Current prevalence of multidrug-resistant organisms in long-term care facilities in the Rhine-Main district, Germany, 2013

Multidrug-resistant organisms (MDRO) and in particular multidrug-resistant Gram-negative organisms (MRGN) are an increasing problem in hospital care. However, data on the current prevalence of MDRO in long-term care facilities (LTCFs) are rare. To assess carriage rates of MDRO in LTCF residents in the German Rhine-Main region, we performed a point prevalence survey in 2013. Swabs from nose, throat and perineum were analysed for meticillin-resistant Staphylococcus aureus (MRSA), perianal swabs were analysed for extended-spectrum beta-lactamase (ESBL)-producing organisms, MRGN and vancomycin-resistant enterococci (VRE). In 26 LTCFs, 690 residents were enrolled for analysis of MRSA colonisation and 455 for analysis of rectal carriage of ESBL/MRGN and VRE. Prevalences for MRSA, ESBL/MRGN and VRE were 6.5%, 17.8%, and 0.4%, respectively. MRSA carriage was significantly associated with MRSA history, the presence of urinary catheters, percutaneous endoscopic gastrostomy tubes and previous antibiotic therapy, whereas ESBL/MRGN carriage was exclusively associated with urinary catheters. In conclusion, this study revealed no increase in MRSA prevalence in LTCFs since 2007. In contrast, the rate of ESBL/MRGN carriage in German LTCFs was remarkably high. In nearly all positive residents, MDRO carriage had not been known before, indicating a lack of screening efforts and/or a lack of information on hospital discharge

Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma

Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxic side effects, poor bioavailability and low efficacy of the available MDM2 inhibitors that have entered phase I/II trials drive the development of novel MDM2 inhibitors with an improved risk-benefit profile. We investigated the effect of the novel MDM2 small molecular inhibitor, DS-3032b, on viability, proliferation, senescence, migration, cell cycle arrest and apoptosis in a panel of six neuroblastoma cell lines with different TP53 and MYCN genetic backgrounds, and assessed efficacy in a murine subcutaneous model for high-risk neuroblastoma. Re-analysis of existing expression data from 476 primary neuroblastomas showed that high-level MDM2 expression correlated with poor patient survival. DS-3032b treatment enhanced TP53 target gene expression and induced G1 cell cycle arrest, senescence and apoptosis. CRISPR-mediated MDM2 knockout in neuroblastoma cells mimicked DS-3032b treatment. TP53 signaling was selectively activated by DS-3032b in neuroblastoma cells with wildtype TP53, regardless of the presence of MYCN amplification, but was significantly reduced by TP53 mutations or expression of a dominant-negative TP53 mutant. Oral DS-3032b administration inhibited xenograft tumor growth and prolonged mouse survival. Our in vitro and in vivo data demonstrate that DS-3032b reactivates TP53 signaling even in the presence of MYCN amplification in neuroblastoma cells, to reduce proliferative capacity and cause cytotoxicity

Cloning and sequencing of the cDNA encoding human neurotrypsin.

cDNA clones encoding human neurotrypsin have been isolated from a human fetal brain cDNA library using a PCR-amplified probe. The assembled cDNA sequence contains a 2625 bp open reading frame encoding a multidomain serine protease with an overall sequence identity of 82.5% to murine neurotrypsin. Surprisingly, the human neurotrypsin exhibits an additional scavenger receptor cysteine-rich repeat