Acute audiogenic stress-induced activation of CRH neurons in the hypothalamic paraventricular nucleus and catecholaminergic neurons in the medulla oblongata

Strong c-fos expression was induced in neuronal cells of several brain nuclei and the auditory cortex by a short duration auditory stimulation (white noise) in rats. By double immunostaining, Fos-immunoreactive cell nuclei appeared in corticotropin-releasing hormone (CRH)-containing neurons in the hypothalamic paraventricular nucleus, but not in CRH neurons elsewhere in the brain including the central nucleus of the amygdala. Among brain catecholaminergic neurons, only cells in the medulla oblongata (in the A1/C1and A2/C2 cell groups) established double immunostaining for Fos and tyrosine hydroxylase. Sound stimulus in rats with unilateral tympanotomy and plugging the airways resulted in side differences of Fos immunoreactivity in neurons of the auditory pathways and the auditory cortex, but the effect was bilateral in hypothalamic and amygdaloid nuclei. The present data provide evidence for the participation of CRH-synthesizing neurons in hypothalamus and medullary catecholaminergic neurons in the central organization of responses to audiogenic stress stimuli.     

A novel drug discovery concept for tuberculosis: inhibition of bacterial and host cell signalling

The Mycobacterium tuberculosis genome encodes for eleven eukaryotic-like Ser/Thr protein kinases. At least three of these (PknA, PknB and PknG) are essential for bacterial growth and survival. PknG is secreted by pathogenic mycobacteria, in macrophages to intervene with host cell signalling pathways and to block the fusion of the lysosomes with the phagosome by a still unknown mechanism. Based on our previously published results, we have initiated a drug discovery program, aiming to improve the potency against PknG and the physiochemical properties of the initially identified hit compound, AX20017, from the class of the tetrahydrobenzothiophenes. We have established a radioactive biochemical PknG kinase assay to test the novel analogues around AX20017. We have developed lead molecules with IC50 values in nanomolar range, and demonstrated their antituberculotic effects on human macrophages. Selected leads might ultimately serve the purpose of inducing phagosomal-lysosomal fusion and therefore destroy the residence of the intracellular mycobacteria. It is unclear at this time if these "homeless" mycobacteria are getting killed by the host, but they will be at least vulnerable to the activity of antimycobacterial agents. Released mycobacteria rely on the essential function of PknB for survival, which is our second molecular kinase target. PknB is a transmembrane protein, responsible for the cell growth and morphology. We have screened our library and synthesized novel compounds for the inhibition of PknB. A pharmacophore model was built and 70,000 molecules from our synthesizable virtual library have been screened to identify novel inhibitor scaffolds for the generation of templated compound libraries. Currently, we are using a radioactive kinase assay employing GarA as the putative, physiological substrate of PknB kinase. We have identified hits and generated optimised hit compounds with IC50 values for the inhibition of PknB in the nanomolar range. Yet those promising hits are not potent enough to yield meaningful "minimum inhibitory concentrations" in mycobacterial growth assays. In the course of our future work, we will increase the potency of the next generation of PknB inhibitors in order to improve their antibacterial activity.     

Sorptions- und diffusionsuntersuchungen an polypropylenfasern

The equilibrium swelling and sorption, and the diffusion coefficient of methylmethacrylat vapour in unstretched and to various degrees stretched polypropylene fibres were determined. The crystallinity of the fibres increased by heat treatment. The equilibrium swelling and sorption alter inversely with the change of orientation and cristallinity. The alteration of the specific gravity respectively the crystallinity as a consequence of heat treatment is appreciated by the sorption and swelling results, especially at less oriented specimens. The diffusion coefficient is influenced first of all by the change of orientation, which is demonstrated by the difference of activation energies of stretched and unstretched specimens too.     

