Lithium rescues cultured rat metatarsals from dexamethasone-induced growth failure.

BACKGROUND: Glucocorticoids are commonly used in children with different chronic diseases. Growth failure represents a so far untreatable undesired side-effect. As lithium chloride (LiCl) is known to induce cell renewal in various tissues, we hypothesized that LiCl may prevent glucocorticoid-induced growth failure. METHODS: We monitored growth of fetal rat metatarsals cultured ex-vivo with dexamethasone and/or LiCl, while molecular mechanisms were explored through RNA sequencing by implementing the differential gene expression and gene set analysis. Quantification of ß-catenin in human growth plate cartilage cultured with dexamethasone and/or LiCl was added for verification. RESULTS: After 14 days of culture, the length of dexamethasone-treated fetal rat metatarsals increased by 1.4 ± 0.2 mm compared to 2.4 ± 0.3 mm in control bones (p < 0.001). The combination of LiCl and dexamethasone led to bone length increase of 1.9 ± 0.3 mm (p < 0.001 vs. dexamethasone alone). By adding lithium, genes for cell cycle and Wnt/ß-catenin, Hedgehog and Notch signaling, were upregulated compared to dexamethasone alone group. CONCLUSIONS: LiCl has the potential to partially rescue from dexamethasone-induced bone growth impairment in an ex vivo model. Transcriptomics identified cell renewal and proliferation as candidates for the underlying mechanisms. Our observations may open up the development of a new treatment strategy for bone growth disorders. IMPACT: LiCl is capable to prevent glucocorticoid-induced growth failure in rat metatarsals in vitro. The accompanying drug-induced transcriptomic changes suggested cell renewal and proliferation as candidate underlying mechanisms. Wnt/beta-catenin pathway could be one of those novel mechanisms.

Frequency of moderate-to-severe obstructive sleep apnea syndrome among children with snoring and blood pressure in the hypertensive range.

BACKGROUND: It is recommended that children with hypertension and loud snoring should be referred for polysomnography. We aimed to compare the frequency of moderate-to-severe obstructive sleep apnea syndrome (OSAS) among snorers with and without hypertension. Thus, it was hypothesized that systolic or diastolic hypertension among children with snoring is a risk factor for moderate-to-severe OSAS. METHODS: Data of children with snoring and adenotonsillar hypertrophy and/or obesity referred for polysomnography were retrospectively analyzed. Blood pressure (BP) was measured three times in the morning after polysomnography and percentiles were calculated for the average of the second and third measurement. Association of systolic or diastolic hypertension with moderate-to severe OSAS (apnea-hypopnea index-AHI > 5 episodes/h) adjusted for age and obesity was assessed by logistic regression. RESULTS: Data of 646 children with snoring (median age, 6.5 years; 3-14.9 years; 25.7% obese) were analyzed. Prevalence of systolic or diastolic hypertension was 14.1% and 16.1%, respectively and frequency of AHI > 5 episodes/h was 18.3%. Systolic hypertension was a significant predictor of moderate-to-severe OSAS (OR 1.87; 95% CI 1.10 to 3.17; P = 0.02) after adjustment for age and obesity, but diastolic hypertension was not (OR, 0.96; 0.55 to 1.67; P > 0.05). Odds of AHI > 5 episodes/h prior to considering systolic hypertension was 0.25 and after considering its presence, increased to 0.46 (Bayes' theorem), or for every three children with systolic hypertension and snoring tested, one had AHI > 5 episodes/h. CONCLUSIONS: In the context of systolic hypertension and snoring, referral for polysomnography to rule out moderate-to-severe OSAS is a clinically productive practice.

Bone Mineral Density in Survivors of Childhood Cancer: A Meta-Analysis.

CONTEXT: There is an increasing population of childhood cancer survivors (CCS) at risk for treatment-related toxicities, including skeletal morbidities. Bone mineral density (BMD) is a proxy for bone health and reductions are associated with osteoporosis and fractures. OBJECTIVE: To investigate bone health in CCS by conducting a systematic review and meta-analysis of BMD after completed treatments. DATA SOURCES: We searched Medline, Embase, Cochrane, and Web of Science in May 2019 and updated in May 2023. STUDY SELECTION: Studies reporting BMD Z-scores measured with dual-energy x-ray absorptiometry in CCS after treatment completion. DATA EXTRACTION: We performed a pooled analysis of studies reporting BMD Z-scores and thereafter we analyzed studies comparing BMD in survivors and healthy controls. All analyses were performed based on the site of BMD measurement. RESULTS: Of 4243 studies, 84 were included (N = 8106). The mean time off-treatment across the studies ranged from 2 months to 24 years. The overall pooled mean Z-score was -0.57 (95% confidence interval [CI] -0.59 to -0.55) in the whole-body, -0.84 (95% CI -0.86 to -0.83) in the lumbar spine, -0.79 (95% CI -0.81 to -0.77) in the femoral neck and -0.14 (95% CI -0.18 to -0.11) in the total hip. When comparing survivors with controls, BMD was significantly lower in survivors at all sites. LIMITATIONS: English publications, study-level meta-analysis. CONCLUSIONS: We showed a significant reduction of BMD Z-scores in CCS. Given the increased fracture risk already within -1 SD, these results emphasize the need for BMD surveillance and secondary prevention in CCS.

