Ultraviolettes Licht und Entstehung der Hautkrebse

Ohne Zusammenfassung     

Regionally defective colonization of the terminal bowel by the precursors of enteric neurons in lethal spotted mutant mice

In order to gain insight into the process of colonization of the bowel by the neural crest-derived precursors of enteric neurons, the development of the enteric nervous system was examined in lethal spotted mutant mice, a strain in which a segment of bowel is congenitally aganglionic. In addition, nerve fibers within the ganglionic and aganglionic zones of the gut of adult mutant mice were investigated with respect to their content of acetylcholinesterase, immunoreactive substance P, vasoactive intestinal polypeptide and serotonin, and their ability to take up [³Hserotonin. In both the fetal gut of developing mutant mice and in the mature bowel of adult animals abnormalities were limited to the terminal 2 mm of colon. The enteric nervous system in the proximal alimentary tract was indistinguishable from that of control animals for all of the parameters examined. In the terminal bowel, the normal plexiform pattern of the innervation and ganglion cell bodies were replaced by a coarse reticulum of nerve fibers that stained for acetylcholineserase and were continuous with extrinsic nerves running between the colon and the pelvic plexus. These coarse nerve bundles contained greatly reduced numbers of fibers that displayed substance P- and vasoactive intestinal polypeptide-like immunoreactivity, but a serotonergic innervation was totally missing from the aganglionic bowel. During development, acetylcholineserase and uptake of [³Hserotonin appeared in neural elements in the foregut of mutant mice on the 12th day of embryonic life (E12), about the same time these markers appeared in the forgut in normal mice. By day E14, neurons expressing one or the other marker were recognizable as far distally as about 2 mm from the anus. The appearance of neurons in segments of gut grown for 2 weeks as expiants in culture was used as an assay for the presence of neuronal progenitor cells in the segments of fetal bowel at the time of explantation. Both acetyl- cholinesterase activity and uptake of [³Hserotonin developed in neuronsin vitro in expiants of proximal bowel between days E10 and E17. At all times, however, the terminal 2mm of mutant but not normal fetal gut gave rise to aneuronal cultures. In some mutant mice rare, small, ectopically-situated pelvic ganglia were found just outside aganglionic segments of fetal colon. Uptake of [³Hserotonin, normally a marker for intrinsic enteric neurites, was found in these ganglia.The experiments suppport the hypothesis that the terminal 2 mm of the gut in lethal spotted mutant mice is intrinsically abnormal and thus cannot be colonized by the precursors of enteric neurons. The defect seems to be specific in that both cells and processes of intrinsic enteric neurons, including all serotonergic and most peptidergic neurites, seem to be excluded from the abnormal region while extrinsic nerve fibers, including sympathetic and sensory axons, are able to enter the aganglionic zones. Since examination of neural progenitor cells has failed to reveal a significant proximo-distal displacement of these cells through the enteric tube during development of the murine bowel, a defect in the migration of precursor cells down the alimentary tract to the terminal gut seems unlikely to be substantially involved in the pathogenesis of aganglionosis. This conclusion is supported by the normal enteric nervous system in proximal regions of the mutant gut and the presence of enteric type neurons outside of, but at the same level as the aganglionic region.     

Research approaches in health manpower development. Some alternatives

Traditional scientific research approaches have contributed only minimally to the resolution of problems related to the educational aspects of health manpower development. It has been suggested that this lack of impact has been due mainly to the incompatibility of the traditional approaches with the phenomena of concern--naturally occurring educational, human, and social events. The problem has been addressed in considerable detail in the literature that relates to the more general view of education, and the alternative research approaches described in this article are derived from this broader-based literature.     

Discovery of novel peptidic dopamine transporter ligands by screening a positional scanning combinatorial hexapeptide library.

The acute reinforcing effects of cocaine are thought by some to result from cocaine binding to the dopamine (DA) transporter, which inhibits DA uptake and increases synaptic DA levels in the mesolimbic system. Other data suggest that neurotransmitters other than DA contribute to cocaine reinforcement and addiction. These considerations illustrate the need to have additional research tools with which to test the "DA hypothesis." One strategy is to identify drugs which bind to the DA transporter (DAT ligands) but which do not inhibit DA uptake as effectively as cocaine. The purpose of the present study was to identify members of a novel structural class of DAT ligands and to characterize their interactions at the DA transporter. A positional scanning hexapeptide D-amino acid library was screened for inhibition of [(125)I]RTI-55 binding to rat caudate DA transporters. Based on the results, 12 peptides were synthesized. All 12 peptides inhibited [(125)I]RTI-55 binding to DA transporters with IC(50) values, which ranged from 1.8 microM to 12 microM. The two most potent peptides (TPI-669-1 and TPI-669-4) were prepared in larger quantities and were characterized further for activity at the DAT and 5-HT transporter. Both peptides inhibited DA and 5-HT uptake and transporter binding with IC(50)/K(i) values in the low micromolar range. In vivo microdialysis studies demonstrated that both peptides increase extracellular DA and 5-HT in the nucleus accumbens of rats. These data demonstrate that peptides can function as inhibitors of biogenic amine transport. Future work will focus on developing more potent and selective peptides. Published 1999 Wiley-Liss, Inc.     