Anesthesiological hazards during laparoscopic transhiatal esophageal resection: a case control study of the laparoscopic-assisted vs the conventional approach

Background Interest for minimal invasive approach of esophagus resection is increasing. Today, a minimally invasive transhiatal esophagectomy is possible and is accepted widespread. Since cardiopulmonary changes during laparoscopic dissection of the mediastinum has not been studied yet we assessed the anesthesiological consequences of pneumothorax during laparoscopic mediastinal dissection.Methods In this case control study, 25 laparoscopically assisted transhiatal espohagus resections were compared with a control group consisting of 20 open transhiatal esophagus resections. Patient characteristics and intraoperative haemodynamic, respiratory, and ventilatory parameters were assessed.Results The laparoscopic assisted procedure was performed successfully in 12 of the 20 patients. The duration of the laparoscopic assisted procedure, compared to the open group was significantly longer (p<0.05). Intraoperative blood loss was significantly less in the laparoscopic group (p<0.05). Mediastinal dissection resulted in entry of the pleura in 84% of the open and 93% of the laparoscopic assisted procedure. Carbondioxide pneumothorax resulted in increased end-tidal CO₂ and airway pressure levels and decreased lunng compliance. Airway pressure showed a significant difference between the groups (p<0.05). Hemodynamic parameters did not differ between groups significantly. There were no differences in postoperative cardiopulmonary complications.Conclusions Laparoscopic assisted transhiatal esophagectomy is a safe procedure and has no increased risk of postoperative cardiopulmonary complications compared to thr conventional approach. The anesthesiologist and the surgeon must be aware of the potential risk of pleural injury to manage cardiopulmonary compromises and minimize complications.     

Improved, high yield synthesis of 3H-quinazolin-4-ones, the key intermediates of recently developed drugs

Purine bases and their bioisosteric analogs are widely used as building blocks in combinatorial chemistry. Recently a great number of fused pyrimidine derivatives became known as potential drug molecules against various types of proliferative diseases, caused by over-expression of protein kinases. One of the most important compound families are quinazolines : e.g. the best inhibitor of EGFR tyrosine kinase is PD153035 (6,7-dimethoxy-4-(3'-bromophenyl)amino-quinazoline) and IRESSA (gefitinib, ZD1839), developed from this compound family, is presently the only one approved and granted drug by the FDA for the treatment of advanced non-small-cell lung cancer (NSCLC). KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]-quinazoline-2-thione dihydrochloride) from this group, showed significantly higher inhibitory activity on cyclic GMP-specific phosphodiesterase compared with those of sildenafil (Viagra). The synthetic procedures of the example compounds are based on imidoyl chloride intermediates that were prepared from the appropriate 3H-quinazoline-4-ones. Although the key intermediates, quinazoline-4-ones, have been known since more than hundred years, their synthetic procedures have been improved much only in the past ten years. In this paper we reviewed the efficient synthetic methods of quinazolin-4-ones, and presented a novel, reliable method for their synthesis. There was no considerable effect of microwave-, or traditional thermal activation on the yield and compound purity.     

The effects on the fetus of an abnormal contraction pattern in the induction of labor with oxytocin

In a group of 29 pregnant women labor was induced with the help of an oxytocin infusion. The intrauterine pressure and fetal heart rate were monitored continuously; at the same time the pH, pCO₂, buffer base, and base excess of the fetus were repeatedly measured. The same measurements were carried out in a control group consisting of 47 pregnant women, who gave birth spontaneously at term without pathology occurring. Thirteen times (nine times in the oxytocin group and four times in the control group) there was initially a period of irregular uterine activity, accompanied by an increased basal tone (≥ 20 mm. Hg). It seems that during this period there may be a deterioration in the acid-base balance of the child. The possible etiology and consequences of these phenomena are discussed with respect to induction by an oxytocin infusion in a pregnancy in which the fetomaternal exchange is already disturbed.     

Über probleme der kationischen polymerisation des caprolactams. V. Die rolle der N-acyllactamgruppen bei der polymerisation mit caprolactam-hydrochlorid

During polymerisation of caprolactam with caprolactam hydrochloride as catalyst N-acyllactam groups act as cocatalysts in the first part, later on they have a pronounced retarding effect. The promotion is due to their participation in the chain propacration, the retarding effect to side reactions in which strongly basic compounds (amidines) are formed.