Contrasting Patterns of Serologic and Functional Antibody Dynamics to Plasmodium falciparum Antigens in a Kenyan Birth Cohort

IgG antibodies to Plasmodium falciparum are transferred from the maternal to fetal circulation during pregnancy, wane after birth, and are subsequently acquired in response to natural infection. We examined the dynamics of malaria antibody responses of 84 Kenyan infants from birth to 36 months of age by (i) serology, (ii) variant surface antigen (VSA) assay, (iii) growth inhibitory activity (GIA), and (iv) invasion inhibition assays (IIA) specific for merozoite surface protein 1 (MSP1) and sialic acid-dependent invasion pathway. Maternal antibodies in each of these four categories were detected in cord blood and decreased to their lowest level by approximately 6 months of age. Serologic antibodies to 3 preerythrocytic and 10 blood-stage antigens subsequently increased, reaching peak prevalence by 36 months. In contrast, antibodies measured by VSA, GIA, and IIA remained low even up to 36 months. Infants sensitized to P. falciparum in utero, defined by cord blood lymphocyte recall responses to malaria antigens, acquired antimalarial antibodies at the same rate as those who were not sensitized in utero, indicating that fetal exposure to malaria antigens did not affect subsequent infant antimalarial responses. Infants with detectable serologic antibodies at 12 months of age had an increased risk of P. falciparum infection during the subsequent 24 months. We conclude that serologic measures of antimalarial antibodies in children 36 months of age or younger represent biomarkers of malaria exposure rather than protection and that functional antibodies develop after 36 months of age in this population.     

Lactobacillus reuteri DSM 17938 as a Probiotic for Preterm Neonates

Introduction: Prevention of necrotizing enterocolitis (NEC) while optimizing enteral nutrition (EN) is a priority in preterm neonates. Lactobacillus reuteri DSM 17938 (L reuteri) is known to improve gut motility. Previous systematic reviews have not adequately assessed the effects of L reuteri in improving feed tolerance in preterm neonates. Objective: To assess the effects of L reuteri in preterm neonates. Design: A systematic review of randomized controlled trials (RCTs) and non‐RCTs of L reuteri was conducted. We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and CINAHL databases and proceedings of Pediatric Academic Society meetings in December 2014. Results: Six RCTs (n = 1778) and 2 non‐RCTs (n = 665) were included. Meta‐analysis of RCTs estimated that the time to full feeds (mean difference [MD], –1.34 days; 95% confidence interval [CI], ?1.81 to ?0.86; 2 RCTs), duration of hospitalization (–10.77 days; 95% CI, ?13.67 to ?7.86; 3 RCTs), and late‐onset sepsis (LOS) (relative risk [RR], 0.66; 95% CI, 0.52 to 0.83; 4 RCTs) were reduced in the L reuteri group. Mortality (RR, 0.79; 95% CI, 0.57–1.09; 3 RCTs) and ≥ stage II NEC (RR, 0.69; 95% CI, 0.47–1.01; 3 RCTs) were reduced but statistically not significant. There were no adverse effects of supplementation. Both non‐RCT studies showed significant improvement in the incidence of NEC with L reuteri supplementation. Conclusions: Evidence from a limited number of studies suggests that L reuteri supplementation has the potential to reduce the risk of NEC and LOS while facilitating EN in preterm infants. Larger definitive RCTs are needed to confirm these findings.     

Ethanol metabolism by HeLa cells transduced with human alcohol dehydrogenase isoenzymes: control of the pathway by acetaldehyde concentration

Background: Human class I alcohol dehydrogenase 2 isoenzymes (encoded by the ADH1B locus) have large differences in kinetic properties; however, individuals inheriting the alleles for the different isoenzymes exhibit only small differences in alcohol elimination rates. This suggests that other cellular factors must regulate the activity of the isoenzymes. Methods: The activity of the isoenzymes expressed from ADH1B*1, ADH1B*2, and ADH1B*3 cDNAs was examined in stably transduced HeLa cell lines, including lines which expressed human low K_m aldehyde dehydrogenase (ALDH2). The ability of the cells to metabolize ethanol was compared with that of HeLa cells expressing rat class I alcohol dehydrogenase (ADH) (HeLa‐rat ADH cells), rat hepatoma (H4IIEC3) cells, and rat hepatocytes. Results: The isoenzymes had similar protein half‐lives in the HeLa cells. Rat hepatocytes, H4IIEC3 cells, and HeLa‐rat ADH cells oxidized ethanol much faster than the cells expressing the ADH1B isoenzymes. This was not explained by high cellular NADH levels or endogenous inhibitors; but rather because the activity of the β1 and β2 ADHs was constrained by the accumulation of acetaldehyde, as shown by the increased rate of ethanol oxidation by cell lines expressing β2 ADH plus ALDH2. Conclusion: The activity of the human β2 ADH isoenzyme is sensitive to inhibition by acetaldehyde, which likely limits its activity in vivo. This study emphasizes the importance of maintaining a low steady‐state acetaldehyde concentration in hepatocytes during ethanol metabolism.     

Blood-stage Plasmodium berghei infection generates a potent, specific CD8+ T-cell response despite residence largely in cells lacking MHC I processing machinery

Murine cerebral malaria is a complex disease caused by Plasmodium berghei ANKA infection. Several cell types, including CD8(+) T cells, are essential effectors of disease. Although the use of transgenic parasites expressing model antigens has revealed the induction of cytotoxic T lymphocytes (CTL) specific for these model antigens, there is no direct evidence for a response to authentic blood-stage parasite antigens, nor any knowledge of its magnitude. Our studies show that there is a dramatic primary parasite-specific CTL response, akin to viral immunity, reaching approximately 30% of splenic CD8(+) T cells, with many producing interferon-γ and tumor necrosis factor-α. These cells express granzyme B and other markers of specific responders, are cytolytic, and respond to a broad array of major histocompatibility complex (MHC) I-restricted epitopes, 5 of which are identified here. Our studies indicate that vigorous CTL responses can be induced to pathogens even when they largely reside in red blood cells, which lack MHC I processing machinery.