Mutations in isocitrate dehydrogenase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas and share hypermethylation targets with glioblastomas.

Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in 34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P=0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P=0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.

Cardiovascular responses to beta-blockade and 5 degrees C cold air stress.

To determine the cardiovascular responses to beta-blockade and cold air stress, six males were randomly exposed at rest to three drug conditions (placebo, nonselective beta-blockade (propranolol), and selective beta-blockade (atenolol)) in each of two environments (5 and 25 degrees C) for 1 h. Cardiac output was lower on beta-blockade than on the placebo in both the 25 and 5 degrees C environments. Cardiac output on propranolol (4.2 +/- 0.3 L.min-1) at 5 degrees C was lower than on atenolol (4.7 +/- 0.4 L.min-1, p < 0.05). Mean arterial pressure was greater (p < 0.05) at 5 than 25 degrees C for each drug condition. There was no drug effect on total peripheral resistance at 25 degrees C. At 5 degrees C, total peripheral resistance on both beta-blockers (propranolol 1942.7 +/- 169.9 dyn.s.cm-5 (1 dyn = 10 microN); atenolol 1706.7 +/- 160.0 dyn.s.cm-5) was higher (p < 0.05) than on the placebo (1485.3 +/- 111.8 dyn.s.cm-5). Total peripheral resistance was also higher on propranolol than atenolol (p < 0.05). In conclusion, cold air stress interacts with beta-blockade to elevate total peripheral resistance by decreasing cardiac output while having little effect on mean arterial pressure. These effects are greater on nonselective than on selective blockade.

cis-acting mutations that affect rop protein control of plasmid copy number.

A number of pMB1 derivatives provide a trans-acting function that can suppress lethal runaway replication of a temperature-sensitive copy-number mutant of NTP1. Deletion analysis indicates that the region of the pMB1 genome that contains the rop gene is required for this suppression. Mutant derivatives of the temperature-sensitive copy-number mutant plasmid whose conditional lethal phenotype is not suppressed in trans by the region encoding the rop gene have been isolated. These rop-insensitive derivatives contain single nucleotide changes within the RNA I coding region.

Suppressors of a temperature-sensitive copy-number mutation in plasmid NTP1.

A temperature-sensitive high copy-number mutant of plasmid NTP1, first described by Grindley et al. (1978), is lethal to bacterial cells at the non-permissive temperature. This behavior has been used to select mutations in the plasmid replication origin region that suppress the over-replication phenotype. We have identified the site of the original ts lethal mutation and the positions of the reversion mutations. The ts mutation, designated orp, for over-replication, is a single nucleotide change 23 base-pairs upstream from the transcription start site for RNA I, the repressor of plasmid replication. This change simultaneously affects the promoter for RNA I and the precursor of the primer for plasmid replication, RNA II, which is also transcribed from this region. Fusions of the mutant promoter region with the galK gene indicate that transcription is not temperature sensitive. This result suggests that the mutation affects RNA II secondary structure. The reversion mutations are also located within the RNA II coding region more than 200 bp from the site of the original ts mutation. These mutations may also affect RNA II structure.

[Horner's syndrome: a rare complication of internal jugular vein cannulation (author's transl)]. / Horner-Syndrom: Ein seltenes Ereigins nach Punktion der Vena jugularis interna.

Percutaneous internal jugular vein cannulation has become an accepted method for insertion of central venous catheters. There are many indications for such a procedure, but a variety of complications may arise due either to direct injury of local structures or else to secondary tissue damage due to long-standing presence of the catheter in situ. Direct injury to the sympathetic trunk causing Horner's syndrome is extremely rare. This report describes a case in which Horner's syndrome occurred a few days after insertion of the catheter into the right internal jugular vein.

[Amanita phalloides poisoning in Austria (author's transl)]. / Knollenblätterpilzvergiftungen in Osterreich.

An analysis of 28 cases of amanita phalloides poisoning serves as basis for a discussion of the clinical features and therapeutic problems involved. A critical review of recent experimental investigations in animals points to new possibilities in the treatment of amanita phalloides poisoning.