Controversies exist about the management of esophageal perforation in order to eliminate the septic focus. The aim of this study was to assess the etiology, management, and outcome of esophageal perforation over a 12-year period, in order to characterize optimal treatment options in this severe disease. Between May 1996 and May 2008, 44 patients (30 men, 14 women; median age 67 years) with esophageal perforation were treated in our department. Etiology, diagnostic procedures, time interval between clinical presentation and treatment, therapeutic management, and outcome were analyzed retro- or prospectively for each patient. Iatrogenic injury was the most frequent cause of esophageal perforation (n= 28), followed by spontaneous (n= 9) and traumatic (n= 4) esophageal rupture (in three patients, the reasons were not determinable). Eight patients (18%) underwent conservative treatment with cessation of oral intake, antibiotics, and parenteral nutrition. Twelve (27%) patients received an endoscopic stent implantation. Surgical therapy was performed in 24 (55%) patients with suturing of the lesion in nine patients, esophagectomy with delayed reconstruction in 14 patients, and resection of the distal esophagus and gastrectomy in one patient. In case of iatrogenic perforation, conservative or interventional therapy was performed each in 50% of the patients; 89% of the patients with a Boerhaave syndrome underwent surgery. The hospital mortality rate was 6.8% (3 of 44 patients): one patient with an iatrogenic perforation after conservative treatment, and two patients after surgery (one with Boerhaave syndrome, one with iatrogenic rupture). No death occurred in the 25 patients with a diagnostic interval less than 24 hours, whereas the mortality rate in the group (n= 16 patients) with a diagnostic interval of more than 24 hours was 19% (P= 0.053). In three patients, the diagnostic interval was not determinable retrospectively. An individualized therapy depending on etiology, diagnostic delay, and septic status leads to a low mortality of esophageal perforation.

Changes induced with transgenic cardiac HIF-1α possibly mediate beneficial effects in the short term; however, with increased mechanical load and ageing they become detrimental for cardiac function. Together with the finding of increased HIF-1α protein levels in samples from human patients with cardiomyopathy, these data indicate that chronic HIF-1α stabilization drives autonomous pathways that add to disease progression.

Prolylhydroxylase domain proteins (PHD) are cellular oxygen-sensing molecules that regulate the stability of the ␣-subunit of the transcription factor hypoxia inducible factor (HIF)-1. HIF-1 affects cardiac development as well as adaptation of the heart toward increased pressure overload or myocardial infarction. We have disrupted PHD2 in cardiomyocytes (cPhd ؊/؊ ) When oxygen availability is impaired, the resulting hypoxia activates homeostatic mechanisms at the systemic and cellular level (1). Hypoxia-inducible factors (HIFs) 2 are essential players in these responses because they regulate the transcription of a large number of genes that affect a myriad of cellular processes, including angiogenesis, metabolism, cell survival, and oxygen delivery (2). HIF is a heterodimeric protein comprising the oxygen-sensitive ␣-subunit HIF-1␣ or the more cell type-specifically expressed HIF-2␣ or HIF-3␣ and the oxygen-insensitive ␤-subunit (3). In the presence of oxygen, HIF␣ becomes hydroxylated at two critical proline residues by prolylhydroxylase domain (PHD) enzymes (4, 5). The PHD protein family responsible for HIF␣ regulation consists of three members called prolylhydroxylase domain (PHD)1, PHD2, and PHD3 (6, 7). Following prolyl-4-hydroxylation of the critical prolyl residues under normoxic conditions, the ubiquitin ligase von Hippel-Lindau tumor suppressor protein recognizes ⌯⌱F-1␣ subunits and targets them for rapid ubiquitination and proteasomal degradation (8 -10).Based on the ubiquitous expression pattern and its dominant effect in normoxia, it had to be assumed that PHD2 is the most critical HIF-1␣-regulating PHD isoform in most tissues (11)(12)(13). This notion, learned from in vitro studies, was confirmed by the up to now available genetically modified Phd2 mouse models (14). Phd2 knock-out embryos die between embryonic day (E) 12.5 and E14.5 (15). This time point coincides with the increased levels of PHD2 in wild-type (wt) mice starting from E9.0. A major role of PHD2 in regulating the HIF system is further underscored by mouse models with a somatic Phd2 Ϫ/Ϫ knock out, which enable to analyze the in vivo function of PHD2 in the adult mice. Two independent inducible Phd2 Ϫ/Ϫ mouse models were developed by Takeda et al. (16) and Minamishima et al. (17). The phenotype of these mice most obviously resembles the consequences of HIF␣ overexpression with increased angiogenesis, erythropoiesis, and extramedullar hematopoiesis (17,18). Most interestingly, these mice also develop a cardiac phenotype with symptoms of dilated cardiomyopathy. In the heart, HIF-1␣ and thereby also the PHDs are known to influence key components of heart development, morphogenesis, and function (19,20). Long term activation of HIF-1␣ in the heart seems to activate detrimental pathways resulting in the development of heart failure (21). Thus, it is tempting to speculate that loss of PHD2 in the heart is responsible for the dilated cardiomyopathy as observed in the inducible Phd2 Ϫ/Ϫ mice. However, because these mice also develop an inc...

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Aims: The prolyl-4-hydroxylase domain (PHD) enzymes are representing novel therapeutic targets for ischemic tissue protection. Whereas the consequences of a knock out of the PHDs have been analyzed in the context of cardioprotection, the implications of PHD overexpression is unknown so far. Methods and Results: We generated cardiomyocyte-specific PHD3transgenic mice (cPhd3tg). Resting cPhd3tg mice did not show constitutive accumulation of HIF-1α or HIF-2α or changes in HIF target gene expression in the heart. Cardiac function was followed up for 14 months in these mice and found to be unchanged. After challenging the cPhd3tg mice with ligation of the left anterior descending artery, HIF-1α/-2α accumulation in the left ventricles was blunted. This was associated with a significantly increased infarct size of the cPhd3tg compared to wild type mice. Conclusion: Whereas overexpression of PHD3 in the resting state does not significantly influence cardiac function, it is crucial for the cardiac response to ischemia by affecting HIFα accumulation in the ischemic tissue.

From 1982 to 1992 103 patients with ovarian cancer stage FIGO III have been treated. In 38% of the patients there was no residual tumour postoperatively, in 40.8% the residual tumour was smaller than 2 cm. In 51.5% bowel resections were necessary, a stoma was unavoidable in just one case. A lymphadenectomy (pelvic, paraaortic or combined) was done in 46.6% of the patients. Postoperatively, 54.4% of the patients received a platinum-based chemotherapy, in the other patients other kinds of chemotherapy were applied. A radiation of the whole abdomen was done only in 3.9%. A median survival time for more than 60 months could be achieved in tumour-free patients due to the increased radical operations in combination with the platinum based chemotherapy. The lymphadenectomy seems to prolong the survival time of the patients. The positive nodal status is definitely unfavourable for the prognosis. By this therapeutic approach, an increased survival time with a good life quality can be achieved.

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