High frequency of MYC gene amplification is a common feature of radiation‐induced sarcomas. Further results from EORTC STBSG TL 01/01

Irradiation is a major causative factor among the small subgroup of sarcomas with a known etiology. The prognosis of radiation‐induced sarcomas (RIS) is significantly worse than that of their spontaneous counterparts. The most frequent histological subtypes include undifferentiated pleomorphic sarcomas, angiosarcomas, and leiomyosarcomas. A high frequency of MYC amplifications in radiation‐induced angiosarcomas, but not in primary angiosarcomas, has recently been described. To investigate whether MYC amplifications are also frequent in RIS other than angiosarcomas, we analyzed the MYC amplification status of 83 RIS and 192 sporadic sarcomas by fluorescence in situ hybridization. We found significantly higher numbers of MYC amplifications in RIS than in sporadic sarcomas (P < 0.0001), especially in angiosarcomas, undifferentiated pleomorphic sarcomas, and leiomyosarcomas. Angiosarcomas were special in that MYC amplifications were particularly frequent and always high level, while other RIS showed low‐level amplifications. We conclude that MYC amplifications are a frequent feature of RIS as a group and may contribute to the biology of these tumors. © 2012 Wiley Periodicals, Inc.     

Clinical predictors and outcomes associated with acute return of pulmonary vein conduction during pulmonary vein isolation for treatment of atrial fibrillation.

BACKGROUND: Pulmonary vein electrical isolation (PVI) is an effective treatment for atrial fibrillation (AF). However, recurrence of pulmonary vein (PV) conduction after ablation may limit long-term success. OBJECTIVE: We sought to determine the clinical predictors of acute PV reconnection during PVI and assess the long-term clinical outcomes associated with this phenomenon. METHODS: We studied all patients with AF referred for PVI between November 2000 and August 2004. Over the course of the study period, PVI of arrhythmogenic PVs was performed segmentally using a 4-mm tip (52 degrees , 40 W, up to 90 seconds) or 8-mm tip catheter (50 degrees , 70 W, up to 60 seconds). PVI was defined as entry and exit block using a multipolar Lasso catheter. All veins were resampled to confirm isolation after 20-60 minutes. AF control was defined as no AF on or off a previously ineffective antiarrhythmic drug. Follow-up data included transtelephonic monitoring and clinical data collection from patient interviews. RESULTS: There were 424 patients who underwent isolation of 1,347 PVs during the study period. Acute reconnection of at least one PV occurred in 211 (50%) of the 424 patients and 326 (24%) of 1,347 of the PVs targeted. The left superior PV was most likely to acutely recover conduction compared with the other veins (left superior 31%, right superior 26%, right inferior 22%, left inferior 24%; P = .03). Patients with acute reconnection were more likely to be older, have a larger left atrium, have a history of hypertension or obstructive sleep apnea, and demonstrate persistent AF. After a single procedure, AF control was achieved in 153 (70%) of the 213 patients who demonstrated acute PV reconnection compared with 148 (73%) of 211 patients without acute PV reconnection observed (P = .52). CONCLUSIONS: Acute return of PV conduction is common after successful PVI and is more likely to occur in older patients with nonparoxysmal AF, hypertension, a large left atrium, and sleep apnea. There was no significant difference in acute PV reconnection between the 4-mm and 8-mm tip RF catheter despite differences in power and duration of energy delivery. Furthermore, there was no effect of PV reconnection on long-term AF control after repeated disconnection was performed.     

Cobalamin Dependent Methionine Synthesis and Methyl-Folate-Trap in Human Vitamin B12 Deficiency

The activity of methionine synthetase (MS) is important for the rapid growth of human haematopoietic cells and cultured lymphoblastoid cells. The MS reaction is the only known metabolic step in which both vitamin B₁₂ and folate are essential in a single enzyme reaction. In vitamin B₁₂ deficiency the MS activity in bone marrow cells is significantly lower than that in normal bone marrow. Free tetrahydrofolic acid (H₄PteGlu) is normally liberated from its metabolically inactive storage form, 5-methyl-H₄PteGlu (CH₃H₄PteGlu), in the cobalamindependent MS reaction. Thus, in vitamin B₁₂ deficiency H₄PteGlu is not available in sufficient concentration to maintain the de novo synthesis of thymidylate and purines, and accords with the methyl-folate-trap hypothesis. After treatment with amethopterin (Methotrexate^TM), the incorporation of ³Hdeoxyuridine into cellular DNA is reduced. In proliferating normal cells this effect of methotrexate can be prevented (and the cells rescued) with CH₃-H₄PteGlu or with CHO-H₄PteGlu (5-formyl-H₄PteGlu; Leucovorin^TM). On the other hand, in vitamin B₁₂ deficient bone marrow cells this so-called rescue-effect could only be achieved with CHO-H₄PteGlu and not with CH₃-H₄PteGlu. These observations also support the hypothesis of the methyl-folate-trap in vitamin B₁₂ deficiency. Decreased MS activity in vitamin B₁₂ deficiency seems to be the essential metabolic fault, which is responsible for secondary alterations of folate metabolism. Thus, measurement of MS activity may allow direct functional assessment of vitamin B₁₂ deficiency, at least with regard to DNA metabolism.     

