FGF Signaling Regulates Development of the Anterior Fontanelle.

The calvarial bones of the infant skull are connected by transient fibrous joints known as sutures and fontanelles, which are essential for reshaping during birth and postnatal growth. Genetic disorders such as Apert, Pfeiffer, Crouzon, and Bent bone dysplasia linked to FGFR2 variants often exhibit multi-suture craniosynostosis and a persistently open anterior fontanelle (AF). This study leverages mouse genetics and single-cell transcriptomics to determine how Fgfr2 regulates closure of the AF closure and its transformation into the frontal suture during postnatal development. We find that cells of the AF, marked by the tendon/ligament factor SCX, are spatially restricted to ecto- or endocranial domains and undergo regionally selective differentiation into ligament, bone, and cartilage. Differentiation of SCX+ AF cells is dependent on FGFR2 signaling in cells of the osteogenic fronts which, when fueled by FGF18 from the ectocranial mesenchyme, express the secreted WNT inhibitor WIF1 to regulate WNT signaling in neighboring AF cells. Upon loss of Fgfr2 , Wif1 expression is lost, and cells of the AF retain a connective tissue-like fate failing to form the posterior frontal suture. This study provides new insights into regional differences in suture development by identifying an FGF-WNT signaling circuit within the AF that links frontal bone advancement with suture joint formation.

Fibroblast growth factor 2.

Fibroblast Growth Factor 2 (FGF2), also known as basic fibroblast growth factor, is a potent stimulator of growth and differentiation in multiple tissues. Its discovery traces back over 50 years ago when it was first isolated from bovine pituitary extracts due to its ability to stimulate fibroblast proliferation. Subsequent studies investigating the genomic structure of FGF2 identified multiple protein isoforms, categorized as the low molecular weight and high molecular weight FGF2. These isoforms arise from alternative translation initiation events and exhibit unique molecular and cellular functions. In this concise review, we aim to provide an overview of what is currently known about the structure, expression, and functions of the FGF2 isoforms within the contexts of development, homeostasis, and disease.

A screen of small molecule and genetic modulators of life span in female Drosophila identifies etomoxir, RH5849 and unanticipated temperature effects.

Mifepristone increases life span in female Drosophila melanogaster, and its molecular target(s) remain unclear. Here small molecule and genetic interventions were tested for ability to mimic mifepristone, or to decrease life span in a way that can be rescued by mifepristone. Etomoxir inhibits lipid metabolism, and significantly increased life span in virgin and mated females, but not males, at 50 µM concentration. Pioglitazone is reported to activate both mammalian PPARγ and its Drosophila homolog Eip75B. Pioglitazone produced minor and inconsistent benefits for female Drosophila life span, and only at the lowest concentrations tested. Ecdysone is a Drosophila steroid hormone reported to regulate responses to mating, and RH5849 is a potent mimic of ecdysone. RH5849 reduced virgin female life span, and this was partly rescued by mifepristone. Mifepristone did not compete with RH5849 for activation of an ecdysone receptor (EcR)-responsive transgenic reporter, indicating that the relevant target for mifepristone is not EcR. The conditional GAL4/GAL80ts system was used in attempt to test the effect of an Eip75B RNAi construct on female life span. However, the 29°C temperature used for induction reduced or eliminated mating-induced midgut hypertrophy, the negative life span effects of mating, and the positive life span effects of mifepristone. Even when applied after mating was complete, a shift to 29°C temperature reduced mating-induced midgut hypertrophy by half, and the life span effects of mating by 4.8-fold. Taken together, these results identify promising small molecules for further analysis, and inform the design of experiments involving the GAL4/GAL80ts system.

Mifepristone Increases Life Span in Female Drosophila Without Detectable Antibacterial Activity.

Mifepristone dramatically increases the life span of mated female Drosophila while reducing the expression of innate immune response genes. Previous results indicated that mifepristone also reduced the load of aero-tolerant bacteria in mated females. Experiments were conducted to further investigate the possible role of bacteria in mifepristone life span effects. Life span was assayed in flies grown from sterilized eggs on autoclaved media and in normally cultured controls in two independent assays. Sterilization increased mated female life span (+8.3% and +57%, respectively), and the effect of mifepristone was additive (+53% and +93%, respectively). High-throughput sequencing of 16S sequences revealed that sterilization reduced the abundance of multiple species and the classes Bacteroidia, Bacilli, Actinobacteria, and Cytophagia. By contrast, mifepristone caused no decreases and instead increased the abundance of three species. Five aero-tolerant bacterial species were cultured from extracts of mated female flies, including both Gram-positive and Gram-negative species (Acetobacter sicerae, Enterococcus faecalis, Lactobacillus plantarum, Serratia rubidea, and Paenibacillus glucanolyticus). There was no detectable effect of mifepristone on the growth of these bacteria in vitro, indicating that mifepristone does not have a direct antibiotic effect. To test if antibiotics could mimic the effects of mifepristone in vivo, mated female flies were treated throughout adult life span with high concentrations of the individual antibiotics doxycycline, ampicillin, kanamycin, and streptomycin, in replicate experiments. No significant effect on life span was observed for ampicillin, kanamycin, or streptomycin, and an inconsistent benefit was observed for doxycycline. Finally, supplementation of media with Enterococcus faecalis did not alter adult female life span in the presence or absence of mifepristone. Taken together, the results indicate the life span benefits of mifepristone are not due to an antibiotic effect.

