Pyridazines,LVII: Synthesis and Cyclocondensation Reactions of (2-Aminophenyl)-(4-pyridazinyl)-ketone,a New Diaza Isoster of 2-Aminobenzophenone

A convenient approach to the new 2-aminobenzophenone analogue 4 is reported. Condensation reactions of 4 with ortho esters or amide acetals, respectively, followed by intramolecular cyclisations were found to provide smooth access to (4-pyridazinyl)-substituted quinolines 10, 13a,b , and the quinazoline derivative 15 .     

Expression of pS2, c-erbB-2, and cathepsin D during the menstrual cycle in human breast cancers

Background: Many studies have addressed the effect of the timing of surgery for breast cancer relative to menstrual cycle phase, with conflicting results. Explanations for the possibility that survival could be altered by the appropriate timing of breast cancer surgery in humans remain speculative. Methods: We examined the expression of three estrogen related proteins (c-erbB-2, cathepsin D, pS2) in the breast tumors from 69 premenopausal women sampled in different phases of the menstrual cycle. Data on S-phase fraction and hormone receptor expression were also analyzed. Immunohistochemical assays were used to measure the proteins of interest. S-phase fraction was determined by flow cytometry. Analyses were performed based on fraction of cells staining positive for the protein, density of stain, and a histoscore that combined both fraction of positive cells and density. Results: We found no differences in c-erbB-2, cathepsin D, hormone receptor, or S-phase levels in tumors sampled in the follicular versus luteal phase, or perimenstrual versus periovulatory phase. The exception was pS2, which was expressed at greater levels during the luteal than during the follicular phase of the cycle (p<0.01); but there was no difference in pS2 expression when the patients were classified as periovulatory versus perimenstrual. Conclusions: Our findings do not support a variation in c-erbB-2, cathepsin D, S-phase fraction, or receptor expression as an explanation for the differences in breast cancer prognosis when surgery is timed by menstrual cycle phase. The finding that pS2 (an indicator of hormone sensitivity, and possibly better prognosis) is expressed at higher levels in tumor samples during the luteal phase suggests that the biologic profile of breast tumors may vary with the menstrual cycle and that these variations deserve further study.     

Systemic angioendotheliomatosis of the lung

Systemic angioendotheliomatosis is a very rare malignant disease characterized by intravascular neoplastic proliferation of reticuloendothelial cells. According to the clinical features three different types of prognostic value can be distinguished: Exclusive skin involvement; Progressive skin lesions disseminating to internal organs; Aggressive and lethal type affecting primarily internal organs. Until now about 60 cases of systemic angioendotheliomatosis have been reported in the literature. Here we describe the first well-documented case with almost isolated lung involvement. The presentation of morphologic and clinical signs and differential-diagnostic considerations are followed by a critical review of the literature.     

Antifungal potential of disulfiram.

Disulfiram, an alcohol antagonistic drug has been on the market since 1949 with 80% bioavailability and an established safety profile. Recently it has been reported as a P-glycoprotein efflux pump modulator. Herein we report its antifungal potential. The MIC50 and MIC90 of disulfiram for yeast isolates is 4 and 8 microg/ml, respectively, and the MIC range is 1-16 micro g/ml for both fluconazole sensitive and resistant strains. Interestingly, disulfiram also showed fungicidal activity on Aspergillus spp. with MIC50 and MIC90 of 2 and 8 microg/ml, respectively.     

Other genomic disorders and congenital heart disease

Congenital heart disease (CHD) is the common birth defect worldwide. Despite its recognized burden on public health, the etiology in the vast majority of individuals remains unknown. Chromosomal abnormality plays an important role, frequently observed as large cytogenetically visible rearrangement or small submicroscopic structural variation in the genome. Several genomic disorders are now recognized that are increasingly responsible for CHD with variable penetrance. Single gene disorders, epigenetic alterations, and environmental etiologies are also significant contributors. Our understanding of the genetic basis of CHD has increased exponentially with the escalating use of next generation sequencing to identify ever so small submicroscopic genomic imbalances at the level of coding exons in CHD. This review focuses on genomic disorders other than 22q11.2 deletion, that are major players in the etiology of human cardiac malformations.     

Characterization of Aeromonas caviae antigens which cross-react with Shigella boydii 5.

Live and boiled cells of 16 strains of Aeromonas caviae, isolated from patients with diarrhea, agglutinated with Shigella boydii 5 antiserum in a slide test. Further studies with seven selected strains showed agglutination with boiled cells in a tube test. Lipopolysaccharide antigen extracted from one of these strains cross-reacted with S. boydii 5 in enzyme-linked immunosorbent assay and immunoblot studies. Either all or the majority of the seven strains possessed properties deemed to be diarrheagenic.     

