Synthesis and biological evaluation of analogues of the peptaibol ampullosporin A

A series of analogues of the fungal peptaibol type metabolite ampullosporin A containing modifications in the C and N terminus as well as alpha-aminoisobutyric acid (Aib) substitutions in different positions of the peptide were synthesized by solid phase synthesis using the 9-fluorenylmethyloxycarbonyl strategy. Depending on the sequence position, couplings were performed with 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/1-hydroxybenzotriazole and tetramethylfluoroformamidinium hexafluorophosphate, respectively. The structures of the target peptides were analyzed by electrospray ionization mass spectrometry and chromatographic methods (high-performance liquid chromatography, thin-layer chromatography). The biological activities of these compounds have been evaluated by assaying their potencies for the induction of pigment formation on the fungus Phoma destructiva as well as for the induction of hypothermia and inhibition of locomotoric activity in mice and were compared to the naturally occurring ampullosporins. Native ampullosporin A and analogues with C-terminal Leu or Leu-NH(2) showed comparable activity in the pigmentation assay. Similarly, the ampullosporin A analogues with N-terminal aromatic amino acid residues, such as D-Trp and Tic, also have high potency for pigment formation. The peptides containing structural modifications of ampullosporin A by systematic replacement of Aib by Ala (Ala scan) displayed moderate or high activity in the pigmentation assay, whereas simultaneous substitution of all Aib residues by Ala and Ile, respectively, or by insertion of nonaromatic residues into position 1 resulted in a loss of the effect on P. destructiva. Most of the compounds with no or weak activity in the microbial assay were not active in the hypothermic test, too, except the compound with 1-amino-1-cyclohexane carboxylic acid in position 4 instead of Aib. However, only a few compounds with high potency for pigmentation induction were found to produce strong hypothermia in mice. Thus, in contrast to the native ampullosporins, we succeeded to a certain degree in differentiation of the bioactivities with our synthetic analogues.     

Propranolol and atropine do not alter choroidal blood flow regulation during isometric exercise in healthy humans

Recent studies indicate that the human choroid has a considerable capacity to keep blood flow constant despite exercise-induced increases in perfusion pressure. The mechanisms underlying this vasoconstrictor response remain unclear. We hypothesized that pharmacological modulation of the autonomic nervous system may alter the choroidal pressure/flow relationship during squatting. To test this hypothesis, we performed a randomized, double-masked, placebo-controlled, three-way crossover study in 15 healthy male volunteers. Subjects received, on different study days, intravenous infusions of the beta-adrenoceptor antagonist propranolol, the muscarinic receptor antagonist atropine, or placebo. During these infusions, subjects performed squatting for 6 min. Choroidal blood flow was assessed with laser Doppler flowmetry and ocular perfusion pressure (OPP) was calculated from mean arterial pressure and intraocular pressure. As expected, propranolol reduced basal pulse rate, whereas atropine increased pulse rate, indicating that the drugs were administered at systemically effective doses. None of the drugs altered the choroidal pressure/flow relationship during isometric exercise. These data indicate that the regulatory vasoconstrictor capacity of the choroid during exercise is not affected by systemic blockade of beta-adrenoceptors or muscarinic receptors.     

Intraoperative Navigation in der Nasennebenhöhlenchirurgie mit dem Philips „Neuroguide”-System

OBJECTIVE: To investigate the feasibility, precision and usefulness of computer aided surgery in ENT-sinus surgery. MATERIAL AND METHODS: 5 Patients with chronic sinus pathology and an indication for sinus surgery were elected. For intraoperative navigation we used a Philips "NEUROGUIDE" system and surgical instruments with LED's. Navigation procedures are described in detail in the paper, the system's precision was measured by pointing at anatomical landmarks. The accuracy was measured as the distance in millimeter between the bony structures of the CT scan on screen and the haircross of the pointer's tip on the screen. Another parameter of the systems accuracy was calculated by the system itself as the root mean square error in millimeter (RMSE) between the registered markers position and the marker position in the CT data set. RESULTS: Axial 3/3/1 mm spiral CT provided sufficient resolution, data transfer via optical disk was practicable. Positioning of the navigation equipment required some experience and the registration of the patients head position needed attention, as the markers have to be pointed at precisely. During operation, the head tracking system must not change its position on the patients head to ensure a correct navigation display. The main advantage of the computed navigation system was the constant orientation during the sinus surgical procedure. Frontiers and critical anatomical structures could be identified in the corresponding CT data set, thus enabling the surgeon to decide on the further procedure. At present stage, the operation time was increased through the handling of the navigation system for at about 15 min, resulting in additional time of narcosis. CONCLUSION: We found the computed navigation system Philips "NEUROGUIDE" system to be an established technical aid, ready to use for ENT sinus surgery, in our cases with a precision between 1 and 3 mm. These results were similar to results obtained with a SPOCS Navigation System from Aesculap, as previously published by us [17].     

Magnetresonanztomographie (MRT) des Gelenkknorpels Aktueller Wissensstand und neue Entwicklungen

MRI is the most accurate noninvasive technique available for assessment of normal articular cartilage and cartilage lesions. MRI cannot only provide morphologic information about the area of damage, but can also provide unique insight into the biochemical composition of the articular cartilage. New image processing techniques such as three-dimensional mapping of cartilage thickness will help to establish automated analysis of cartilage loss. Theses techniques are ideally suited for monitoring patients who undergo treatment with new chondroregenerative drugs.     

Attentional and neuromotor deficits in ADHD

In order to classify attention-deficit-hyperactivity disorder (ADHD) in 11-year-old children, the role of specific attentional and motor deficits was examined. Participants comprised 22 children with ADHD (19 male, 3 female; median age 11 years, range 8.8 to 13.5 years) and 20 control children (17 male, 3 female; median age 10.6 years, range 8.2 to 12.6 years). Neuromotor assessment indicated that while both groups needed more time to complete finger compared to hand movements, this increase was more pronounced in children with ADHD. Reaction-time testing with continuous-force recording identified both motor and attentional deficits in children with ADHD. Longer intervals between force onset and force peak, and higher rate of responses with multiple force peaks (particularly in the bilateral condition) revealed specific deficits in the speed and quality of their motor output. Increase in errors and variability of force onsets indicated attentional deficits. Prediction analysis indicated that force-onset variability contributed significantly to group classification which was 85.7% correct. Neither neuromotor assessment nor specific motor deficits contributed significantly to classification, indicating that pure motor-speed measures play a minor role in characterizing ADHD in this age range.     

Introduction: How can research discover how to do psychotherapy?

It is almost exceptional that psychotherapy researchers set out to answer questions like these: What are some new and better ways of doing actual in-session psychotherapeutic work? What are some new and better changes that psychotherapy can help bring about, and what are some new and better ways of helping to bring them about? The purpose of this special series of papers is to provide a forum for researchers to tell how to do research to answer those questions, i.e., to present practical and useful methodologies, designs, and strategies that are helpful in answering these questions.