Multidisciplinary Management of Pediatric Sports-Related Concussion.

OBJECTIVES: To summarize the clinical characteristics and outcomes of pediatric sports-related concussion (SRC) patients who were evaluated and managed at a multidisciplinary pediatric concussion program and examine the healthcare resources and personnel required to meet the needs of this patient population. METHODS: We conducted a retrospective review of all pediatric SRC patients referred to the Pan Am Concussion Program from September 1st, 2013 to May 25th, 2015. Initial assessments and diagnoses were carried out by a single neurosurgeon. Return-to-Play decision-making was carried out by the multidisciplinary team. RESULTS: 604 patients, including 423 pediatric SRC patients were evaluated at the Pan Am Concussion Program during the study period. The mean age of study patients was 14.30 years (SD: 2.32, range 7-19 years); 252 (59.57%) were males. Hockey (182; 43.03%) and soccer (60; 14.18%) were the most commonly played sports at the time of injury. Overall, 294 (69.50%) of SRC patients met the clinical criteria for concussion recovery, while 75 (17.73%) were lost to follow-up, and 53 (12.53%) remained in active treatment at the end of the study period. The median duration of symptoms among the 261 acute SRC patients with complete follow-up was 23 days (IQR: 15, 36). Overall, 25.30% of pediatric SRC patients underwent at least one diagnostic imaging test and 32.62% received referral to another member of our multidisciplinary clinical team. CONCLUSION: Comprehensive care of pediatric SRC patients requires access to appropriate diagnostic resources and the multidisciplinary collaboration of experts with national and provincially-recognized training in TBI.

Binding of AP-2 and ETS-domain family members is associated with enhancer activity in the hypersensitive site III region of the human growth hormone/chorionic somatomammotropin locus.

The human GH gene family is specifically expressed in somatotrophs of the anterior pituitary and placental syncytiotrophoblast. Two nuclease-hypersensitive sites, HS III and HS V, are associated with a region of chromatin located 28 and 30 kb upstream of the pituitary GH gene transcription initiation site (+1) in both pituitary and placenta nuclei. A role for this region in pituitary GH gene expression has been reported, but the potential relevance to placental gene expression has not been determined. Deletion analysis of a 5.2-kb region (nucleotides - 27,568/-32,746) containing HS III to V-related sequences localized significant enhancer activity to a 574-bp HS III fragment (nucleotides -27,676/-28,249) in multiple transfected cell lines. Four nuclease-protected regions [footprints (FP) 1-4] were identified in the 574-bp fragment. FP2 and FP3 were detected with placenta cell nuclear protein, whereas FP1 and FP4 were observed with placental and nonplacental cell nuclear extract. Disruption of FP1 had no effect on heterologous promoter activity in transfected pituitary and placental cells, whereas loss of FP2 and FP3 resulted in modest increases in placental cells, reflecting the presence of repressor activity associated with these regions in vitro. In contrast, disruption of the FP4 region by mutation or deletion significantly reduced enhancer activity. As a result, 30-fold enhancer activity was localized to a 41-bp region in transfected placental tumor cells. Binding of candidate proteins, activator protein (AP)-2 (FP3) and Elk-1 (FP4), was confirmed using competition assays with specific oligonucleotides and antibodies. Moreover, these factors were associated with the hyperacetylated HS III region in human pituitary [activator protein 2 (AP-2) and Elk-1] and term placenta (AP-2) chromatin. These data implicate AP-2 and ETS-domain family members in the regulation of the GH/CS locus and raise the possibility that different complexes form in the HS III region in placenta and pituitary cells.

RFX1 and NF-1 associate with P sequences of the human growth hormone locus in pituitary chromatin.

The human GH family consists of five genes, including the placental chorionic somatomammotropins (CS), within a single locus on chromosome 17. Based on nuclease sensitivity, the entire GH/CS locus is accessible in pituitary chromatin, yet only GH-N is expressed. Previously, we reported a P sequence element (263P) capable of repressing placental CS promoter activity in transfected pituitary (GC) cells. Regions of protein binding within 263P include P sequence elements A and B (PSE-A and PSE-B), and we reported nuclear factor-1 (NF-1) recognition of PSE-B. We now provide evidence for multiple interactions on PSE-A, including binding of the regulatory factor X (RFX) family. Disruption of the RFX site within 263P blunts repressor activity in transfected GC cells; however, repression is only abolished when both PSE-A/RFX and PSE-B/NF-1 sites are mutated. The capacity of RFX and NF-1 to participate in a novel common complex is further suggested by coimmunoprecipitation of RFX1 and epitope-tagged NF-1 family members. Finally, we confirm the association of NF-1 and RFX1 with P sequences in human pituitary tissue by chromatin immunoprecipitation. Taken together, our data suggest that an inverse relationship exists between 263P and CS promoter histone hyperacetylation and the association of these factors in vivo.