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Bloodstream infections exacerbate incidence and severity of symptomatic glucocorticoid-induced osteonecrosis.

ABSTRACT: BACKGROUND:Osteonecrosis is a common toxicity associated with glucocorticoid (e.g., dexamethasone and prednisone) treatment of children with acute lymphoblastic leukemia (ALL), but risk factors are incompletely defined. Infections are also a common complication of ALL therapy. Lipopolysaccharide (LPS) is used experimentally to mimic infection-related systemic effects. To our knowledge, the contribution of systemic infections to the risk of glucocorticoid-induced osteonecrosis has not been investigated. PROCEDURE:Patients with ALL on St. Jude Total Therapy XV (n = 365) were assessed for documented bacteremia prior to development of osteonecrosis, which was confirmed by MRI, and graded using the National Cancer Institute's Common Terminology for Adverse Events (version 3.0). In a preclinical model, Balb/cJ mice treated with dexamethasone plus or minus LPS were assessed for frequency and severity of osteonecrosis and arteriopathy. RESULTS:We found that patients with ALL who experienced bacteremia had a higher frequency of symptomatic osteonecrosis (?grade 2) than those who did not (OR: 1.88; 95% CI, 1.03-3.41, P = 0.038). LPS exacerbated experimental dexamethasone-induced osteonecrosis. Mice treated with dexamethasone plus LPS had a higher incidence of osteonecrosis (P = 0.00086) and arteriopathy (P = 0.0047) than did those treated with dexamethasone alone, and the severity of osteonecrosis (P = 0.00045) and arteriopathy (P = 0.0048) was also more pronounced with the addition of LPS treatment. The increase in osteonecrosis was not explained by any alteration of dexamethasone pharmacokinetics by LPS. CONCLUSIONS:These data identify systemic infection during ALL therapy as a novel risk factor in the development of glucocorticoid-induced osteonecrosis.

SUBMITTER: Finch ER

PROVIDER: S-EPMC6472979 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Bloodstream infections exacerbate incidence and severity of symptomatic glucocorticoid-induced osteonecrosis.

Finch Emily R ER Janke Laura J LJ Smith Colton A CA Karol Seth E SE Pei Deqing D Cheng Cheng C Kaste Sue C SC Inaba Hiroto H Pui Ching-Hon CH Wolf Joshua J Relling Mary V MV

Pediatric blood & cancer 20190213 6

<h4>Background</h4>Osteonecrosis is a common toxicity associated with glucocorticoid (e.g., dexamethasone and prednisone) treatment of children with acute lymphoblastic leukemia (ALL), but risk factors are incompletely defined. Infections are also a common complication of ALL therapy. Lipopolysaccharide (LPS) is used experimentally to mimic infection-related systemic effects. To our knowledge, the contribution of systemic infections to the risk of glucocorticoid-induced osteonecrosis has not bee ...[more]

PMID: 30758124

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Project description:BackgroundGlucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common disease in osteoarticular surgery, with a high disability rate, which brings great physical and mental pain and economic burden to patients. Its specific pathogenesis has not been fully demonstrated, and there is a lack of recognized effective biomarkers for earlier detection and prompt treatment. This has become an urgent clinical problem for orthopedic scholars.Materials and methodsWe downloaded the gene expression profile dataset GSE123568 from the Gene Expression Omnibus database, used STRING and Cytoscape to carry out module analysis and built a gene interaction network. The four core genes most related to GIONFH in this network were ultimately found out by precise analysis and animal experiment were then conducted for verification. In this verification process, thirty-six New Zealand white rabbits were randomly divided into blank control group, model group and drug group. Except for the blank control group, the animal model of GIONFH was established by lipopolysaccharide and methylprednisolone, while the drug group was given the lipid-lowering drugs for intervention as planned. The rabbits were taken for magnetic resonance imaging at different stages, and their femoral head specimens were taken for pathological examination, then the expression of target genes in the femoral head specimens of corresponding groups was detected. Validation methods included RT-PCR and pathological examination.ResultsA total of 679 differential genes were selected at first, including 276 up-regulated genes and 403 down-regulated genes. Finally, four genes with the highest degree of correlation were screened. Animal experiment results showed that ASXL1 and BNIP3L were in low expression, while FCGR2A and TYROBP were highly expressed.ConclusionThrough animal experiments, it was confirmed that ASXL1, BNIP3L, FCGR2A and TYROBP screened from the comparative analysis of multiple genes in the database were closely related to GIONFH, which is important for early diagnosis of Glucocorticoid-induced osteonecrosis of the femoral head.

