HtrA2/Omi Terminates Cytomegalovirus Infection and Is Controlled by the Viral Mitochondrial Inhibitor of Apoptosis (vMIA)

Viruses encode suppressors of cell death to block intrinsic and extrinsic host-initiated death pathways that reduce viral yield as well as control the termination of infection. Cytomegalovirus (CMV) infection terminates by a caspase-independent cell fragmentation process after an extended period of continuous virus production. The viral mitochondria-localized inhibitor of apoptosis (vMIA; a product of the UL37x1 gene) controls this fragmentation process. UL37x1 mutant virus-infected cells fragment three to four days earlier than cells infected with wt virus. Here, we demonstrate that infected cell death is dependent on serine proteases. We identify mitochondrial serine protease HtrA2/Omi as the initiator of this caspase-independent death pathway. Infected fibroblasts develop susceptibility to death as levels of mitochondria-resident HtrA2/Omi protease increase. Cell death is suppressed by the serine protease inhibitor TLCK as well as by the HtrA2-specific inhibitor UCF-101. Experimental overexpression of HtrA2/Omi, but not a catalytic site mutant of the enzyme, sensitizes infected cells to death that can be blocked by vMIA or protease inhibitors. Uninfected cells are completely resistant to HtrA2/Omi induced death. Thus, in addition to suppression of apoptosis and autophagy, vMIA naturally controls a novel serine protease-dependent CMV-infected cell-specific programmed cell death (cmvPCD) pathway that terminates the CMV replication cycle

Prevalence and nature of off-label antibiotic prescribing for children in a tertiary setting: A descriptive study from Jordan

Objective: The aim of the present study was to evaluate the use of off-label antibiotics in neonatal intensive care units (NICUs) and paediatric wards in Jordan. Methods: Data of patients admitted to the neonatal intensive care units and paediatric wards in King Abdulla University Hospital were collected over an 8-week survey between May and July 2012. Data collected in this study included patients’ age, weight, medical history, diagnosis and the details of antibiotics prescribed to each patient. Results: The study involved a total of 250 children (80 admitted to the NICU and 170 admitted to the wards). A total of 598 antibiotic prescriptions were issued for these patients (244 in NICUs and 354 in paediatricwards). The results of the present study show that off-label antibiotic prescribing to paediatric patients is very common. Off-label antibiotic prescribing to paediatric patients is related mostly to doses and indications, and rarely to age. The majority of admitted patients received at least one off-label antibiotic during their hospital stay. Conclusion: This study reveals the high prevalence of off-label use of antibiotic among paediatric children in Jordan. There is a serious need for robust and continuous educational programs to improve the awareness of paediatricians of guidelines surrounding the use of antibiotics in paediatric patients. Furthermore, true collaboration between paediatricians and clinical pharmacists towards safe and effective antibiotic prescribing in paediatric patients is crucial