Adverse effects of early dexamethasone in extremely-low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network

BACKGROUND: Early administration of high doses of dexamethasone may reduce the risk of chronic lung disease in premature infants but can cause complications. Whether moderate doses would be as effective but safer is not known. METHODS: We randomly assigned 220 infants with a birth weight of 501 to 1000 g who were treated with mechanical ventilation within 12 hours after birth to receive dexamethasone or placebo with either routine ventilatory support or permissive hypercapnia. The dexamethasone was administered within 24 hours after birth at a dose of 0.15 mg per kilogram of body weight per day for three days, followed by a tapering of the dose over a period of seven days. The primary outcome was death or chronic lung disease at 36 weeks' postmenstrual age. RESULTS: The relative risk of death or chronic lung disease in the dexamethasone-treated infants, as compared with those who received placebo, was 0.9 (95 percent confidence interval, 0.8 to 1.1). Since the effect of dexamethasone treatment did not vary according to the ventilatory approach, the two dexamethasone groups and the two placebo groups were combined. The infants in the dexamethasone group were less likely than those in the placebo group to be receiving oxygen supplementation 28 days after birth (P=0.004) or open-label dexamethasone (P=0.01), were more likely to have hypertension (P<0.001), and were more likely to be receiving insulin treatment for hyperglycemia (P=0.02). During the first 14 days, spontaneous gastrointestinal perforation occurred in a larger proportion of infants in the dexamethasone group (13 percent, vs. 4 percent in the placebo group; P=0.02). The dexamethasone-treated infants had a lower weight (P=0.02) and a smaller head circumference (P=0.04) at 36 weeks' postmenstrual age. CONCLUSIONS: In preterm infants, early administration of dexamethasone at a moderate dose has no effect on death or chronic lung disease and is associated with gastrointestinal perforation and decreased growth.     

Epicutaneous immunotherapy protects cashew-sensitized mice from anaphylaxis

Background

The prevalence of tree nut allergy has increased worldwide, and cashew has become one of the most common food allergens. More critically, cashew allergy is frequently associated with severe anaphylaxis. Despite the high medical need, no approved treatment is available and strict avoidance and preparedness for prompt treatment of allergic reactions are considered dual standard of care. In the meantime, Phase III study results suggest investigational epicutaneous immunotherapy (EPIT) may be a relevant and safe treatment for peanut allergy and may improve the quality of life for many peanut allergic children.

Objective

We aimed to evaluate the capacity of EPIT to provide protection against cashew-induced anaphylaxis in a relevant mouse model.

Methods

The efficacy of EPIT was evaluated by applying patches containing cashew allergens to cashew-sensitized mice. As negative control, sham mice received patches containing excipient. Following treatment, mice were challenged orally to cashew and anaphylactic symptoms, as well as plasmatic levels of mast-cell proteases (mMCP)-1/7, were quantified.

Results

Of 16 weeks of EPIT significantly protects against anaphylaxis by promoting a faster recovery of challenged mice. This protection was characterized by a significant reduction of temperature drop and clinical symptoms, 60 minutes after challenge. This was associated with a decrease in mast-cell reactivity as attested by the reduction of mMCP-1/7 in plasma, suggesting that EPIT specifically decrease IgE-mediated anaphylaxis.

Conclusion

We demonstrate that EPIT markedly reduced IgE-mediated allergic reactions in a mouse model of cashew allergy, which suggests that EPIT may be a relevant approach to treating cashew allergy.

     

The cotton rat: an underutilized animal model for human infectious diseases can now be exploited using specific reagents to cytokines, chemokines, and interferons.

The cotton rat represents the best or only animal model for a large number of human infectious diseases, and it may be unique among small laboratory animals in its susceptibility to several potential agents of bioterrorism. Although the cotton rat is a reliable model to define pathologic changes produced during infection with human pathogens, the lack of specific reagents has precluded a more extensive analysis of the molecular basis of pathogenesis. Here, we report the cloning of 24 cotton rat genes encoding various cytokines, chemokines, and interferons (IFNs). Analysis of the expression of most of these genes was performed by RT-PCR in cotton rat macrophages during treatment with lipopolysaccharide (LPS) and in cotton rat lungs after infection with influenza virus. The availability of these reagents will provide the tools for molecular analysis of pathogenesis and immune responses to a wide variety of pathogens and set the basis for the development of new prophylactic and therapeutic strategies against human infectious diseases.     

