Das Verhalten von Blutdruck und Nierendurchblutung während des Carotissinus-Reflexes am wachen Hund

Zusammenfassung An 15 Bastardhunden wurde der Einfluß einer Na-Pentobarbital-Narkose sowei einer zusätzlichen chirurgischen Präparation auf die Ruhewerte von Blutdruck und Nierendurchblutung und deren Änderung nach doppelseitigem Carotisverschluß im Vergleich zum wachen Tier untersucht.Barbiturat-Injektion (30 mg/kg i.v.) allein erhöhte die Herzfrequenz, den systolischen und diastolischen Blutdruck, änderte jedoch nicht die mittlere Nierendurchblutung. Zusätzliche chirurgische Präparation verstärkte diese Veränderungen mit Ausnahme vom systolischen Blutdruck und der Nierendurchblutung.Bei Carotisverschuluß kam es im steady state zu einer vermehrten reflektorischen Herzfrequenzsteigerung nach Barbiturat-Injektion sowie nach Barbiturat mit chirurgischer Präparation. In Barbiturat-Narkose stieg der mittlere Blutdruck stärker an als am wachen Tier; diese Veränderung war nach chirurgischer Präparation noch deutlicher ausgeprägt. Die mittlere Nierendurchblutung wurde im steady state in keiner der 3 Gruppen signifikant verändert. Der reflektorische Herzfrequenz- und Blutdruckanstieg erfolgte im Wachzustand rascher als nach Barbiturat und Barbiturat mit chirurgischem Trauma. Unter letzteren Bedingungen fehlte auch das im Wachzustand beobachtete Unterschießen der Herzfrequenz nach Öffnen der Carotismanschetten. Der druckpassive overshoot der Nierendurchblutung am wachen Tier fehlte sowohl nach Barbiturat als auch nach zusätzlicher chirurgischer Präparation.Die Ergebnisse zeigen, daß der mit Na-Pentobarbitural narkotisierte und der narkotisierte, akut operierte Hund gegenüber dem Wachzustand betreffend der Ruhewerte und der reflektorischen Veränderungen der Herzfrequenz und des Blutdrucks im steady state des Carotissinus-Reflexes zwei quantitativ unterschiedlich reagierende Kreilaufpräparate liefert. Gemessen an der Beseitigung sowohl der raschen Herzfrequenz- und Blutdruckveränderungen als auch des phasischen Einschwingvorganges der Nierendurchblutung durch Narkose und Narkose mit Trauma unterscheiden sich solche Präparate auch qualitativ vom Wachzustand.Mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Seven novel and four recurrent point mutations in the factor VIII (F8C) gene

Haemophilia A is a X‐linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and small deletions/insertions are responsible for the majority of cases with moderate to mild clinical course and for half of the severe hemophilia A occurrences. The majority of these mutations are “private”, because of the high mutation rate for this particular gene. We report on eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. Seven of these mutations are novel [E204N, E265X, M320T, F436C, S535C, N2129M and R2307P] and four have been previously identified [V162M, R527W, R1966X, and R2159C]. Genotype‐phenotype correlations and computer prediction analysis on the effect of missense mutations on the secondary structure of the factor VIII protein are performed and the relationships evaluated. © 2001 Wiley‐Liss, Inc.     

Klarzelltumor der Lunge

Clear cell tumors of the lung are rare tumors composed of epithelioid HMB45 positive tumor cells. It has been proposed that clear cell tumors generate from perivascular epithelioid cells which are also found in renal angiomyolipoma. Due to its morphologic epithelioid features with clear cytoplasm the distinction from either primary or metastatic clear cell carcinoma is difficult. Usually clinical investigations do not lead to the final diagnosis so that only subsequent histological examination and immunophenotyping can establish the correct tumor classification. We describe the case of a 52 year old woman who underwent exploratory thoracotomy because of a lung mass in the right lower lobe. In frozen sections a solid trabecular tumor was diagnosed, paraffin histology and immunohistochemistry revealed a clear cell tumor of the lung. The difficulty of the correct diagnosis of the clear cell tumor of the lung in frozen sections is discussed as well as the differential diagnosis.     

