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Ictal and interictal epileptic activity was recorded for the first time by multichannel magnetoencephalography (MEG) in three patients with partial epilepsy. Pre- and intra-operative localization of the epileptogenic region was compared. The interictal epileptic activity was localized at the same region of the temporal or frontal lobe as the ictal activity. Main zones of ictal activity were shown to evolve from the tissue at the centers of interictal activity. Pre- and intra-operative electrocorticography (ECoG) as well as postoperative outcome confirmed localization in the temporal and frontal lobe. Results also correlated with findings from scalp EEG, interictal and ictal single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance imaging (MRI). Combined multichannel MEG/EEG recording permitted dipole localization of interictal and ictal activity.

A DESIRE TO MOVE THE LEGS usually associated with paresthesias/dysesthesias, 2 motor restlessness, 3 worsening or exclusive presence of symptoms at rest (i.e., lying, sitting) with at least partial or temporary relief by activity, and 4 worsening of symptoms during the evening or night. According to the International RLS Study Group these four minimal criteria already allow clinical diagnosis. 1 Sensory and motor symptoms in RLS often result in severe sleep disturbances with prolonged sleep latency, decreased total sleep time with reduced or absent slow wave sleep and decreased sleep efficiency. Almost all RLS patients present periodic leg movements (PLM) during sleep and also while being awake. 2 In RLS patients the number of PLM and related parameters are often used as a marker for the severity of RLS since PLM are frequently associated with nocturnal arousals or awakenings. If present during wakefulness PLM may prevent patients from falling asleep. Therefore, performing polysomnography is mandatory to evaluate the efficacy of drug therapies. Various agents have been used to treat RLS. However, no substance is approved for this indication so far. The drug of first choice is levodopa in conjunction with a dopa decarStudy objectives: To define the effective dose of cabergoline and to evaluate the tolerability and efficacy of cabergoline in patients with restless legs syndrome (RLS). Design: Treatment of idiopathic RLS patients with cabergoline in a 12-week open label trial. Patients on levodopa therapy were allowed to either stop levodopa prior to study entry or to continue, taper or discontinue levodopa during the study. Efficacy parameters were assessed by polysomnography and subjective ratings at baseline and at week 12. Primary efficacy parameters were the number of PLM and total sleep time. Setting: Dept. of Neurology, Sleep Disorders Center Patients: Nine patients with moderate to severe RLS (age 38.1 to 64.3 years, mean 54.1 years) who had experienced insufficient benefit under levodopa therapy and/or in part developed daytime augmentation participated. At study entry five patients were still under levodopa therapy (400-800 mg). Interventions: Up-titration of cabergoline (single evening dose) until RLS symptoms clearly improved. Initial comedication with domperidone 20 mg t.i.d. Measurements and Results:At the endpoint all patients were on cabergoline monotherapy (mean dosage 2.1 mg, range 1 to 4 mg). Domperidone was stopped in all patients due to good tolerability. Polysomnographic data showed a significant reduction of the number of periodic leg movements (PLM) (195.8±109.1 (baseline) vs. 26.4±40.2 (12 weeks cabergoline monotherapy; p = 0.002), PLM arousals (51.7±42.3 vs. 6.4±11.2; p=0.017) and PLM awakenings (10.4±7.8 vs. 1.0±1.7; p=0.001). Total sleep time was prolonged (302.7±50.7 vs. 379.4±59.8 min; p=0.018), sleep latency shortened (42.4±49.1 vs. 16.3±22.8 min; p=0.214) and sleep efficiency increased (63.1±10.5 vs. 79.1±12.5%; p = 0.017). All patients reported a impressive relief or became free of ...

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins (KLKs). Many KLKs are investigated as potential biomarkers for cancer as well as therapeutic drug targets for a number of pathologies. KLK6, in particular, has been implicated in neurodegenerative diseases and cancer, but target validation has been hampered by a lack of selective inhibitors. This work introduces a class of depsipeptidic KLK6 inhibitors, discovered via high-throughput screening, which were found to function as substrate mimics that transiently acylate the catalytic serine of KLK6. Detailed structure-activity relationship studies, aided by in silico modeling, uncovered strict structural requirements for potency, stability, and acyl-enzyme complex half-life. An optimized scaffold, DKFZ-251, demonstrated good selectivity for KLK6 compared to other KLKs, and on-target activity in a cellular assay. Moreover, DKFZ-633, an inhibitor-derived activity-based probe, could be used to pull down active endogenous KLK6.