Klinischer Stellenwert von Monointoxikationen mit Ibuprofen, Diclofenac und Metamizol

Zusammenfassung Fragestellung Aufgrund der steigenden Anzahl suizidaler und parasuizidaler Intoxikationen mit Schmerzmitteln, soll die Häufigkeit und der klinische Stellenwert von Monointoxikationen der drei häufigsten Generika der Gruppe der nichtsteroidalen und steroidalen Antirheumatika/Analgetika (ohne Berücksichtigung der Acetylsalicylsäure), Diclofenac, Ibuprofen und Metamizol, untersucht werden und eruiert werden, ab welcher Dosierung eine intensivmedizinische Überwachung nötig erscheint. Patienten und Methodik Im Untersuchungszeitraum vom 1. Januar 1995 bis 31. Dezember 2001 wurden alle beim Giftinformationszentrum Mainz dokumentierten Monointoxikationen o. g. Generika mittels des Datenverarbeitungsprogramms ADAM-Dok/-Aus (basierend auf Microsoft^®Access^®) ausgewertet. Die Feststellung des Schweregrades erfolgte mittels des Poison Severity Scores. Zur speziellen Betrachtung gelangten nur die nichtsteroidalen Antirheumatika/Analgetika. Ergebnisse Im o. g. Zeitraum kam es zu 1281 Monointoxikationen mit NSAR und SAR, davon 40% Ibuprofen, 31% Diclofenac und 13% Metamizol. Bei Monointoxikationen mit Ibuprofen kam es erst ab einer Dosierung von 300 mg/kg KG zu schwerwiegenden, lebensbedrohlichen Vergiftungserscheinungen. Bei Diclofenac und Metamizol zeigten sich komplett unterschiedliche klinische Verläufe (Hypotonie, Herzrhythmusstörung und Niereninsuffizienz bei niedriger Dosierung, Symptomfreiheit bei hoher Dosierung). Zusammenfassung Bei Monointoxikationen mit Ibuprofen sollte erst ab einer Dosierung von 300 mg/ kg KG eine intensivmedizinische Überwachung angestrebt werden. Aufgrund komplett unterschiedlicher klinischer Verläufe (schwere Symptome bei niedriger Dosierung und keine Symptome bei hoher Dosierung) ist bezüglich der Festlegung einer kritischen Dosierung bei Monointoxikationen mit Diclofenac und Metamizol zur Zeit keine klare Aussage möglich. Hierzu sollten weitere Untersuchungen folgen. Bei jeder Art von Intoxikation empfehlen wir die Rücksprache mit einem Giftinformationszentrum, z. B. 06131/19240.     

Cloning of Physarum actin sequences in an exonuclease-deficient bacterial host.

A genomic library of Physarum was constructed in the replacement vector EMBL3. Efficient propagation of the recombinant phages occurred only on the recBC-sbcB- host Escherichia coli CES200, which is deficient in the exonucleases I and V. Thirteen different recombinants with actin-related sequences were detected and 10 were purified from 90,000 plaques (the equivalent of 6 Physarum genomes) on strain CES200. Comparison of the plating efficiencies of the library and the actin-related isolates suggests that palindromic DNA sequences are responsible for the instability of Physarum DNA in E. coli. In one of these isolates, lambda PpA10, and in a 2.81-kilobase subclone of that isolate in plasmid pBR322, a deletion of 360 base pairs was detected that led to stable propagation of the recombinant DNA molecules in Rec+ E. coli. Electron microscopic analysis of the 2.81-kilobase fragment, after denaturation and self-hybridization, revealed secondary structures consistent with "foldback" structures. Restriction and DNA blot analysis of lambda PpA10 suggest that the unstable DNA segment is in close proximity to, if not part of, the previously defined actin-gene locus ardA.