Melatonin as an immunomodulator in children with Down syndrome.

BACKGROUND: Down syndrome (DS) is a disorder characterised by marked immune dysfunction, increased mortality from sepsis, chronic inflammation, increased oxidative stress, sleep disturbance and possibly abnormal endogenous melatonin levels. Melatonin has a myriad of immune functions, and we hypothesised that this therapeutic agent could modulate the innate immune system in this cohort. METHODS: We investigated neutrophil and monocyte function (CD11b, TLR4 expression by flow cytometry), genes involved in TLR signalling (MyD88, IRAK4, TRIF), the inflammasome (NLRP3, IL-1ß), and circadian rhythm (BMAL, CLOCK, CRY) by qPCR, and inflammatory cytokines (IL-2, IL-6, IL-8, IL-18, IL-1ß, TNF-α, IFN-γ, IL-10, IL-1ra, VEGF, Epo, GM-CSF) by enzyme-linked immunosorbent assay (ELISA) following immunomodulation with LPS endotoxin and melatonin. 47 children with DS and 23 age- and sex-matched controls were recruited. RESULTS: We demonstrated that melatonin has several significant effects by reducing CD11b and TLR4 expression, attenuating TLR signalling, genes involved in the inflammasome and has the potential to reduce LPS-induced inflammatory responses. CONCLUSIONS: Immunomodulatory effects of melatonin were found in both paediatric cohorts with more marked effects in the children with DS. Melatonin mediates immune response through a wide array of mechanisms and this immunomodulator may buffer the inflammatory response by regulating pro and anti-inflammatory signalling. IMPACT: We highlight that melatonin mediates its immune response through a wide array of mechanisms, its effects appear to be dose dependant and children with Down syndrome may be more receptive to treatment with it. Immunomodulatory effects of melatonin were demonstrated with marked effects in the children with Down syndrome with a reduction of MyD88, IL-1ß and NLRP3 expression in whole-blood samples. Melatonin is a proposed anti-inflammatory agent with a well-established safety profile, that has the potential for mitigation of pro- and anti-inflammatory cytokines in paediatric Down syndrome cohorts, though further clinical trials are warranted.

Psychotropic medication use and future unexplained and injurious falls and fracture amongst community-dwelling older people: data from TILDA.

PURPOSE: Psychotropic medications (antidepressants, anticholinergics, benzodiazepines, 'Z'-drugs and antipsychotics) are frequently identified as Falls Risk Increasing Drugs. The aim of this study is to clarify the association of psychotropic medication use with future falls/fracture amongst community-dwelling older people. METHODS: Participants ≥ 65 years from TILDA were included and followed from Waves 1 to 5 (8-year follow-up). Incidence of falls (total falls/unexplained/injurious) and fracture was by self-report; unexplained falls were falls not caused by a slip/trip, with no apparent cause. Poisson regression models reporting incidence rate ratios (IRR) assessed the association between medications and future falls/fracture, adjusted for relevant covariates. RESULTS: Of 2809 participants (mean age 73 years), 15% were taking ≥ 1 psychotropic medication. During follow-up, over half of participants fell, with 1/3 reporting injurious falls, over 1/5 reporting unexplained falls and almost 1/5 reporting fracture. Psychotropic medications were independently associated with falls [IRR 1.15 (95% CI 1.00-1.31)] and unexplained falls [IRR 1.46 (95% CI 1.20-1.78)]. Taking ≥ 2 psychotropic medications was further associated with future fracture (IRR 1.47 (95% CI 1.06-2.05)]. Antidepressants were independently associated with falls [IRR 1.20 (1.00-1.42)] and unexplained falls [IRR 2.12 (95% CI 1.69-2.65)]. Anticholinergics were associated with unexplained falls [IRR 1.53 (95% CI 1.14-2.05)]. 'Z'-drug and benzodiazepine use were not associated with falls or fractures. CONCLUSION: Psychotropic medications, particularly antidepressants and anticholinergic medications, are independently associated with falls and fractures. Regular review of ongoing need for these medications should therefore be central to the comprehensive geriatric assessment.