Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezuelan Equine Encephalitis virus within olfactory sensory neurons.

BACKGROUND: Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. METHODS: We utilized an established murine model of intranasal infection with VEEV and a repository of scRNAseq data from IFN-treated OSN to assess the cellular targets and IFN signaling responses after VEEV exposure. RESULTS: We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 h during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFNα triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFNα treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. CONCLUSIONS: Our results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human encephalitic alphavirus exposures.

Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezuelan Equine Encephalitis virus within olfactory sensory neurons.

Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. Here, we utilized an established murine model of intranasal infection with VEEV to assess the cellular targets and IFN signaling responses after VEEV exposure. We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 hours during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFNα triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFNα treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. Our results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human encephalitic alphavirus exposures.

Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained

Intracytoplasmic sperm injection improves in vitro embryo production from poor quality bovine oocytes.

The objective was to use subzonal sperm injection (SUZI) to understand sperm penetration patterns and to use intracytoplasmic sperm injection (ICSI) to improve production of bovine embryos using poor quality gametes. In experiment 1, poor versus good quality oocytes were fertilized with sperm from two bulls, A and B, with poor and good sperm vigor, respectively. The blastocyst rate was higher for good versus poor quality oocytes (23.3% vs. 11.1%, P < 0.05), regardless of the bull used. There was no significant difference in blastocyst rate for bull A (low vigor) regardless of oocyte quality, and for bull B (high vigor), blastocyst rate was better for good versus poor quality oocytes (25.7% vs. 9.2%, P < 0.05). In experiment 2, poor quality oocytes were subjected to SUZI. The oocyte penetration rate was lower for bull A than for bull B (29.6% vs. 53.8%, P < 0.05), when SUZI was performed within 1 hour after sperm processing. However, when SUZI was performed 2 to 3 hours after sperm processing, penetrating capacity was similar between bulls, but for bull B, penetrating capacity significantly decreased after 3 hours of sperm processing. In an attempt to overcome sperm penetrating disorders, poor and good quality oocytes were subjected to ICSI (experiment 3). Irrespective of the bull or of the oocyte quality grade, there were no differences in cleavage or blastocyst rates. Both bulls had distinct IVF embryo production rates, which we inferred were because of particular individual sperm characteristics. In conclusion, ICSI was an effective means to achieve in vitro production of bovine embryos with gametes of variable quality.

Health of very low birth weight children during their first eight years.

To determine the impact of very low birth weight (VLBW) on medical outcomes during childhood, we compared the health of 249 VLBW children born from 1977 through 1979 with that of 363 normal birth weight (NBW) control children at 8 years of age. Measures included the rates of specific illnesses, surgical procedures and accidents, growth, and other physical findings. The number of medical conditions and surgical procedures was significantly greater in the VLBW children than in the NBW control children. Eighteen percent of VLBW versus 5% of NBW children had had respiratory conditions (p < 0.001), mainly before 3 years of age. Surgical procedures were more common both before and after 3 years of age, but accidents occurred with similar frequency. The VLBW children had significantly lower weight, height, and head circumference and more minor physical stigmata. Thus medical illness, surgical interventions, and poor growth attainment are part of the ongoing morbidity of VLBW children during childhood.