Catherine A. Gilchrist

The mouse polyubiquitin gene UbC is essential for fetal liver development, cell‐cycle progression and stress tolerance

UbC is one of two stress‐inducible polyubiquitin genes in mammals and is thought to supplement the constitutive UbA genes in maintaining cellular ubiquitin (Ub) levels during episodes of cellular stress. We have generated mice harboring a targeted disruption of the UbC gene. UbC−/− embryos die between embryonic days 12.5 and 14.5 in utero, most likely owing to a severe defect in liver cell proliferation. Mouse embryonic fibroblasts from UbC−/− embryos exhibit reduced growth rates, premature senescence, increased apoptosis and delayed cell‐cycle progression, with slightly, but significantly, decreased steady‐state Ub levels. UbC−/− fibroblasts are hypersensitive to proteasome inhibitors and heat shock, and unable to adequately increase Ub levels in response to these cellular stresses. Most, but not all of the UbC−/− phenotypes can be rescued by providing additional Ub from a poly hemagglutinin‐tagged Ub minigene expressed from the Hprt locus. We propose that UbC is regulated by a process that senses Ub pool dynamics. These data establish that UbC constitutes an essential source of Ub during cell proliferation and stress that cannot be compensated by other Ub genes.

Vitamin D supplementation during pregnancy and infancy reduces aeroallergen sensitization: a randomized controlled trial

Vitamin D has immune‐modulating effects. We determined whether vitamin D supplementation during pregnancy and infancy prevents aeroallergen sensitization and primary care respiratory illness presentations.

The impact of primary care on emergency department presentation and hospital admission with pneumonia: a case-control study of preschool-aged children.

Background:In children, community-acquired pneumonia is a frequent cause of emergency department (ED) presentation and hospital admission. Quality primary care may prevent some of these hospital visits.Aims:The aim of this study was to identify primary care factors associated with ED presentation and hospital admission of preschool-aged children with community-acquired pneumonia.Methods:A case–control study was conducted by enrolling three groups: children presenting to the ED with pneumonia and admitted (n=326), or discharged home (n=179), and well-neighbourhood controls (n=351). Interviews with parents and primary care staff were conducted and health record review was performed. The association of primary care factors with ED presentation and hospital admission, controlling for available confounding factors, was determined using logistic regression.Results:Children were more likely to present to the ED with pneumonia if they did not have a usual general practitioner (GP) (odds ratio (OR)=2.50, 95% confidence interval (CI)=1.67–3.70), their GP worked ⩽20 h/week (OR=1.86, 95% CI=1.10–3.13) or their GP practice lacked an immunisation recall system (OR=5.44, 95% CI=2.26–13.09). Lower parent ratings for continuity (OR=1.63, 95% CI=1.01–2.62), communication (OR=2.01, 95% CI=1.29–3.14) and overall satisfaction (OR=2.16, 95% CI=1.34–3.47) increased the likelihood of ED presentation. Children were more likely to be admitted when antibiotics were prescribed in primary care (OR=2.50, 95% CI=1.43–4.55). Hospital admission was less likely if children did not have a usual GP (OR=0.22, 95% CI=0.11–0.40) or self-referred to the ED (OR=0.48, 95% CI=0.26–0.89).Conclusions:Accessible and continuous primary care is associated with a decreased likelihood of preschool-aged children with pneumonia presenting to the ED and an increased likelihood of hospital admission, implying more appropriate referral. Lower parental satisfaction is associated with an increased likelihood of ED presentation.

The ubiquitin–proteasome system is inhibited by p53 protein expression in human ovarian cancer cells

The ubiquitin-proteasome system (UPS) and autophagy provide major cellular pathways for protein degradation. Since the p53 pathway controls autophagy, we investigated whether p53 regulates UPS in ovarian tumour cell lines. A reporter cell line (SKOV3-EGFPu) was established to measure UPS function against a constant genetic background. Transient expression of either wild type or mutant p53 in SKOV3-EGFPu cells reduced UPS activity as compared to vector control. These results, together with those from endogenous p53 expression in seven ovarian cancer cell lines, suggest that expression of both wild-type and mutant p53 protein impairs UPS function. Thus, p53 expression may regulate protein homeostasis by down-regulating UPS function in response to cellular stress.

Vaccine Education During Pregnancy and Timeliness of Infant Immunization

We identify pregnant women’s sources of immunization information and determine the associations of receiving encouraging or discouraging information with their infants’ immunization timeliness. OBJECTIVES: Pregnant women routinely receive information in support of or opposing infant immunization. We aimed to describe immunization information sources of future mothers’ and determine if receiving immunization information is associated with infant immunization timeliness. METHODS: We analyzed data from a child cohort born 2009–2010 in New Zealand. Pregnant women (N = 6822) at a median gestation of 39 weeks described sources of information encouraging or discouraging infant immunization. Immunizations received by cohort infants were determined through linkage with the National Immunization Register (n = 6682 of 6853 [98%]). Independent associations of immunization information received with immunization timeliness were described by using adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Immunization information sources were described by 6182 of 6822 (91%) women. Of these, 2416 (39%) received information encouraging immunization, 846 (14%) received discouraging information, and 565 (9%) received both encouraging and discouraging information. Compared with infants of women who received no immunization information (71% immunized on-time), infants of women who received discouraging information only (57% immunized on time, OR = 0.49, 95% CI 0.38–0.64) or encouraging and discouraging information (61% immunized on time, OR = 0.51, 95% CI 0.42–0.63) were at decreased odds of receiving all immunizations on time. Receipt of encouraging information only was not associated with infant immunization timeliness (73% immunized on time, OR = 1.00, 95% CI 0.87–1.15). CONCLUSIONS: Receipt, during pregnancy, of information against immunization was associated with delayed infant immunization regardless of receipt of information supporting immunization. In contrast, receipt of encouraging information is not associated with infant immunization timeliness.

Increasing Incidence of Life-threatening Pertussis: A Retrospective Cohort Study in New Zealand

Background: Pertussis immunization programs aim to prevent severe infant disease. We investigated temporal trends in infant pertussis deaths and pediatric intensive care unit (PICU) admissions and associations of changes in disease detection and vaccines used with death and PICU admission rates. Methods: Using national data from New Zealand (NZ), we described infant pertussis deaths and PICU admissions from 1991 to 2013, over which time national immunization coverage at 2 years of age increased from <80% to 92%. In NZ, pertussis became a notifiable disease with polymerase chain reaction (PCR) diagnosis available in 1997 and acellular replaced whole-cell vaccine in 2000. We used Poisson regression to model temporal trends and compared rates in time intervals using rate ratios (RRs) with 95% confidence intervals (CIs). Results: There were 10 pertussis deaths and 159 infant PICU admissions with pertussis from 1991 to 2013. The annual number of infant pertussis PICU admissions increased from 1991 to 2013 (P = 0.02) but the number of pertussis deaths did not (P = 0.09). The risk of PICU admission during infancy with pertussis was increased in the notification/PCR versus the non-notification/PCR era (RR: 1.12; 95% CI: 1.02–1.19) and when acellular replaced whole-cell vaccine (RR: 1.19; 95% CI: 1.06–1.31). Median Pediatric Index of Mortality scores during 2001–2013 were lower than during 1991–1999 (P < 0.001). Conclusions: Infant PICU pertussis admission rates have increased in NZ despite improvements in immunization coverage. Higher rates have occurred since pertussis notification/PCR became available and since acellular replaced whole-cell vaccine. The severity of disease in infants admitted to PICU with pertussis has decreased in recent years.