Differential recruitment of CD8+ macrophages during Wallerian degeneration in the peripheral and central nervous system

The strong macrophage response occurring during Wallerian degeneration in the peripheral but not central nervous system has been implicated in tissue remodeling and growth factor production as key requirements for successful axonal regeneration. We have previously identified a population of CD8+ phagocytes in ischemic brain lesions that differed in its recruitment pattern from CD4+ macrophages/microglia found in other lesion paradigms. In the present study we show that crush injury to the sciatic nerve induced strong infiltration by CD8+ macrophages both at the crush site and into the degenerating distal nerve stump. At the crush site, CD8+ macrophages appeared within 24 hours whereas infiltration of the distal nerve parenchyma was delayed to the second week. CD8+ macrophages were ED1+ and CD11b+ but always MHC class II-. Most CD8+ macrophages coexpressed CD4 while a significant number of CD4+/CD8-macrophages was also present. Expression of the resident tissue macrophage marker ED2 was largely restricted to the CD4+/CD8- population. Following intraorbital crush injury to the optic nerve, infiltration of CD8+ macrophages was strictly confined to the crush site. Taken together, our study demonstrates considerable spatiotemporal diversity of CD8+ macrophage responses to axotomy in the peripheral and central nervous system that may have implications for the different extent of axonal regeneration observed in both systems.     

Usefulness of a registry of congenital malformations for genetic counseling and prenatal diagnosis

During three years, 39,924 infants born consecutively in the area covered by our registry of congenital malformations were surveyed; 775 had major congenital malformations. Recurrence risks for the major malformation was estimated and classified as high (greater than 10%, 5.3% of the cases), low (1 to 10%, 85.3% of the cases) or occasional (less than 1%, 9.4% of the malformed). Feasibility of prenatal diagnosis was considered. On the basis of the recurrence risk of 1% or higher and the feasibility of prenatal diagnosis, such a procedure should be considered in future pregnancies in 64.1% of the mothers. Genetic counseling has to be given to couples at risk of having a malformed child. For this purpose, as is shown in our study, the best way is the possibility of using a registry of congenital malformations.     

Phosphate transport by rat renal brush border membrane vesicles: Influence of dietary phosphate,thyroparathyroidectomy, and 1,25-dihydroxyvitamin D3

In the present work we have investigated whether the changes in the renal handling of inorganic phosphate (Pi) induced by 1) dietary Pi, 2) removal of parathyroid glands and 3) 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], are associated with alterations in the Na-dependent Pi uptake by brush border membrane vesicles (BBMV) isolated from renal cortex. Shamoperated (SHAM) or thyroparathyroidectomized (TPTX) rats treated or not with 26 pmol/day of 1,25 (OH)₂D₃i.p. were fed low (0.2%) or high (1.2%)P diet for 7 days. The results showed that in SHAM, TPTX and TPTX+1,25 (OH)₂D₃ the Pi uptake by BBMV was greater after low than high Pi diet. It was greater in TPTX than in SHAM counterparts fed either diets. In TPTX fed low or high Pi diet 1,25 (OH)₂D₃ decreased the Pi uptake to the level observed in SHAM. A striking parallelism was found between variations in Pi uptake by BBMV and in the tubular Pi reabsorption of the whole kidney. The Na-dependent glucose, the mannitol uptake by BBMV, and the alkaline phosphatase activity in cortical homogenates and BBMV were not affected by the various treatments. Thus, dietary Pi, chronic TPTX and 1,25 (OH)₂D₃ appear to specifically affect the Na-dependent Pi transport system bound to the brush border membranes of renal cortical tubules. The alterations observed at this membrane level could account, at least in part, for the changes induced by these three factors on the overall tubular reabsorption of Pi.     

Enhanced Pseudomonas aeruginosa biofilm development mediated by human neutrophils

Cystic fibrosis (CF) lung disease features persistent neutrophil accumulation to the airways from the time of infancy. CF children are frequently exposed to Pseudomonas aeruginosa, and by adulthood, 80% of CF patients are chronically infected. The formation of biofilms is a particularly important phenotypic characteristic of P. aeruginosa that allows for bacterial survival despite aggressive antibiotic therapy and an exuberant immune response. Here, we show that the presence of neutrophils enhances initial P. aeruginosa biofilm development over a period of 72 h through the formation of polymers comprised of actin and DNA. F-actin was found to be a site of attachment for P. aeruginosa. These actin and DNA polymers are present in CF sputum, and disruption of the polymers dispersed the associated P. aeruginosa cells and reduced biofilm development. These findings demonstrate a potential maladaptation of the primary innate response. When the host fails to eradicate the infection, cellular components from necrotic neutrophils can serve as a biological matrix to facilitate P. aeruginosa biofilm formation.