Humanin Treatment Protects Against Venetoclax-Induced Bone Growth Retardation in Ex Vivo Cultured Rat Bones.

Context: Recent preclinical studies reported that the BCL-2 inhibitor venetoclax can impair bone growth. A strategy to prevent such a side effect of this promising anticancer drug is highly desired. Earlier in vitro and in vivo studies suggested that the mitochondrial peptide humanin has the potential to prevent drug-induced growth impairment. Objective: We hypothesized that co-treatment with the humanin analog HNG may prevent venetoclax-induced bone growth impairment. Methods: Ex vivo studies were performed in fetal rat metatarsal bones and human growth plate samples cultured for 12 and 2 days, respectively, while in vivo studies were performed in young neuroblastoma mice being treated daily for 14 days. The treatment groups included venetoclax, HNG, venetoclax plus HNG, or vehicle. Bone growth was continuously monitored and at the end point, histomorphometric and immunohistochemical analyses were performed in fixed tissues. Results: Venetoclax suppressed metatarsal bone growth and when combined with HNG, bone growth was rescued and all histological parameters affected by venetoclax monotherapy were normalized. Mechanistic studies showed that HNG downregulated the pro-apoptotic proteins Bax and p53 in cultured metatarsals and human growth plate tissues, respectively. The study in a neuroblastoma mouse model confirmed a growth-suppressive effect of venetoclax treatment. In this short-term in vivo study, no significant bone growth-rescuing effect could be verified when testing HNG at a single dose. We conclude that humanin dose-dependently protects ex vivo cultured metatarsal bones from venetoclax-induced bone growth impairment by restoring the growth plate microstructure.

Pharmacological inhibition of BCL-2 with the FDA-approved drug venetoclax impairs longitudinal bone growth.

Treatment-related skeletal complications are common in childhood cancer patients and survivors. Venetoclax is a BCL-2 inhibitor that has shown efficacy in hematological malignancies in adults and is being investigated in pediatric cancer clinical trials as a promising therapeutic modality. Venetoclax triggers cell death in cancer cells, but whether it exerts similar effects in normal bone cells, is unknown. Chondrogenic ATDC5 cells, E20 fetal rat metatarsal bones, and human growth plate biopsies were treated with different concentrations of venetoclax. Female NMRI nu/nu mice were treated with venetoclax or vehicle for 15 days. Mice were X-rayed at baseline and at the end of the experiment to assess longitudinal bone growth and body weight was monitored throughout the study. Histomorphometric and immunohistochemical analyses were performed to evaluate treatment effects on the growth plate cartilage. Venetoclax decreased the viability of chondrocytes and impaired the growth of ex vivo cultured metatarsals while reducing the height of the resting/proliferative zone and the hypertrophic cell size. When tested in vivo, venetoclax suppressed bone growth and reduced growth plate height. Our experimental data suggest that venetoclax directly targets growth plate chondrocytes suppressing bone growth and we, therefore, encourage careful monitoring of longitudinal bone growth if treating growing children with venetoclax.

Bone health in glucocorticoid-treated childhood acute lymphoblastic leukemia.

Glucocorticoids (GCs) are widely used in the treatment of childhood acute lymphoblastic leukemia (ALL), but their long-term use is also associated with bone-related morbidities. Among others, growth deficit, decreased bone mineral density (BMD) and increased fracture rate are well-documented and severely impact quality of life. Unfortunately, no efficient treatment for the management of bone health impairment in patients and survivors is currently available. The overall goal of this review is to discuss the existing data on how GCs impair bone health in pediatric ALL and attempts made to minimize these side effects.

Antihistamines in the Management of Pediatric Allergic Rhinitis: A Systematic Review.

BACKGROUND: The clinical benefit of newer antihistamines (AHs) versus other active treatments has not been assessed in pediatric patients with allergic rhinitis. METHODS: A systematic literature search was performed in MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials from inception through August 2020. Randomized controlled trials (RCTs) comparing newer with older AHs, corticosteroids, or montelukast were included. The Cochrane Risk of Bias Tool was used for quality assessment. RESULTS: Out of 10,656 citations, 16 RCTs (N = 1653) with a duration from 10 days to 3 months were included. When compared with older-generation AHs, the administration of newer AHs did not confer significant benefit and appeared less effective compared with intranasal corticosteroids. However, newer AHs were more potent in achieving symptom control compared with montelukast. Data regarding quality of life were generally missing. The incidence of adverse events was low in all treatment groups. The included RCTs were characterized by moderate risk of bias. CONCLUSIONS: Newer AHs are effective in symptom control and well tolerated in the pediatric population. However, inadequate reporting, variation in outcome measures, and a paucity of sufficient randomized comparisons precluded us from quantifying the relative efficacy of newer AHs compared with other treatment options.