Project description:BackgroundWe conducted for the first time a systematic review, including a meta-analysis, of the incidence of symptomatic rotavirus (RV) infections, because (1) it was shown to be an influential factor in estimating the cost-effectiveness of RV vaccination, (2) multiple community-based studies assessed it prospectively, (3) previous studies indicated, inconclusively, it might be similar around the world.MethodologyPubmed (which includes Medline) was searched for surveys assessing prospectively symptomatic (diarrheal) episodes in a general population and situation, which also reported on the number of the episodes being tested RV+ and on the persons and the time period observed. A bias assessment tool was developed and used according to Cochrane guidelines by 4 researchers with different backgrounds. Heterogeneity was explored graphically and by comparing fits of study-homogenous 'fixed effects' and -heterogeneous 'random effects' models. Data were synthesized using these models. Sensitivity analysis for uncertainty regarding data abstraction, bias assessment and included studies was performed.Principal findingsVariability between the incidences obtained from 20 studies is unlikely to be due to study groups living in different environments (tropical versus temperate climate, slums versus middle-class suburban populations), nor due to the year the study was conducted (from 1967 to 2003). A random effects model was used to incorporate unexplained heterogeneity and resulted in a global incidence estimate of 0.31 [0.19; 0.50] symptomatic RV infections per personyear of observation for children below 2 years of age, and of 0.24 [0.17; 0.34] when excluding the extreme high value of 0.84 reported for Mayan Indians in Guatemala. Apart from the inclusion/exclusion of the latter study, results were robust.Conclusions/significanceRather than assumptions based on an ad-hoc selection of one or two studies, these pooled estimates (together with the measure for variability between populations) should be used as an input in future cost-effectiveness analyses of RV vaccination.

Project description:Objective:Glucocorticoids (GCs) are commonly prescribed as treatment for chronic inflammatory diseases. Prolonged use of GCs is a common cause of atraumatic osteonecrosis (ON) and secondary osteoporosis. Currently, there is no effective treatment for this disease; therefore, a reliable animal model would be useful to study both the pathology and novel treatment strategies for patients with the disease. The aim of this study was to establish a validated, reproducible model of GC-induced ON and bone loss in two different mouse strains (BALB/c and C57BL/6). Methods:Seven-week-old male BALB/c (n = 32) and male C57BL/6 mice (n = 32) were randomised into placebo or GC groups and treated with daily 4 mg/L oral dexamethasone in drinking water for 90 days. Study outcome measures included histologic assessment of ON of the distal femur, bone mass and mechanical strength of tibia and lumbar vertebral body, osteoclast number, biochemical measure of bone formation and bone marrow fat quantitation. Results:GC-induced ON lesions were observed in the distal femur in 47% of the male BALB/c mice and 25% of the male C57BL/6 mice. GC treatment decreased the trabecular bone volume and serum pro-collagen type 1N-protease (P1NP) in BALB/c mice compared with the placebo (p < 0.05) and reduced tibial bone strength in both BALB/c and C57BL/6 mice. GC-treated BALB/c mice had significantly greater marrow fat levels compared to the placebo group. Conclusion:GC-induced ON was more prevalent in the male BALB/c mice compared to the male C57BL/6 mice. GC treatment significantly reduced bone mass, bone formation measured by P1NP, bone strength and increased marrow fat levels in male BALB/c mice. Therefore, the use of male BALB/c mice strain is recommended for both diagnostic and therapeutic studies for the prevention and treatment of ON and bone loss following prolonged treatment with GCs. The Translational Potential of this Article:GCs are commonly used to treat patients with various chronic inflammatory diseases, and this is associated with both the development of ON and bone loss. Our study confirmed that the BALB/c mouse strain treated for 90 days with GC may be useful for developing novel treatments for ON.

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Bloodstream infections exacerbate incidence and severity of symptomatic glucocorticoid-induced osteonecrosis.

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Bloodstream infections exacerbate incidence and severity of symptomatic glucocorticoid-induced osteonecrosis.

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