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Recent observational studies document that non-adherence to mesalamine therapy during remission is frequent. We aimed to investigate patient impact of patient education using objective assessments of adherence.A 14-month randomised, prospective clinical trial of adherence to mesalamine was conducted in 248 patients with ulcerative colitis [UC], Colitis Activity Index [CAI] ≤ 9, receiving standard care [n = 122] versus a standardised patient education programme [n = 126]. Primary endpoint was adherence at all visits (5-aminosalicylic acid [5-ASA] urine levels). Secondary endpoints included quality of life (inflammatory bowel disease questionnaise [IBDQ]), disease activity, partial adherence, and self-assessment of adherence.Patient allocation was well balanced. Baseline non-adherence was high in quiescent/mildly active UC [52.4%] without difference between the groups (52.4% of patients in the education group versus 52.5% in the standard care group [p = 0.99]). No difference between the intervention group and standard care was seen in IBDQ, partial adherence, self-assessment of adherence, or therapy satisfaction at all visits. We suggest a model in which individual risks for non-adherence are driven by patients with young age, short disease duration, and low education levels.Non-adherence is frequent in a population with quiescent/mildly active UC. Although more than 25% of the population was not in remission at the various time points, no relationship between disease activity and adherence was seen over the 14-month observation period. Physicians should maximise their efforts to motivate high-risk patients for adherence. Future trials should use objective exposure assessments to examine the impact of continuous education and consultations on the background of individual risks to develop non-adherence.

Some patients with sacral scars, e. g. those developing after pilonidal sinus surgery, report discomfort when sitting or putting strain on the scars. In order to establish objective criteria for the assessment of this kind of discomfort and for the evaluation of scar quality after various types of surgical interventions, it is of interest to provide a method which enables physicians to assess skin quality in the sacral region. For this purpose, we developed a mechanical, non-invasive, fast and cost-neutral method for the measurement of skin distensibility and mobility. We examined a healthy sample of 100 study participants to establish benchmark values for scar-free skin in the sacral region and to identify the factors which impact skin quality, e. g. age, weight and sex.With the participant in a standing position, 4 vertically arranged measurement points, which are exactly spaced in cranial to caudal direction by 10 mm-100 mm-10 mm, are marked in the lumbar and sacral region, respectively. The participant is then asked to bend forward and - with arms and legs fully stretched on both sides - to touch both their patellae with the balls of their hands so that the distance between the measurement points can be measured in this position as well. Then, with the participant standing upright again, another measurement is taken to establish the distance by which the lowest point can be manually moved in cranial direction.The sacral-lumbar skin distension quotient (lumbar skin distension / sacral skin distension×100), which can easily be calculated from the measurements, is independent of age and BMI and has a standard range of about 80-93%. Sacral skin mobility ranges from 11 to 18 mm, but is slightly negatively influenced by a high BMI.By comparing lumbar and sacral skin distension in the same study participant, we are able to obtain intraindividually valid findings about possible changes in skin and scar quality. Owing to the lack of known published data about sacral skin elasticity, the proposed measurement method, while restricted to a number of special cases, seems to be practicable and independent of the patient's general condition. Compared with devices that have been used for the measurement of elasticity in other skin areas, our procedure is generally available and cost-neutral.

The cytoplasmic disassembly of Ran.GTP.importin and Ran.GTP.exportin. cargo complexes is an essential step in the corresponding nuclear import and export cycles. It has previously been shown that such disassembly can be mediated by RanBP1 in the presence of RanGAP. The nuclear pore complex protein RanBP2 (Nup358) contains four Ran-binding domains (RanBDi) that might function like RanBP1. We used biophysical assays based on fluorescence-labeled probes and on surface plasmon resonance to investigate the dynamic interplay of Ran in its GDP- and GTP-complexed states with RanBDis and with importin-beta. We show that RanBP1 and the four RanBDis from RanBP2 have comparable affinities for Ran.GTP (10(8)-10(9) M(-1)). Deletion of Ran's C-terminal (211)DEDDDL(216) sequence weakens the interaction of Ran.GTP with RanBPis approximately 2000-fold, but accelerates the association of Ran.GTP with importin-beta 10-fold. Importin-beta binds Ran.GTP with a moderate rate, but attains a high affinity for Ran (K(D) = 140 pM) via an extremely low dissociation rate of 10(-5) s(-)(1). Association with Ran is accelerated 3-fold in the presence of RanBP1, which presumably prevents steric hindrance caused by the Ran C-terminus. In addition, we show that the RanBDis of RanBP2 are full equivalents of RanBP1 in that they also costimulate RanGAP-catalyzed GTP hydrolysis in Ran and relieve the GTPase block in a Ran.GTP.transportin complex. Our data suggest that the C-terminus of Ran functions like a loose tether in Ran.GTP complexes of importins or exportins that exit the nucleus. This flag is then recognized by the multiple RanBDis at or near the nuclear pore complex, allowing efficient disassembly of these Ran.GTP complexes.

