Interactions between maternal fluoxetine exposure, the maternal gut microbiome and fetal neurodevelopment in mice.

Selective serotonin reuptake inhibitors (SSRIs) are the most widely used treatment by women experiencing depression during pregnancy. However, the effects of maternal SSRI use on early offspring development remain poorly understood. Recent studies suggest that SSRIs can modify the gut microbiota and interact directly with particular gut bacteria, raising the question of whether the gut microbiome impacts host responses to SSRIs. In this study, we investigate effects of prenatal SSRI exposure on fetal neurodevelopment and further evaluate potential modulatory influences of the maternal gut microbiome. We demonstrate that maternal treatment with the SSRI fluoxetine induces widespread alterations in the fetal brain transcriptome during midgestation, including increases in the expression of genes relevant to synaptic organization and neuronal signaling and decreases in the expression of genes related to DNA replication and mitosis. Notably, maternal fluoxetine treatment from E7.5 to E14.5 has no overt effects on the composition of the maternal gut microbiota. However, maternal pretreatment with antibiotics to deplete the gut microbiome substantially modifies transcriptional responses of the fetal brain to maternal fluoxetine treatment. In particular, maternal fluoxetine treatment elevates localized expression of the opioid binding protein/cell adhesion molecule like gene Opcml in the fetal thalamus and lateral ganglionic eminence, which is prevented by maternal antibiotic treatment. Together, these findings reveal that maternal fluoxetine treatment alters gene expression in the fetal brain through pathways that are impacted, at least in part, by the presence of the maternal gut microbiota.

The maternal microbiome modulates fetal neurodevelopment in mice.

'Dysbiosis' of the maternal gut microbiome, in response to challenges such as infection1, altered diet2 and stress3 during pregnancy, has been increasingly associated with abnormalities in brain function and behaviour of the offspring4. However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain.

Pediatric supracondylar humerus fractures: is surgeon experience a surrogate for the need of open reduction?

Although there are many factors that are likely to influence the need for open reduction and percutaneous pinning (ORPF) in the treatment of pediatric supracondylar humerus fractures (SCHFs), the role of surgeon's experience (as represented by the total number of surgically treated SCHFs) on the need for ORPF has seldom been investigated. We reviewed the data on all completely displaced, pediatric SCHFs that were treated surgically by a single, fellowship-trained, pediatric orthopedic surgeon over the first 10 years of the surgeon's clinical practice. The incidence of ORPF was calculated as the percentage of open reductions among surgically treated, completely displaced, consecutive SCHFs at any given time during the 10-year period. From September 2005 to August 2015, a total of 212 completely displaced SCHFs were treated surgically at our institution by a single surgeon. When analyzing the incidence of ORPFs among surgically treated, completely displaced SCHFs at any given time, a bimodal curve was found: there was an increasing slope over the first 30 surgically treated SCHFs, with a progressive decreasing slope afterward. The incidence of ORPF within the first 10, 20, and 30 surgically treated, completely displaced SCHFs was 10.0, 30.0, and 26.7%, respectively, decreasing to 16.0, 9.0, 6.7, and 5.0% within the first 50, 100, 150, and 200 surgeries, respectively. The incidence of ORPF was almost 17-fold higher within the first 30 surgically treated, completely displaced SCHFs (17%), when compared with the following 182 (1.1%) cases (P<0.00001). Although it is likely that many factors influence the need for ORPF in the treatment of completely displaced SCHFs, surgeon's experience appears to play a significant role. Strategies aimed to accelerate the learning curve in the treatment of pediatric SCHFs should be undertaken.