Multiple brain lesions in sport divers were associated with presence of a large patent foramen ovale. This association suggests paradoxical gas embolism as the pathological mechanism. A patent foramen ovale of high haemodynamic relevance seems to be an important risk factor for developing multiple brain lesions in sport divers.

The adenovirus mutant dl1520 (ONYX-015) does not express the E1B-55K protein that binds and inactivates p53. This virus replicates in tumor cells with mutant p53, but not in normal cells with functional p53. Although intra-tumoral injection of dl1520 shows promising responses in patients with solid tumors, previous in vitro studies have not established a close correlation between p53 status and dl1520 replication. Here we identify loss of p14ARF as a mechanism that allows dl1520 replication in tumor cells retaining wild-type p53. We demonstrate that the re-introduction of p14ARF into tumor cells with wild-type p53 suppresses replication of dl1520 in a p53-dependent manner. Our study supports the therapeutic use of dl1520 in tumors with lesions within the p53 pathway other than mutation of p53.

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Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Here, we show that the mdm2 gene is also regulated by the Ras-driven Raf/MEK/MAP kinase pathway, in a p53-independent manner. Mdm2 induced by activated Raf degrades p53 in the absence of the Mdm2 inhibitor p19ARF. This regulatory pathway accounts for the observation that cells transformed by oncogenic Ras are more resistant to p53-dependent apoptosis following exposure to DNA damage. Activation of the Ras-induced Raf/MEK/MAP kinase may therefore play a key role in suppressing p53 during tumor development and treatment. In primary cells, Raf also activates the Mdm2 inhibitor p19ARF. Levels of p53 are therefore determined by opposing effects of Raf-induced p19ARF and Mdm2.

Accumulated knowledge in the molecular processes of tumour development combined with the availability of genetically modified viruses resemble the basis for new promising cancer therapeutics. The main advantages of employing replicationcompetent viruses are achievement of tumour selective killing and amplification of their oncolytic potential within the tumour mass. In this review, we describe the development of ONYX-015, one of the first and most advanced replication-competent viruses for cancer therapy. We discuss the molecular biology of this therapeutic approach and the interesting results obtained with this virus in clinical trials.

There is increasing experimental evidence for an important role of Angiopoietin-2 (Ang-2) in tumor angiogenesis and progression. In addition, Ang-2 is up-regulated in many cancer types and correlated with poor prognosis. To investigate the functional role of Ang-2 inhibition in tumor development and progression, we generated novel fully human antibodies that neutralize specifically the binding of Ang-2 to its receptor Tie2. The selected antibodies LC06 and LC08 recognize both rodent and human Ang-2 with high affinity, but LC06 shows a higher selectivity for Ang-2 over Ang-1 compared to LC08 which can be considered an Ang-2/Ang-1 cross-reactive antibody. Our data demonstrate that Ang-2 blockade results in potent tumor growth inhibition and pronounced tumor necrosis in subcutaneous and orthotopic tumor models. These effects are attended with a reduction of intratumoral microvessel density and tumor vessels characterized by fewer branches and increased pericyte coverage. Furthermore, anti-Ang-2 treatment strongly inhibits the dissemination of tumor cells to the lungs. Interestingly, in contrast to the Ang-2/Ang-1 cross-reactive antibody LC08 that leads to a regression of physiological vessels in the mouse trachea, the inhibition with the selective anti-Ang-2 antibody LC06 appears to be largely restricted to tumor vasculature without obvious effects on normal vasculature. Taken together, these data provide strong evidence for the selective Ang-2 antibody LC06 as promising new therapeutic agent for the treatment of various cancers.

Cerebral ischaemia is a common complication of bacterial meningitis. Although cerebrovascular involvement in the acute phase of inflammation may be particularly important for the still unacceptably high morbidity and mortality, only, a few studies have investigated cerebrovascular changes in bacterial meningitis. We prospectively investigated changes of intracranial cerebral blood flow velocities (CBFV) in 22 patients (12 men, 10 women, mean age 48 years, 19 years, SD) with bacterial meningitis, by means of transcranial Doppler sonography (TCD). According to previously published criteria the degree of arterial narrowing was assessed and related to the patients' outcome. Elevated CBFVs in the middle cerebral artery were documented in 18/22 patients with markedly increased systolic peak velocities (CBFV of > 210 cm/s) in 7 patients. Serial examinations performed in 11 patients showed elevated CBFV as early as day 1, reaching peak CBFV between day 3 and day 6 after onset of symptoms in most cases. Furthermore, cerebrovascular involvement was also documented by disturbances of physiological slow spontaneous oscillations of blood flow velocities in 5/10 patients examined with TCD. Low Glasgow Coma Scales (< 7) on admission (29% vs 0%), focal cerebral ischaemic deficits (29% vs 7%) and, seizures (43% vs 7%) were more frequent in patients with CBFV of > 210 cm/s. Finally, a poor clinical outcome was significantly related to severe vascular involvement (P < 0.05). In conclusion, cerebrovascular complications are frequently found in patients with bacterial meningitis. TCD is an easily applicable technique for revealing vascular changes non-invasively, even in severely ill patients. Since our data suggest an unfavourable course of the disease in association with increased CBFV in intracranial arteries, probably indicating vasospasm, TCD could potentially be used to identify high-risk patients who could benefit from adjuvant therapeutic interventions.

Quality of life is considerably impaired in early stages of MS. Treatment initiation with IM IFNbeta attenuates MS disease activity and improves QoL. Inability to work early during the disease is a major challenge for the social security systems.