Nuclear transport factor 2 (NTF2) is a small, homodimeric protein that binds to both RanGDP and xFxFG repeat-containing nucleoporins, such as yeast Nsp1p and vertebrate p62. NTF2 is required for efficient nuclear protein import and has been shown to mediate the nuclear import of RanGDP. We have used the crystal structures of rat NTF2 and its complex with RanGDP to design a mutant, W7A-NTF2, in which the affinity for xFxFG-repeat nucleoporins is reduced while wild-type binding to RanGDP is retained. The 2.5 A resolution crystal structure of W7A-NTF2 is virtually superimposable upon the wild-type protein structure, indicating that the mutation had not introduced a more general conformational change. Therefore, our data suggest that the exposed side-chain of residue 7 is crucial to the interaction between NTF2 and xFxFG repeat-containing nucleoporins. Consistent with its reduced affinity for xFxFG nucleoporins, fluorescently labelled W7A-NTF2 binds less strongly to the nuclear envelope of permeabilized cultured cells than wild-type NTF2 and, when microinjected into Xenopus oocytes, colloidal gold coated with W7A-NTF2 binds less strongly to the central channel of nuclear pore complexes than wild-type NTF2-coated gold. Significantly, W7A-NTF2 only weakly stimulated the nuclear import of fluorescein-labelled RanGDP, providing direct evidence that an interaction between NTF2 and xFxFG repeat-containing nucleoporins is required to mediate the nuclear import of RanGDP.

Antikonvulsiva werden in der Regel zur Langzeitbehandlung eingesetzt. Klinisch oder laborchemisch beobachtete unerwunschte Ereignisse konnen als direkte pharmakologische Wirkung des Arzneimittels, als Folge von Arzneimittelinteraktionen oder als Ergebnis einer erhohten Empfindlichkeit des Organismus auftreten. Diese wiederum kann durch die Grunderkrankung oder eine Disposition verursacht werden.

Many proteins are transported through the ER membrane as they are synthesized. These include secretory proteins and proteins of the plasma membrane, of lysosomes, and of all organelles of the secretory pathway. Synthesis of these proteins begins in the cytoplasm, but they are then targeted to the ER membrane by signal sequences, which are characterized by a stretch of at least six apolar amino acids, and which are often located at the amino terminus of precursor molecules. Recognition of the signal sequence and targeting of the nascent chain generally requires the function of the signal recognition particle (SRP) and of its membrane receptor (also called docking protein), but alternative targeting pathways exist. The targeting phase is followed by the actual translocation process. Proposed mechanisms of translocation have ranged from the idea that the transport of a polypeptide chain occurs directly through the phopholipid bilayer without participation of membrane proteins, to models according to which polypeptides are transported through a hydrophilic or amphiphilic channel formed from transmembrane proteins (for discussion, see Rapoport 1991). It now appears that a protein-conducting channel does exist. The evidence comes from electrophysiological data and from the identification of membrane proteins as putative channel constituents. The present paper summarizes our knowledge on the components involved in the actual translocation process. The mechanisms by which polypeptides are targeted to the ER membrane have been discussed elsewhere (Rapoport 1992).

164 patients (m = 45, w = 119; age 55.7 +/- 14.7 years) took part in a multicentric controlled parallel-double blind study in which efficacy and tolerability of the combination quinine sulfate (CAS 6119-70-6) plus theophylline ethylene diamine (CTED, CAS 317-34-0) (Limptar) in the treatment of the recurrent nocturnal leg cramps were investigated. Only patients who suffered before the begin of the study in at least three nights per week from leg cramps were included. The duration of the study was three weeks. In the first week all patients were treated in a single blind design with placebo. The subsequent 2 weeks were carried out double-blind. The global efficacy judged by the physicians and investigated for the 126 patients who took the compounds at least four days within the random phase was remarkably better for the combination than for quinine or placebo (very good and good in 87.1 vs. 63.7 vs. 39.5% of the cases; p less than 0.001; x-test). In 117 patients an analysis of the time course of the efficacy could be done from the notes in the diary (minimum duration of treatment 11 d). Already within the first week there was a highly significant decrease of nights with leg cramps within the CTED group (n = 34) from 4.68 (95% confidential interval 2.26-7.0) to 2.25 (0-6.78) in comparison to placebo (n = 40; from 4.32 [1.9-7.0] to 3.69 [1.22-6.91]) and quinine (n = 43; from 4.78 [2.22-7.0] to 3.27 [0-7.0]; F-test; p = 0.0001 resp. 0.0012).(ABSTRACT TRUNCATED AT 250 WORDS)

The signal sequence receptor (SSR), an integral membrane glycoprotein of 34 kDa, has previously been shown to be a component of the molecular environment which nascent polypeptide chains meet in passage through the endoplasmic reticulum (ER) membrane. We have used antibodies directed against the SSR and both immunocytochemistry and cell fractionation to determine its distribution in rat liver cells. SSR was found largely restricted to the rough ER. Only small amounts of the protein were detected in smooth ER. These results provide further evidence for a functional differentiation of rough and smooth ER and for a role of SSR in protein translocation across the ER membrane.

Seit Sciner Erstanwendung am Menschen hat Clonidin aufgrund Scines spezifischen Wirkungsmechanismus, der Alpha2 -Rezeptorenstimulation, die eine Reduktion neuronaler noradrenerger Aktivitat bewirkt, Physiologie und Pathophysiologie um neue Erkenntnisse bereichert. Dies fuhrte auch dazu, das die Substanz Clonidin, ursprunglich als Antihypertonikum in Anwendung, bei einer Reihe weiterer Erkrankungen genutzt werden kann. Das Spektrum der Erkrankungen, die durch Clonidin gunstig zu beeinflussen sind, ist immer noch nicht vollstandig bekannt.