Evidence against a role of nitric oxide in the indirect negative inotropic-effect of M-cholinoceptor stimulation in human ventricular myocardium

Nitric oxide (NO) has been reported to mediate several effects in response to muscarinic cholinergic stimulation in cardiovascular tissues. Recently, an attenuation of guinea pig cardiac myocyte contraction by NO has been described. The aim of the present study was to determine whether the indirect negative inotropic effect of M-cholinoceptor stimulation in human myocardium is in part due to an effect of endogenous NO. Therefore, the effect of carbachol was studied under control conditions and during inhibition of NO-synthase by pretreatment with N^G-monomethyl-l-arginine (NMMA). Functional experiments were performed in isolated, electrically driven (1 Hz, 37°C) left ventricular papillary muscle strips of human myocardium. Since cytokines have been reported to be increased in the serum of patients with heart failure and could induce NO-synthase activity in failing myocardium, we compared samples from nonfailing and terminally failing (classified as NYHA IV) hearts. The indirect negative inotropic effect of carbachol (10 mol/l) was studied in the presence of the \-adrenoceptor agonist isoprenaline (0.03 mol/l).After stimulation with isoprenaline, carbachol significantly (P < 0.05) reduced force of contraction. This effect was diminished in failing myocardium compared to nonfailing, probably due to the diminished inotropic response most likely due to the lower cAMP levels in response to \-adrenoceptor stimulation in the former condition. Pretreatment with NMMA (100 mol/l) altered the antiadrenergic effect of carbachol neither in nonfailing nor in failing preparations. Furthermore, inhibition of guanylyl cyclase, the target enzyme of NO, by preincubation with methylene blue (10 mol/l) for 30 min had no effect on the carbachol-induced decrease in force of contraction. Basal force of contraction, as well as the positive inotropic effect of isoprenaline remained unaffected by NMMA or methylene blue.The present study provides evidence that the indirect negative inotropic effect of M-cholinoceptor agonists is not due to an effect of NO in the human myocardium. Furthermore, the well known enhancement of cGMP in response to M-cholinoceptor stimulation appears not to be involved in this antiadrenergic effect.     

Molekulare und phänotypische Charakterisierung von Methicillin-resistenten Staphylococcus-aureus-Isolaten Untersuchungen an einer Unfallchirurgischen Klinik von 1994–1997

Methicillin resistant Staphylococcus aureus-strains, isolated from 1994 to 1997 from patients of the traumatic surgery hospital Tübingen, were compared using lysotyping and pulsed-field gel electrophoresis. Both typing methods detected two clones causing an outbreak 1994 in 6 patients and a third endemic clone of MRSA, which was isolated from 5 patients (1995), 4 patients (1996), and 6 patients (1997). Additionally other MRSA-types were found in 6 cases of which transmissions occurred in up to three patients. An epidemiological connection to MRSA isolated from patients of the university hospital of Tübingen was made. Possible consequences for patient management and antibiotic strategies in MRSA-infections were discussed.     

Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study.

PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. EXPERIMENTAL DESIGN: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. RESULTS: Three of four chemotherapy-na?ve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. CONCLUSION: Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.     

Sonographische Untersuchung des fetalen Lungenkreislaufs

Zusammenfassung Die Arbeit gibt eine übersicht über die pr?natale Erfassung der H?modynamik in der Lunge. Seit der Einführung der Farbdopplersonographie in die pr?natale Diagnostik, konnten neue Erfahrungen auf dem Gebiet der Analyse der Lungenarterien und -venen gewonnen werden. Nach Darstellung der Entwicklung und der Besonderheiten des fetalen Lungenkreislaufs, wird in der Arbeit die systematische sonographische Beurteilung der rechten und linken Lungenarterien und -venen erl?utert. Ferner werden Daten zur Biometrie der Lungenarterien, sowie zur Dopplersonographie der zentralen und peripheren Pulmonalarterien unter normalen und pathologischen Bedingungen vorgestellt. Die Beurteilung der Lungenvenen wird erkl?rt, nicht nur unter Berücksichtigung des Dopplerspektrums unter normalen und pathologischen Bedingungen, sondern auch unter dem Aspekt der pr?natalen Diagnostik der Lungenvenenfehlmündung. Die Analyse der fetalen pulmonalen H?modynamik k?nnte in Zukunft nicht nur in der Entdeckung von Fehlbildungen, sondern auch m?glicherweise in der Voraussage von neonatalen Lungenerkrankungen, wie die Lungenhypoplasie oder die pulmonale Hypertension, eine wichtige Rolle spielen.     

X-radiation induces 8-hydroxy-2'-deoxyguanosine formation in vivo in rat mammary gland DNA

Ionizing radiation is a carcinogen that induces oxidative DNA damage. 8- Hydroxy-2'-deoxyguanosine (8-OHdG) is a relatively abundant, mutagenic lesion that is widely regarded as a reliable index of oxidative DNA damage. The purpose of this study was to examine the effects of X- radiation on levels of 8-OHdG in the context of an experimental model for breast cancer in which chronic radiation exposure has been shown to be carcinogenic in Sprague-Dawley rats. A secondary objective of this study was to determine if the use of phenol during DNA isolation affected the concentration of 8-OHdG subsequently measured. Our results indicate that a profoundly carcinogenic dose of radiation induced a small but significant increase in 8-OHdG concentration in mammary gland DNA, and that the use of a phenol-based versus a salt-based method of DNA isolation had no significant impact on the levels of 8-OHdG detected in either control or irradiated tissue.      

