Adjuvant pretreatment with alum protects neonatal mice in sepsis through myeloid cell activation.

The high mortality in neonatal sepsis has been related to both quantitative and qualitative differences in host protective immunity. Pretreatment strategies to prevent sepsis have received inadequate consideration, especially in the premature neonate, where outcomes from sepsis are so dismal. Aluminium salts-based adjuvants (alum) are used currently in many paediatric vaccines, but their use as an innate immune stimulant alone has not been well studied. We asked whether pretreatment with alum adjuvant alone could improve outcome and host innate immunity in neonatal mice given polymicrobial sepsis. Subcutaneous alum pretreatment improves survival to polymicrobial sepsis in both wild-type and T and B cell-deficient neonatal mice, but not in caspase-1/11 null mice. Moreover, alum increases peritoneal macrophage and neutrophil phagocytosis, and decreases bacterial colonization in the peritoneum. Bone marrow-derived neutrophils from alum-pretreated neonates produce more neutrophil extracellular traps (NETs) and exhibit increased expression of neutrophil elastase (NE) after in-vitro stimulation with phorbol esters. In addition, alum pretreatment increases bone marrow and splenic haematopoietic stem cell expansion following sepsis. Pretreatment of neonatal mice with an alum-based adjuvant can stimulate multiple innate immune cell functions and improve survival. These novel findings suggest a therapeutic pathway for the use of existing alum-based adjuvants for preventing sepsis in premature infants.

Oral colostrum priming shortens hospitalization without changing the immunomicrobial milieu.

OBJECTIVE: Oral colostrum priming (OCP) after birth in preterm infants is associated with improved weight gain and modification of the oral immunomicrobial environment. We hypothesized that OCP would modify salivary immune peptides and the oral microbiota in preterm infants. STUDY DESIGN: We conducted a prospective, randomized clinical trial to determine the effects of OCP on salivary immune peptide representation in preterm infants (<32 weeks completed gestation at birth). Saliva samples were collected before and after OCP. Salivary immune peptide representation was determined via mass spectroscopy. Oral microbiota representation was determined via sequencing of the 16S rRNA gene. RESULTS: Neonates who received OCP (n=48) had a 16-day reduction in the median length of hospitalization as compared with infants who did not receive OCP (n=51). No differences in salivary immune peptide sequence representation before OCP between groups were found. Longitudinal changes in peptides were detected (lysozyme C, immunoglobulin A, lactoferrin) but were limited to a single peptide difference (α-defensin 1) between primed and unprimed infants after OCP. We found no difference in microbial diversity between treatment groups at any time point, but diversity decreased significantly over time in both groups. OCP treatment marginally modified oral taxa with a decline in abundance of Streptococci in the OCP group at 30 days of life. CONCLUSIONS: OCP had neither an effect on the salivary peptides we examined nor on overall oral bacterial diversity and composition. Infants who received OCP had a reduced length of hospitalization and warrants further investigation.

Great expectorations: the potential of salivary 'omic' approaches in neonatal intensive care.

Among those that require critical care, preterm neonates have the greatest limitations on available blood or body fluids for clinical or research-based assessments. Recent technological advancements have improved our ability to detect genetic, proteomic and microbial material at the nanoscale level, making analyte and biomarker assessment from even the smallest quantities possible. Saliva is a unique body fluid that not only may be noninvasively and repeatedly obtained, but also contains multiple serum components, making it promising for noninvasive assessment of the newborn. The integration of high-throughput or 'omic' approaches on neonatal saliva holds great potential to improve diagnostic and prognostic accuracy for a wide range of developmental and pathological conditions affecting the vulnerable preterm neonatal population. Herein, we review the clinical applications and technical considerations regarding the integration of salivary 'omic' technology into the neonatal intensive care unit.

Effects of low-dose dopamine on urine output in normotensive very low birth weight neonates.

OBJECTIVE: To determine the effects of low-dose dopamine on urine output (UOP) in very low birth weight premature neonates. STUDY DESIGN: Retrospective cohort study of all low-dose (3-5 µg kg(-1) per min) dopamine infusions >24-h duration in neonates 1500 g and 32 weeks gestation from August 2009 through September 2011. Linear regression was used to estimate the impact of covariates on UOP. RESULT: We identified 91 episodes of low-dose dopamine use in 65 neonates. Increased UOP occurred in 64% of episodes. Low-dose dopamine use was associated with a 0.6 ml kg(-1) h(-1) increase in UOP (P<0.001) and a 1.3 ml kg(-1)h(-1) increase when baseline UOP was <1.5 ml kg(-1) h(-1) (P<0.001). The improvement remained statistically significant after controlling for medications (diuretics and hydrocortisone) and fluid intake. CONCLUSION: Low-dose dopamine use was associated with increased UOP in very low birth weight neonates.

Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants.

OBJECTIVE: Sepsis in older children and adults modifies immune system function. We compared serotype-specific antibody responses to heptavalent pneumococcal conjugate vaccine (PCV7) in very low birth weight infants (<1500 g,VLBWs) with and without blood stream infection (BSI) during their birth hospitalization. STUDY DESIGN: Retrospective analysis of prospectively collected data for the Neonatal Research Network study of PCV7 responses among VLBWs. Infants received PCV7 at 2, 4 and 6 months after birth with blood drawn 4 to 6 weeks after third dose. Serotype antibodies were compared between infants with or without a history of BSI. Regression models were constructed with BW groups and other confounding factors identified in the primary study. RESULT: In all, 244 infants completed the vaccine series and had serum antibody available; 82 had BSI. After adjustment, BSI was not associated with reduced odds of serum antibody 0.35 µg ml(-1). CONCLUSION: BSI was not associated with reduced odds of World Health Organization-defined protective PCV7 responses in VLBWs.

Does IVIg administration yield improved immune function in very premature neonates?

Intravenous immunoglobulin (IVIg) has been evaluated as an adjunctive therapy for neonatal sepsis with modest clinical success despite strong biological plausibility. Multiple factors contribute to this outcome, but perhaps none greater than the limited immune system function in newborns, especially in the very premature neonates. For very premature neonates (<30 weeks gestational age), understanding the effects of IVIg on specific immature immune system functions is particularly relevant given their preponderance to develop sepsis and therefore potentially benefit from IVIg-mediated immunoenhancement. Here, we review the available evidence for enhanced immune function after IVIg administration in very premature neonates and highlight areas for future research.

Potential of immunomodulatory agents for prevention and treatment of neonatal sepsis.

Prevention of neonatal infection-related mortality represents a significant global challenge particularly in the vulnerable premature population. The increased risk of death from sepsis is likely due to the specific immune deficits found in the neonate as compared to the adult. Stimulation of the neonatal immune system to prevent and/or treat infection has been attempted in the past largely without success. In this review, we identify some of the known deficits in the neonatal immune system and their clinical impact, summarize previous attempts at immunomodulation and the outcomes of these interventions, and discuss the potential of novel immunomodulatory therapies to improve neonatal sepsis outcome.

Extraction of cloransulam-methyl from soil with subcritical water and supercritical CO2.

Cloransulam-methyl was extracted from soil samples with supercritical CO2, subcritical water and conventional organic solvents. Supercritical CO2 was less efficient than conventional organic solvents; polarity modifiers had no impact on extraction efficiency. Extraction with supercritical CO2 exhibited a strong temperature dependence. Water was as effective as strong organic solvents for the extraction of cloransulam-methyl; however cloransulam-methyl hydrolyzed when extracted at 150 degrees C. Extraction temperature was the most important variable in increasing the efficiency and rate of extraction, while extraction pressure was not a significant variable.