Blutlipid- und BlutglukoseverÄnderungen bei Einfach-, Mehrfach- und Wiederholungsstre\

Zusammenfassung Auf den Organismus einwirkende Stressoren, die einen gewissen Schwellenwert überschritten haben, bewirken deutliche StoffwechselverÄnderungen; diese Tatsache ist seit langem experimentell bewiesen.Wir konnten zeigen, da\ diese VerÄnderungen bei Einfach- und Mehrfachstre\ verschieden sind und da\ die StoffwechselverÄnderungen bei wiederholter Belastung offensichtlich Habituationsbzw. AdaptationsvorgÄngen unterworfen sind. Derartige stre\induzierte Stoffwechselmechanismen laufen aber für die einzelnen Blutfette und die Glukose unterschiedlich ab, was durch die verschiedenen Funktionen der einzelnen Parameter in Belastungssituationen erklÄrbar ist. Die Analyse dieser VerÄnderungen ist für die PrÄvention von stre\induzierten Stoffwechelentgleisungen von gro\er Bedeutung.Mit finanzieller Unterstützung des österreichischen Fonds zur Förderung der wissenschaftlichen Forschung     

Bacillus thuringiensis insecticidal delta-endotoxin: diversity of crystal proteins and its relatedness to the toxicity spectrum

Bacillus thuringiensis strains produce crystal delta-endotoxins which exhibit a diverse toxicity spectrum. In order to explore the basis of toxin specificity, a comparison of the activity of 13 strains belonging to seven serotypes was made against three insect species. The delta-endotoxin crystals were purified and their polypeptide composition analyzed by SDS-PAGE. Among the strains studied, the delta-endotoxins consist of a variety of crystal proteins in the 60-144 KDa size range. On the basis of molecular mass, endotoxins maybe grouped into two classes; one contained both high (125-144 KDa, P1) and medium sized (60-66 KDa, P2) proteins and a second class consisting of only the high Mr polypeptides. Immunoblotting with B. aizawai P1 antiserum revealed antigenic cross-reaction with one or more of the polypeptides in 125-144 KDa range in all the strains studied. When the crystal proteins from different strains were immunoblotted with kurstaki P2 antiserum, none of the P1 protein crossreacted suggesting that the P1 and P2 proteins are not structurally related. However, the B. kurstaki P2 antiserum crossreacted with 66 KDa proteins in some other strains which underlines a structural homology in this class of the toxic polypeptides. Toxicity studies revealed that the high Mr P1 proteins of all the strains in this study were active against lepidopteran (Pieris brassicae and Diacrisia obliqua) larvae. B. thuringiensis aizawai strains exhibit a dual toxicity associated with the high Mr (130-135 KDa; P1) proteins. The P2 crystal proteins (60-66 KDa) also showed dual toxicity against the lepidopteran and dipteran larvae but were found to be structurally and immunologically distinct.     

Thoracic duct lymph and PEEP studies in anaesthetized dogs

PEEP impedes thoracic duct drainage (LF). This can be counteracted by a thoracic duct fistula. Consequently, lung oedema (LOE) should develop during PEEP more slowly with LF at atmospheric pressure (LF_AP) than with LF against jugular venous pressure (LF_JVP). In 12 anaesthetized dogs LOE was produced by Ringer's solution i.v. (2.5 ml/min per kg) for 6 h during PEEP (10 mmHg) with either LF_AP or LF_JVP. Ringer's+PEEP greatly increased aortic, pulmonary artery and wedge pressures, JVP, and cardiac output. Colloid osmotic pressures in plasma and lymph were drastically reduced, pulmonary effective filtration pressure (EFP) rose by about 20 mmHg. LF_JVP increased 7-fold, LF_AP about 19-fold, the respective loss of plasma proteins was 1.83 and 1.06 g/kg during 6 h. Thermal-dye extravascular lung water showed an increment of 68 with LF_JVP versus 43 l/h/g per mmHg with LF_AP. Final lung water content was at any EFP (12.8–31.9 mmHg) lower with LF_AP than with LF_JVP amounting 512 with LF_JVP versus 377 l/g/per mmHg with LF_AP. LF_AP decreased the development of LOE during PEEP by bypassing the PEEP-induced high JVP and thus facilitating the removal of interstitial fluid. It is hypothesized that a thoracic duct fistula might aid the treatment of patients with LOE due to ARDS and therefore requiring high levels of PEEP.