Effects of dietary fat and a vegetable-fruit mixture on the development of intestinal neoplasia in the ApcMin mouse

The variation in colorectal cancer (CRC) incidence worldwide strongly suggests a role for dietary influences. Based on epidemiological data, protective effects of vegetables and fruit intake on CRC are widely claimed, while other data indicate a possible increased CRC risk from (higher) dietary fat intake. Therefore, we have investigated single and interactive effects of dietary fat and a vegetable-fruit mixture (VFM) in the ApcMin mouse, a mouse model for multiple intestinal neoplasia. In this study, four different diets (A-D) were compared, which were either low in fat (20% energy diets A/B) or high in fat (40% energy diets C/D). In addition, 19.5% (wt/wt) of the carbohydrates in diets B and D were replaced by a freeze-dried VFM. The diets were balanced so that they only differed among each other in fat/carbohydrate content and the presence of specific plant-constituents. Because the initiation of intestinal tumors in ApcMin mice occurs relatively early in life, exposure to the diets was started in utero. Without the addition of VFM, mice maintained at a high-fat diet did not develop significantly higher numbers of small or large intestinal adenomas than mice maintained at a low-fat diet. VFM added to a low-fat diet significantly lowered multiplicity of small intestinal polyps (from 16.2 to 10.2/mouse, 15 animals/group), but not of colon tumors in male ApcMin mice only. Strikingly, addition of VFM to female mice maintained on a low-fat diet and to both sexes maintained on a high-fat diet significantly enhanced intestinal polyp multiplicity (from 16.5 to 26.7 polyps/mouse). In conclusion, our results indicate that neither a lower fat intake nor consumption of VFM included in a high-fat diet decreases the development of polyps in mice genetically predisposed to intestinal tumor development.      

Extracellular S100B protein modulates ERK in astrocyte cultures

S100B is a calcium binding protein expressed and secreted by astrocytes. Extracellular S100B stimulates the proliferation of astroglial cells and the survival of neurons. Extracellular signal regulated kinases (ERK) are involved in the transduction of proliferating signals in astrocytes. Here we report that S100B significantly increases the activity of ERK in primary cultures of astrocytes, a result which may be related to previous observations of the effect of this protein on glial proliferation. We further confirm that conversion of S100B to its covalent dimer by oxidation of cysteine residues increases its extracellular activity. Although we cannot exclude S100B involvement in other mechanisms of signal transduction, these results suggest that ERK activity in astrocytes is modulated by extracellular S100B.     

Head and neck tumors: imaging recurrent tumor and post-therapeutic changes with CT and MRI

OBJECTIVE: To evaluate criteria for detection of tumor recurrence and post-treatment changes in patients with head and neck malignancies in computed tomography (CT) and magnetic resonance imaging (MRI). METHODS AND MATERIALS: Thirty-nine patients with head and neck carcinoma receiving radiochemotherapy were examined before, during and after therapy with MRI. Changes in signal intensity were correlated to histology or clinical course. Three hundred and thirty-one patients with head and neck malignancies were examined with CT after therapy. CT diagnoses were correlated with histology or clinical course. RESULTS: Main criteria for recurrent/residual tumor in MRI was infiltrative mass with high signal intensity in T2-weighted images and enhancement after Gd-DTPA in T1-weighted images. Radiation-induced changes led to false positive diagnosis in 46% in the interval up to 3 months after therapy and in 58% in the interval 3-6 months after therapy. The combination of a circumscribed, infiltrative mass with contrast enhancement in CT had a sensitivity of 86% and a specificity of 80%. CONCLUSION: CT could accurately demonstrate postoperative changes and tumor recurrence. MRI had advantages in differentiation of tumor and scar, but edema after radiation therapy can spoil diagnosis.     

Taxane-based palliative chemotherapy for metastatic breast cancer: matched pair analysis to compare the efficacy and safety of docetaxel and paclitaxel]

OBJECTIVE: A retrospective comparison of the efficacy and toxicity of docetaxel and paclitaxel in the treatment of metastatic breast cancer (MBC) was conducted based on our institution's experience since 1992. METHODS: Two groups of 43 patients who received a similar chemotherapy regimen containing either docetaxel or paclitaxel were matched for the number of prior treatments. RESULTS: Toxicity was mild in both groups. Tumour growth control, defined as either objective response or stable disease for at least 6 months, was obtained in a significantly higher proportion of patients treated with docetaxel compared with paclitaxel (67 % vs. 44 %, p = 0.001). Moreover, fewer patients progressed during treatment with docetaxel (28 % vs. 53 %, p < 0.001). At a median follow-up of 17 months there was no significant difference between the groups in median progression-free survival (7 vs. 5 months, p = 0.123) or median overall survival (OS) (12 vs. 11 months, p = 0.211). According to the method of Kaplan and Meier estimated OS rates at 1 year (74 % vs. 62 %) and 2 years (50 % vs. 26 %), however, were in favour of docetaxel. In a multivariate analysis only a positive hormone receptor status was significantly associated with improved OS. CONCLUSION: These results suggest that docetaxel may be superior to paclitaxel in the treatment of MBC.     

1-取代吡唑烷酮类抗惊构效关系的研究

1-正癸基吡唑烷-3-酮(Ⅱ结构式见表1)是欧洲专利报道的一种新型减肥剂。White等报道该化合物可通过血脑屏障,并对γ-氨基丁酸氨基转移酶(GABA-T)有强烈的抑制活性,但对谷氨酸脱羧酶的抑制作用较弱,因此可引起脑内γ-氨基丁酸(GABA)水平的升高,故我们相信应有抗惊活性。经我们合成后,发现Ⅱ确有良好的抗癲痫活性,抗小鼠最大电