Diffusion and transmission of carbapenem-resistant Klebsiella pneumoniae in the medical and surgical wards of a university hospital in Milan, Italy

Summary: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is emerging as a public health problem worldwide. In Italy, a remarkable increase in CRKP cases has been reported since 2010. In this study, CRKP diffusion, distribution and in-hospital transmission trends were evaluated in a university hospital in Milan, Italy, from January 2012 to December 2013. Isolates from 63 newly detected CRKP-positive patients were genotyped, and possible transmission was determined by combining the molecular results with data concerning the patients' admission and in-hospital transfers. Most of the cases (90.4%) were from general medical and surgery wards, and the remaining 9.6% were from the intensive care unit. Fifteen of the 46 hospital-associated cases (32.6%) were attributable to in-hospital transmission. After the introduction of targeted and hospital-wide control measures, the transmission index significantly decreased from 0.65 to 0.13 (p = 0.01). There was also a decrease in the overall nosocomial case incidence, from 0.37 to 0.17 per 1000 person-days (p = 0.07).Our findings indicate that the spread of CRKP in Northern Italy hospitals may go far beyond high-risk settings (i.e., intensive care units) and that strict surveillance should be extended to general areas of care. Keywords: Multidrug-resistant agents, Carbapenem-resistant Klebsiella pneumoniae, Cross-transmission, Infections control measures, Active surveillance, Active screenin

Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy

20Spinobulbarmuscular atrophy (SBMA) is an X-linked neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. SBMA belongs to the family of polyQ diseases, which are fatal neurodegenerative disordersmainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of misfolded proteins in the formof aggregates. The neurotoxicity of the polyQproteins can bemodified by phosphorylation at specific sites, thereby providing the rationale for the development of disease-specific treatments.We sought to identify signaling pathways thatmodulate polyQ-AR phosphorylation for therapy development.Wereport that cyclin-dependent kinase 2 (CDK2) phosphorylates polyQ-AR specifically at Ser96. Phosphorylation of polyQ-AR by CDK2 increased protein stabilization and toxicity and is negatively regulated by the adenylyl cyclase (AC)/protein kinase A (PKA) signaling pathway. To translate these findings into therapy, we developed an analog of pituitary adenylyl cyclase activating polypeptide (PACAP), a potent activator of the AC/PKA pathway. Chronic intranasal administration of the PACAP analog to knock-in SBMA mice reduced Ser96 phosphorylation, promoted polyQ-AR degradation, and ameliorated disease outcome. These results provide proof of principle that noninvasive therapy based on the use of PACAP analogs is a therapeutic option for SBMA.nonenonePolanco, Maria Josè; Parodi, Sara; Piol, Diana; Stack, Conor; Chivet, Mathilde; Contestabile, Andrea; Miranda, Helen C.; Lievens, Patricia M.-J.; Espinoza, Stefano; Jochum, Tobias; Rocchi, Anna; Grunseich, Christopher; Gainetdinov, Raul R.; Cato, Andrew C. B.; Lieberman, Andrew P.; La Spada, Albert R.; Sambataro, Fabio; Fischbeck, Kenneth H.; Gozes, Illana; Pennuto, MariaPolanco, Maria Josè; Parodi, Sara; Piol, Diana; Stack, Conor; Chivet, Mathilde; Contestabile, Andrea; Miranda, Helen C.; Lievens, Patricia M. J.; Espinoza, Stefano; Jochum, Tobias; Rocchi, Anna; Grunseich, Christopher; Gainetdinov, Raul R.; Cato, Andrew C. B.; Lieberman, Andrew P.; La Spada, Albert R.; Sambataro, Fabio; Fischbeck, Kenneth H.; Gozes, Illana; Pennuto, Mari