[Entrapment and non-entrapment syndromes at the elbow]. / Entrapment- und Non­Entrapment-Syndrome am Ellenbogen.

CLINICAL/METHODICAL ISSUE: Entrapment syndromes of peripheral nerves at the elbow are common and are often diagnostically challenging disorders. Difficulties consist in lesion localization and recognition of complex spatial lesion patterns as well as in differentiation of focal and multifocal disorders. STANDARD DIAGNOSTIC METHODS: Medical history taking, neurological examination and neurophysiological tests represent the gold standard in the diagnosis of peripheral nerve lesions at the elbow, but have known methodical limitations. METHODICAL INNOVATIONS: Additional diagnostic imaging tools recently developed for high-resolution visualization of extended peripheral nerve segments include 3 T magnetic resonance neurography (MRN) and neurosonography. PERFORMANCE: MRN and neurosonography can directly visualize and thus precisely localize focal and nonfocal peripheral nerve lesions of various origins with high spatial resolution at the anatomical level of nerve fascicles. ACHIEVEMENTS: MRN can cover peripheral nerve structures at the elbow, evaluate spatial nerve lesion patterns and partly disclose underlying causes. PRACTICAL RECOMMENDATIONS: Imaging of peripheral nerves is a valuable addition in the diagnostic work-up of entrapment syndromes at the elbow and provides important assistance in the differentiation of nonfocal differential diagnoses, especially in cases that cannot be clarified using standard diagnostic methods. The evaluation of spatial nerve lesion pattern may give additional information on the origin of the underlying disease, which is essential for further treatment.

[Clinical indications for high-resolution MRI diagnostics of the peripheral nervous system]. / Klinische Indikationen hochauflösender MRT-Diagnostik des peripheren Nervensystems.

CLINICAL/METHODICAL ISSUE: Peripheral neuropathies are common and diagnostically often challenging disorders. Difficulties particularly exist in lesion localization and recognition of complex spatial lesion patterns. STANDARD DIAGNOSTIC METHODS: Medical history taking, neurological examination, neurophysiological tests and nerve ultrasonography represent the gold standard in the diagnosis of peripheral nerve lesions but have known methodical limitations. METHODICAL INNOVATIONS: The use of 3 Tesla magnetic resonance neurography (MRN) is an additional diagnostic imaging tool recently developed for the high-resolution visualization of long segments of peripheral nerves. Reasonable clinical indications for MRN are exemplarily presented. PERFORMANCE: Using MRN a direct visualization and thus precise localization of focal and non-focal peripheral nerve lesions of various origins can be achieved with high spatial resolution down to the anatomical level of nerve fascicles. ACHIEVEMENTS: Using MRN large anatomical areas of the peripheral nervous system (PNS) can be covered in a single examination session, spatial nerve lesion patterns can be evaluated and the underlying causes can often be detected. PRACTICAL RECOMMENDATIONS: The MRN is a valuable supplement to the diagnostic work-up of the PNS, especially in cases that cannot be clarified with standard diagnostic methods. Evaluation of the spatial nerve lesion pattern gives additional information on the origin of the underlying disease. Reasonable indications for MRN are the assessment of proximal nerve structures including the brachial and lumbosacral nerve plexi, the clarification of inconclusive diagnostic results, preoperative, postoperative and posttraumatic assessments, the identification of fascicular nerve lesions and the differential diagnosis of an alleged somatoform disorder.

5-HT(6) receptor antagonists: lead optimisation and biological evaluation of N-aryl and N-heteroaryl 4-amino-benzene sulfonamides.

RO-04-6790 (6a) has been identified in a random screen for 5-HT(6) receptor antagonists. In a medicinal chemistry optimisation program a series of analogs comprising N-heteroaryl- and N-arylbenzenesulfonamides have been synthesised and investigated for their binding affinity. Compounds with a logD profile indicative of brain penetration have been subjected to in vivo testing for reversal of a scopolamine-induced retention deficit in a passive avoidance paradigm.

Dopamine D4/D2 receptor selectivity is determined by A divergent aromatic microdomain contained within the second, third, and seventh membrane-spanning segments.

Conserved features of the sequences of dopamine receptors and of homologous G-protein-coupled receptors point to regions, and amino acid residues within these regions, that contribute to their ligand binding sites. Differences in binding specificities among the catecholamine receptors, however, must stem from their nonconserved residues. Using the substituted-cysteine accessibility method, we have identified the residues that form the surface of the water-accessible binding-site crevice in the dopamine D2 receptor. Of approximately 80 membrane-spanning residues that differ between the D2 and D4 receptors, only 20 were found to be accessible, and 6 of these 20 are conservative aliphatic substitutions. In a D2 receptor background, we mutated the 14 accessible, nonconserved residues, individually or in combinations, to the aligned residues in the D4 receptor. We also made the reciprocal mutations in a D4 receptor background. The combined substitution of four to six of these residues was sufficient to switch the affinity of the receptors for several chemically distinct D4-selective antagonists by three orders of magnitude in both directions (D2- to D4-like and D4- to D2-like). The mutated residues are in the second, third, and seventh membrane-spanning segments (M2, M3, M7) and form a cluster in the binding-site crevice. Mutation of a single residue in this cluster in M2 was sufficient to increase the affinity for clozapine to D4-like levels. We can rationalize the data in terms of a set of chemical moieties in the ligands interacting with a divergent aromatic microdomain in M2-M3-M7 of the D2 and D4 receptors.