally offset images across 1 vibration-cycle. MAIN OUTCOME MEASURES: Changes in shear-wave wavelength (lambda) and muscle stiffness (as expressed by the shear modulus [G]) in the tibialis anterior and gastrocnemius muscles. RESULTS: Wavelength and G differed between the groups in all the muscles studied, and increased as the load increased. Moreover, lambda and G in the neuromuscular disease group at rest (eg, 3.88+/-0.48cm; range, 2.87-4.91cm; 38.40+/-00.77kPa; range, 22.35-59.67kPa) and in the lateral gastrocnemius were, respectively, more than 1.5 and 2.4 times larger than they were in the same muscle in the control group (2.56+/-0.28cm, 16.16+/-00.19kPa; P=.0002) (1Pa=1N/m(2)). CONCLUSIONS: Shear-wave wavelength and muscle stiffness increased with load in healthy muscle. In addition, at least for our sample, these quantities differed significantly between muscles with and without neuromuscular disease. In summary, MRE appears to provide in vivo physiologic information about the mechanical properties of muscle at rest and during contraction that is not otherwise available. The potential of this technique for monitoring the effects of treatment and exercise on both healthy and diseased muscle merits further research.