cDNA arrays: gene expression profiles of Hodgkin's disease and anaplastic large cell lymphoma cell lines

cDNA arrays are a powerful tool for the identification of differentially expressed genes in malignant tumors. We used this technique to study the gene expression profiles of anaplastic large cell lymphoma (ALCL) and Hodgkin's disease (HD). Gene expression of 11 lymphoma cell lines was analyzed covering 1176 cDNA sequences. Comparing these data to the expression profiles of B- and T-lymphocytes, we identified 27 genes that were deregulated in all cell lines or in a particular entity. For the establishment of gene expression profiles the 27 genes were assigned to four groups composed of genes deregulated in (i) all lymphoma cell lines, (ii) ALCL and HD, (iii) only HD, and (iv) ALCL exclusively. Our results indicate that ALCL and HD share the differential expression of at least five genes. In addition, both entities are characterized by the differentially deregulated expression of four genes in HD and seven genes in ALCL. Because the expression profiling was performed on cell lines, further studies are needed to clarify the biological significance of the differentially expressed genes.     

Randomized Controlled Clinical Trial of Blood Glucose Awareness Training (BGAT III) in Switzerland and Germany

Although both diabetes and the efficacy of medical management are international issues, psycho-educational interventions might be culturally bound. Blood Glucose Awareness Training (BGAT) is a psycho-educational program for patients with type 1 diabetes mellitus. It is focused on improving recognition and management of extreme blood glucose levels, and is the best documented American psycho-educational program for this purpose. A randomized controlled clinical trial of BGAT's long-term benefits in a non-American setting has been lacking. One hundred and eleven adults with type 1 diabetes mellitus from Switzerland and Germany participated. After a 6 months baseline assessment, subjects were randomly assigned to receive either 2 months of BGAT (n = 56) or a physician-guided self-help control intervention (n = 55). BGAT improved recognition of low (p = 0.008), high (p = .03), and overall blood glucose (p = 0.001), and reduced frequency of severe hypoglycemia (p = 0.04), without compromising metabolic control. BGAT reduced both the external locus of control (p < 0.02) and fear of hypoglycemia (p < 0.02). BGAT was efficacious in reducing adverse clinical events and achieving clinically desirable goals in a European, as well as American setting.     

c-Fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis

Malignant transformation of mouse skin by tumor promoters and chemical carcinogens, such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process leading to the formation of squamous cell carcinomas. It has been shown that mice lacking the AP-1 family member c-Fos exhibit an impaired transition from benign to malignant skin tumors. Here, we demonstrate enhanced expression of the small Ras-related GTPase Rab11a after short-term TPA treatment of mouse back skin. Expression of Rab11a in vivo and in vitro critically depended on c-Fos, because TPA application to the back skin of c-Fos-deficient mice and to mouse embryonic fibroblasts did not induce Rab11a mRNA or protein expression. Moreover, dexamethasone, which is a potent inhibitor of AP-1-mediated transactivation that exhibits anti-inflammatory and anti-tumor promoting activities, inhibited TPA-induced expression of Rab11a. Within the Rab11a gene promoter, we identified a functional AP-1 binding element that exhibited elevated c-Fos binding activity after TPA treatment of keratinocytes. Enhanced expression was not restricted to chemically induced mouse skin tumors but was also found in tumor specimens derived from patients with epithelial skin tumors. These data identify Rab11a as a novel, tumor-associated c-Fos/AP-1 target and may point to an as yet unrecognized function of Rab11a in the development of skin cancer.     

Mixed hepatoblastoma in an adult

We report a case in an elderly adult of a highly malignant liver tumor with blastoid features that resembled hepatoblastoma. A liver tumor with a diameter of 23 cm was removed in a 78-year-old woman. The tumor showed highly differentiated epithelial hepatocellular and poorly differentiated epithelial and mesenchymal components. The blastoid nature and pluripotent differentiation potential were supported by immunohistologic analysis and suggest an origin of a poorly differentiated pluripotent hepatic cell with the potential to mature. We believe that this case of a mixed hepatoblastoma in an adult should be added to the growing number of presumed hepatic precursor cell neoplasms in adults.     

Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+.

