Neonatal sepsis, antibiotic therapy and later risk of asthma and allergy

Sobko T, Schiött J, Ehlin A, Lundberg J, Montgomery S, Norman M. Neonatal sepsis, antibiotic therapy and later risk of asthma and allergy. Paediatric and Perinatal Epidemiology 2010; 24: 88–92.
Neonatal sepsis and early antibiotic therapy affect bacterial colonisation and immune activation after birth. This could have implications for later risk of allergy and asthma. Using a validated questionnaire (International Study of Asthma and Allergies in Children, ISAAC), we screened for asthma and allergy in three cohorts (total n  = 834; median age 12, range 7–23 years) with different perinatal exposures as regards infection and antibiotics.
Asthma, but not hay fever, was more prevalent after neonatal sepsis with adjusted odds ratio (OR) 1.63 [95% confidence interval (CI) 1.04, 2.56] and early antibiotic therapy (OR 1.48 [0.93, 2.35]) as compared with a control group. There was a trend towards increased atopic eczema after neonatal sepsis (OR = 1.39 [CI = 0.98, 1.98]). We conclude that neonatal sepsis is associated with an increased risk for later development of asthma. Early antibiotic exposure may contribute to this association.     

Plasma lipid concentrations during episodic occupational stress

The possibility that stress affects plasma lipid concentrations has been the subject of recent investigation, but the findings are equivocal in nonlaboratory settings. To determine whether psychological stress contributes to variability in plasma lipid concentrations and concomitant changes in health behaviors, the effect of increased work load on plasma lipids and apolipoproteins was examined in 173 lawyers. Plasma cholesterol, triglyceride, and apolipoprotein concentrations were studied during periods of high work load (corresponding to impending tax deadlines) and during periods of usual work load. Self-reports of stress, work load, and time pressure, and cortisol, blood pressure, and heart rate were measured to verify that impending deadlines were associated with increased stress levels. Health behaviors which may affect plasma lipoprotein concentrations, including dietary intake and exercise, were also examined. High work load was accompanied by increases in self-reported work load among lawyers most directly affected by the impending deadlines. Plasma apolipoprotein B and triglycerides increased during periods of high work load (M = 1.9 mg/dL, SD = 10.1 and M = 5.3, SD = 34.4, respectively). No changes in dietary intake and exercise were observed. Psychological stress (high work load) is associated with potentially atherogenic changes in plasma lipid concentrations. While the lipoprotein effect of this short-term work stress is small, the effects of longer-term stress on multiple rise factors including triglycerides and apolipoprotein B could have significance for the development of coronary artery disease.     

Soluble cell adhesion molecules in monocytes of Alzheimer’s disease and mild cognitive impairment

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with characteristic neuropathological features that are accompanied by inflammatory processes and release of pro-inflammatory cytokines. There is evidence that microglial cells are a key mediator of damage in AD. The microglial compartment may arise to a greater part from activation and transmigration of circulating monocytes. The aim of the present pilot study was to explore, if different cell adhesion molecules (ICAM-1 and -3, PECAM-1, VCAM-1, P-, L- and E-selectins, E-cadherin), RAGE and CD14 are affected in monocytes of healthy subjects compared to patients suffering from AD or mild cognitive impairment (MCI). Monocytes were isolated by negative magnetic selection (MACS) from EDTA blood samples, and extracts were analyzed by Searchlight Multiplex ELISAs. When compared to healthy subjects, the ratio of monocytic ICAM-3/CD14 was significantly decreased in MCI and AD patients and the ratio of the monocytic P-selectin/CD14 was specifically decreased in AD patients. In conclusion, our data show that monocytic cell adhesion molecules are decreased in AD and MCI patients. Further larger longitudinal studies should then clarify whether any of these parameters may be useful as a diagnostic biomarker.     

Production of proinflammatory and immunoregulatory cytokines by inflammatory cells from periapical lesions in culture

Background:  The role of cytokines in pathogenesis of periapical lesions is not well understood. The aim of this study was to study the correlation between proinflammatory and immunoregulatory cytokines in periapical lesions and their relationship with cellular composition and clinical presentation.
Methods:  Inflammatory cells were isolated from 67 human periapical lesions and cultivated for 24 h. The levels of proinflammatory cytokines: interleukin-1 beta (IL-1β), IL-6, IL-8 and tumour necrosis factor alpha (TNF-α) and immunoregulatory cytokines: transforming growth factor-beta (TGF-β) and IL-10 were determined in culture supernatants using a fluorescent bead immunoassay or ELISA. The phenotype of cells was analysed by immunocytochemistry.
Results:  Inflammatory cells from symptomatic lesions which contained higher proportion of granulocytes, secreted higher levels of IL-1, IL-6 and IL-8 compared with asymptomatic lesions. Large-size lesions contained lower percentages of mononuclear phagocytes, higher percentages of CD8⁺ T cells and produced higher levels of TNF-α, IL-6 and IL-10 compared with small-size lesions. There were negative correlations between the concentrations of TGF-β and proinflammatory cytokines. TGF-β, added to cultures, downregulated the levels of proinflammatory cytokines more strongly than IL-10, independently of clinical presentation of the lesions. By contrast, exogenous IL-10 was mainly immunosuppressive in cultures of asymptomatic lesions.
Conclusion:  Symptomatic lesions are characterized by higher production of proinflammatory cytokines. Immunoregulatory cytokines are more important for suppression of inflammation in asymptomatic lesions and in this context the effect of TGF-β is more potent and different from IL-10.     

Binding-site mutations in the α1 subunit of the inhibitory glycine receptor convert the inhibitory metal ion Cu into a positive modulator

The divalent cation copper (Cu²⁺) has been shown to inhibit chloride currents mediated by the inhibitory glycine receptor (GlyR). Here, we analyzed Cu²⁺ inhibition of homo- and hetero-oligomeric GlyRs expressed in Xenopus oocytes. No significant differences in Cu²⁺ inhibitory potency were found between α1, α2 and α3 GlyRs as well as heteromeric α1β receptors. Furthermore, GlyR α1 mutations known to reduce inhibition or potentiation of GlyR currents by Zn²⁺ had no effect on Cu²⁺ inhibition. However, Cu²⁺ was found to competitively antagonize glycine binding, suggesting that Cu²⁺ binds at the agonist-binding site. Mutations within the glycine-binding site of the GlyR α1 subunit reduced the inhibitory potency of Cu²⁺ and led to an up to 4-fold potentiation of glycine-elicited currents by Cu²⁺. Molecular dynamics simulation suggests this to be due to increased Cu²⁺ binding energies. Our data show that GlyR binding-site mutations can convert inhibitors of agonist binding into highly effective positive modulators.