Opioid peptide receptor studies, 11: involvement of Tyr148, Trp318 and His319 of the rat mu-opioid receptor in binding of mu-selective ligands

Previous data obtained with the cloned rat mu opioid receptor demonstrated that the "super-potent" opiates, ohmefentanyl (RTI-4614-4) and its four enantiomers, differ in binding affinity, potency, efficacy, and intrinsic efficacy. Molecular modeling (Tang et al., 1996) of fentanyl derivatives binding to the mu receptor suggests that Asp147, Tyr148, Trp318, and His319 are important residues for binding. According to this model, Asp147 interacts with the positively charged opiate agonist to form potent electrostatic and hydrogen-bonding interactions. In this study, the role of weak electrostatic and hydrogen-bonding "pi-pi" interactions of the O atom of the carbonyl group and the phenyl ring structures of RTI-4614-4 and its four enantiomers with residues Tyr148, Trp318, and His319 were explored via site-directed mutagenesis. Tyr148 (in transmembrane helix 3 {TMH3}), Trp318 (TMH7), and His319 (TMH7) were individually replaced with phenylalanine or alanine. Receptors transiently expressed in COS-7 cells were labeled with [125I]IOXY according to published procedures. Mutation of Tyr148 to phenylalanine reduced the binding affinities of some mu-selective agonists (2-7 fold) but did not alter the affinities of DAMGO, naloxone, and the non-selective opiates etorphine and buprenorphine. In contrast, this mutation significantly increased the binding affinities (decreased the Kd values) of [D-Ala2,D-Leu5]enkephalin, IOXY, and dermorphin. Mutation of Trp318 decreased opioid receptor binding to almost undetectable levels. Substitution of alanine for His319 significantly reduced binding affinities for the opioid ligands tested (1.3- to 48-fold), but did not alter the affinities of naloxone and bremazocine. These results indicate the importance of Tyrl48 and His319 for the binding of fentanyl derivatives to the mu receptor. Functional studies using the mutant receptors will provide additional insight into the mechanism of action of RTI-4614-4 and its four enantiomers.     

Videostroboscopy of the pharyngoesophageal segment in total laryngectomees

Objectives: The reconstructed pharyngoesophageal segment (PES) serves as the neoglottis following total laryngectomy, as it provides the source of vibration for production of tracheoesophageal puncture (TEP) voice. To date, little information exists regarding the vibratory characteristics of the PES. The purpose of this investigation was to study the anatomy and physiology of the PES using videostroboscopy. Study Design: Prospective study investigating the anatomy and physiology of the PES in 34 laryngectomees who used TEP speech as their primary form of communication. Materials and Methods: Videostroboscopy and voice recordings were graded by three trained, blinded judges using a seven-point scale. Results: The patients demonstrated differences that allowed for separation of patients into two main groups: “poor” and “effective” TEP speakers. The voice quality differences were explained by anatomic and physiologic characteristics of the PES. Redundant, thick, and dyssynchronous PES features were observed in patients with poor TEP speech skills; the effective speakers exhibited less redundant, thinner mucosa and more synchronous vibratory patterns. Moreover, the latter subgroup consistently demonstrated a greater degree of volitional PES control and less spasmodic activity than their poorly speaking counterparts. Length of the PES opening (measured in the horizontal plane) as well as amount and consistency of secretions did not appear to influence TEP speech or voice proficiency. Conclusion: Videostroboscopy in laryngectomees is a noninvasive, inexpensive, easily performed procedure that may contribute valuable information regarding the anatomy and physiology of the PES, especially in patients who experience difficulties achieving satisfactory TEP voice and speech production.     

Prostate vascular flow: the effect of ejaculation as revealed on transrectal power Doppler sonography

OBJECTIVE. The objective of our study was to determine the effect of ejaculation on prostate vascular flow. SUBJECTS AND METHODS. Using power Doppler technology, we performed four transrectal sonographic examinations before and immediately, 6 hr, and 24 hr after ejaculation in 10 healthy volunteers. Images were assessed by three independent observers. RESULTS. Ninety-seven percent of the images ranked as having the least flow were from the baseline examination. There was a significant difference between the rankings when categorized into the four time sets (mean score for the baseline group was 1.1, whereas for the immediate, 6-, and 24-hr postejaculation groups it was 2.5, 2.9, and 2.4, respectively (p<0.0001). The only statistically significant difference was between the baseline and the three remaining groups. Interobserver agreement was high, with the chance-corrected measure of agreement of 0.78. CONCLUSION. Transrectal sonography revealed that prostate vascular flow increases dramatically after ejaculation and remains elevated for at least 24 hr. This observation should be considered when power Doppler sonography is used to assess for potential hyperemia in patients suspected of having prostate abnormalities.