The clinical and pathological features of carcinomas of the pancreas with DNA replication errors (RER+) have not been characterized. Eighty-two xenografted carcinomas of the pancreas were screened for DNA replication errors using polymerase chain reaction amplification of microsatellite markers. Cases with microsatellite instability in at least two markers of a minimum of five tested were considered RER+. RER status was correlated with histological appearance, karyotype of the carcinomas when available, K-ras mutational status, and patient outcome. Three (3.7%) of the eighty-two carcinomas were RER+. In contrast to typical gland-forming adenocarcinomas of the pancreas, all three RER+ carcinomas were poorly differentiated and had expanding borders and a prominent syncytial growth pattern. Neither a Crohn's-like lymphoid infiltrate nor extracellular mucin production were prominent. Ductal adenocarcinomas of the pancreas typically contain a mutant K-ras gene, yet all three RER+ carcinomas had wild-type K-ras. One of the three RER+ carcinomas was karyotyped and showed a near diploid pattern. All three of the RER+ tumors were removed via Whipple resection. One of the three patients is free of disease 16 months after pancreaticoduodenectomy, one is alive and free of tumor at 52 months but developed two colon carcinomas during this period, and the third died of pancreatic cancer at 4 months. None of the three patients had a family history of colorectal carcinoma. A review of the K-ras wild-type carcinomas in a previously characterized series of pancreatic carcinomas with known K-ras mutational status identified two additional cancers with poor differentiation, a syncytial growth pattern, and pushing borders. Both of the cancers were diploid and both patients were longterm survivors (over 5 years). The inclusion of such patients in previous prognostic studies of pancreas cancer may explain the failure of histological grade to be a predictor of prognosis. These data suggest that DNA replication errors occur in a small percentage of resected carcinomas of the pancreas and that wild-type K-ras gene status and a medullary phenotype characterized by poor differentiation, and expanding pattern of invasion, and syncytial growth should suggest the possibility of DNA replication errors in carcinomas of the pancreas.     

Functional defects in the fanconi anemia pathway in pancreatic cancer cells

Biallelic BRCA2-mutations can cause Fanconi anemia and are found in approximately 7% of pancreatic cancers. Recently, several sequence changes in FANCC and FANCG were reported in pancreatic cancer. Functional defects in the Fanconi pathway can result in a marked hypersensitivity to interstrand crosslinking agents, such as mitomycin C. The functional implications of mutations in the Fanconi pathway in cancer have not been fully studied yet; these studies are needed to pave the way for clinical trials of treatment with crosslinking agents of Fanconi-defective cancers. The competence of the proximal Fanconi pathway was screened in 21 pancreatic cancer cell lines by an assay of Fancd2 monoubiquitination using a Fancd2 immunoblot. The pancreatic cancer cell lines Hs766T and PL11 were defective in Fancd2 monoubiquitination. In PL11, this defect led to the identification of a large homozygous deletion in FANCC, the first cancer cell line found to be FANCC-null. The Fanconi-defective cell lines Hs766T, PL11, and CAPAN1 were hypersensitive to the crosslinking agent mitomycin C and some to cis-platin, as measured by cell survival assays and G(2)/M cell-cycle arrest. These results support the practical exploration of crosslinking agents for non-Fanconi anemia patients that have tumors defective in the Fanconi pathway.     

Ferroptosis and Acetaminophen Hepatotoxicity: Are We Going Down Another Rabbit Hole?

Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in the US. The mechanisms of APAP-induced liver injury have been under extensive investigations for decades, and many key events of this necrotic cell death are known today. Initially, two opposing hypotheses for cell death were proposed: reactive metabolite and protein adduct formation versus reactive oxygen and lipid peroxidation (LPO). In the end, both mechanisms were reconciled, and it is now generally accepted that the toxicity starts with formation of reactive metabolites that, after glutathione depletion, bind to cellular proteins, especially on mitochondria. This results in a mitochondrial oxidant stress, which requires amplification through a mitogen-activated protein kinase cascade, leading ultimately to enough reactive oxygen and peroxynitrite formation to trigger the mitochondrial membrane permeability transition and cell death. However, the earlier rejected LPO hypothesis seems to make a comeback recently under a different name: ferroptosis. Therefore, the objective of this review was to critically evaluate the available information about intracellular signaling mechanisms of APAP-induced cell death and those of ferroptosis. Under pathophysiologically relevant conditions, there is no evidence for quantitatively enough LPO to cause cell death, and thus APAP hepatotoxicity is not caused by ferroptosis. However, the role of mitochondria-localized minor LPO remains to be further investigated.Key words: Acetaminophen hepatotoxicity, Oncotic necrosis, Apoptosis, Ferroptosis, Lipid peroxidation, Fenton reaction, Glutathione peroxidase 4