Syntheses of Novel Pyridazinomorphinans by Inverse Electron Demand Cycloaddition and their Binding to μ and κ Receptors

A number of novel pyridazinomorphinans have been synthesized by the inverse electron demand Diels-Alder reaction of various 3,6-disubstituted 1,2,4,5-tetrazines with enamines derived from dihydrocodeinone and with codeinone. Reduction of some of the pyridazinomorphinans did not furnish the expected pyrroloepoxymorphinans; in all cases investigated reductive cleavage of the epoxybridge was observed to yield dihydropyridazino- or pyrrolomorphinans. The structures of all new compounds were assigned by the spectral data, that of the cycloadduct of codeinone was additionally verified by X-ray crystallography. Compounds 5a, 8, 11a , and 16 have been evaluated for their affinity at μ and κ opioid receptors in radioligand binding assays. Their ability to inhibit [³H]DAMGO binding at μ and [³H]U 69.593 binding at κ receptors, respectively as compared to codeine has been found to be lower.     

Severe ciguatera poisoning in Madagascar: A case report

In a single outbreak on the East coast of Madagascar, more than 500 people, 98 of whom died, were poisoned by the flesh of a shark, Carcharhinus amboinensis. From clinical symptoms it can be concluded that this poisoning is due to ciguatera toxins. It is the first case of a severe outbreak caused by a shark, and it is the first case with a mortality rate of 20%.     

Exogenous Modulation of TGF-β1 Influences TGF-βR-III-Associated Vascularization during Wound Healing in Irradiated Tissue

BACKGROUND AND PURPOSE: Following preoperative radiotherapy prior to ablative surgery of squamous epithelial cell carcinomas of the head and neck region, wound-healing disorders occur. Previous experimental studies showed altered expression of transforming growth factor-(TGF-)beta isoforms following surgery in irradiated graft beds. Altered levels of TGF-beta(1) are reported to promote fibrosis and to suppress vascularization during wound healing, whereas expression of TGF-beta receptor-III (TGF-betaR-III) is associated with vascularization. The aim of the study was to analyze the influence of anti-TGF-beta(1) treatment on TGF-betaR-III-associated vascularization in the transition area between irradiated graft bed and graft. MATERIAL AND METHODS: Wistar rats (male, weight 300-500 g) underwent preoperative irradiation of the head and neck region with 40 Gy (four fractions of 10 Gy each; n = 16 animals). A free myocutaneous gracilis flap taken from the groin was then transplanted to the neck in all rats. The time interval between operation and transplantation was 4 weeks. Eight animals received 1 micro g anti-TGF-beta(1) into the graft bed by intradermal injection on days 1-7 after surgery. On days 3, 7, 14, 28, 56, and 120, skin samples were taken from the transition area between transplant and graft bed and from the graft bed itself. Immunohistochemistry was performed using the ABC-POX method to analyze the TGF-betaR-III and E-selectin expression. Histomorphometry was performed to analyze the percentage and the area of positively stained vessels. RESULTS: A significantly higher expression of TGF-betaR-III was seen in the irradiated and anti-TGF-beta(1)-treated graft bed in comparison to the group receiving preoperative irradiation followed by transplantation alone. The percentage of TGF-betaR-III positively staining capillaries from the total amount of capillaries in the anti-TGF-beta(1)-treated graft bed was higher than in the group irradiated only. The total area of capillaries was also higher in the TGF-beta(1)-treated group. CONCLUSION: Neutralizing of TGF-beta(1) activity in irradiated tissue undergoing surgery leads to a higher expression of TGF-betaR-III and increased vascularization. TGF-betaR-III seems to be associated with newly formed blood vessels during neovascularization in wound healing.     

Specification and selection of regions of interest (ROIs) in a computerized brain atlas

The computerized individually adjustable brain atlas (CBA) has been further developed. The atlas was primarily designed for anatomical localization and quantitative evaluation of data in positron emission tomography (PET), but may also be employed for other neuroimaging modalities, such as transmission computed tomography (CT) and magnetic resonance imaging (MRI). The atlas is based on anatomical information obtained from digitized cryosectioned brains. Using spatially standardized and then averaged MRI images, we demonstrate the high localization accuracy and precision of the brain atlas. This is a prerequisite for obtaining accuracy when using the atlas in the localization and the quantitative evaluation of PET data. The specification and the selection of region of interests (ROIs) by the CBA are presented and discussed.     

Influence of various concentrations of cefotiam and ceftizoxime on the phagocytosis of gonococci by polymorphonuclear granulocytes

Both cefotiam and ceftizoxime stimulate the uptake of gonococci by polymorphonuclear granulocytes in vitro as can be seen by light microscopy. Although this already holds true of antibiotic concentrations lower than the minimum inhibitory concentration (MIC: 1/4 x) this effect is much more marked at concentrations highly exceeding the MIC (4000 x). As light microscopic investigation allows the analysis of large numbers of cells but no final judgement on actual bacterial engulfment definite phagocytosis is demonstrated by electron microscopy.     

Highly oxygen-permeable copoly(methacrylate/siloxane)s with perfluoroalkyl ester groups

Basic materials for contact lenses were obtained by radical copolymerization of linear α,ω-bis(methacryloyloxy)-terminated oligo- and poly(dimethylsiloxane)s, methyl methacrylate and 2,2,3,3,4,4,4-heptafuorobutyl methacrylate. Oxygen permeabilities, contact angles and ball indentation hardness were determined.     

Imaging of activated microglia with PET and [11C]PK 11195 in corticobasal degeneration.

Positron emission tomography (PET) using [(11)C]PK 11195, a ligand for peripheral benzodiazepine receptor binding sites, offers the opportunity to image activated microglia in vivo. This tool may therefore be used to display the occurrence of microglial activation in the course of neurodegeneration. A patient with the clinical diagnosis of corticobasal degeneration (CBD) and left-sided symptoms was studied using fluorodeoxyglucose (FDG) and [(11)C]PK 11195 PET. We found a marked right hemispheric hypometabolism and asymmetric microglial activation in corresponding areas of the basal ganglia and right temporal and parietal cortex. [(11)C]PK 11195 PET suggests involvement of microglial activation in the pathogenesis of CBD.     

WHERE ARE THE GATES IN GAP JUNCTION CHANNELS?

1. In the formation and function of gap junction channels two types of gates ought to be discriminated: the docking gate and the channel gates proper. The docking gate is involved in the transformation of a closed hemichannel to a patent gap junction channel. By definition the trigger mechanism for this gate and maybe even the gate itself is contained within the extracellular loops of the gap junction proteins, the connexins. The channel gates proper determine the open and closed states of the complete gap junction channels. 2. Probing the docking gate by mutagenesis of connexins and by synthetic peptides indicates that this gate is the consequence of complex interactions between a large fraction of the amino acids comprising the extracellular loops. Probably both inter- and intra-molecular interactions are involved, and disulfide exchange may be entailed in the stabilization of the open and closed states. 3. Of the various effectors on the channel gate(s) the voltage effects have obtained the most scrutiny to date. The response of gap junction channels and hemichannels is diverse, the various channels respond differently to transjunctional and membrane potential. No equivalent to the S4 segment representing the voltage sensor in other voltage dependent ion channels is present in the connexin sequences, instead mutations in various segments of connexins have been reported to affect the voltage dependence of gap junction channels. To understand the complexity of voltage effects on gap junction channels, non-connexin peptides may need to be considered as voltage sensors or as modifiers thereof.