Which general functional outcome measure does a better job of capturing change in clinical status in pelvic and acetabular fracture patients? An analysis of responsiveness over the first year of recovery.

OBJECTIVE: To compare the responsiveness of the Short Form-36 (SF-36) physical component score (PCS) to the Short Musculoskeletal Function Assessment (SMFA) dysfunction index (DI) in pelvic and acetabular fracture patients over multiple time points in the first year of recovery. DESIGN: Prospective cohort study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Four hundred seventy-three patients with surgically treated pelvic and acetabular fractures (Orthopaedic Trauma Association B or C-type pelvic ring disruption or acetabular fracture) were enrolled into the center's prospective orthopaedic trauma database between January 2005 and February 2015. Functional outcome data were collected at baseline, 6 months, and 12 months. MAIN OUTCOME MEASUREMENTS: Evaluation was performed using the SF-36 Survey and Short Musculoskeletal Function Assessment. Responsiveness was assessed by calculating the standard response mean (SRM), the minimal clinically important difference (MCID), and floor and ceiling effects. RESULTS: Three hundred five patients had complete data for both outcome scores. SF-36 PCS and SMFA DI scores showed strong correlation for all time intervals (r = -0.55 at baseline, r = -0.78 at 6 months, and r = -0.85 at 12 months). The SRM of the SF-36 PCS was greater in magnitude than the SRM of SMFA DI at all time points; this was statistically significant between baseline and 6 months (P < .001), but not between 6 and 12 months (P = .29). Similarly, the proportion of patients achieving MCID in SF-36 PCS was significantly greater than the proportion achieving MCID in SMFA DI between baseline and 6 months (84.6% vs 69.8%, P < .001), and between 6 and 12 months (48.5% vs 35.7%, P = .01). There were no ceiling or floor effects found for SF-36 PCS at any time intervals. However, 16.1% of patients achieved the highest level of functioning detectable by the SMFA DI at baseline, along with smaller ceiling effects at 6 months (1.3%) and 12 months (3.3%). CONCLUSIONS: SF-36 PCS is a more responsive measure of functional outcome than the SFMA DI over the first year of recovery in patients who sustain a pelvic ring disruption or acetabular fracture. This superiority was found in using the SRM, proportion of patients meeting MCID, and ceiling effects. Furthermore, the SF-36 PCS correlated with the more disease-specific SMFA DI. LEVEL OF EVIDENCE: Prognostic Level II.

Return to Sport After Hip Arthroscopy for Femoroacetabular Impingement Syndrome: a Comprehensive Review of Qualitative Considerations.

PURPOSE OF REVIEW: Arthroscopic hip surgery for femoroacetabular impingement syndrome has evolved over time and has resulted in significantly improved clinical outcomes. These outcomes can be measured by clinical and radiographic metrics. Return to sport is commonly used as an outcome measure, not only in terms of overall rate but also type of sport, level of competition, and timing of return, as its quantitative definition continues to develop. Qualitative research methods can highlight the patient-derived themes that affect an athlete's individual return to sport pathway, and can augment the existing methods of outcome reporting. We will specifically review the qualitative research that has been performed on evaluating return to sport after arthroscopic hip surgery for femoroacetabular impingement syndrome. RECENT FINDINGS: Current evidence finds a high overall rate of return to sport at 87-93% after arthroscopic hip surgery for femoroacetabular impingement syndrome. The available qualitative research in this body of literature, which is limited, has found three main overarching themes behind athletes' decision and ability, or inability, to return to sport: self-efficacy, social support, and resetting expectations. Athletes experience high rates of return to sport and athletic performance after arthroscopic hip surgery for femoroacetabular impingement syndrome. This review highlights the qualitative considerations for these athletes in their overall readiness to return to sport, and its utility for treating physicians as we interact with these athletes both pre- and post-operatively. Further research is required to elucidate any further overarching themes that may be prevalent in different levels of competition.

Trajectory of Short- and Long-Term Recovery of Tibial Shaft Fractures After Intramedullary Nail Fixation.

OBJECTIVE: To determine the trajectory of recovery after tibial shaft fracture treated with intramedullary nail over the first 5 years and to evaluate the magnitude of the changes in functional outcome at various time intervals. DESIGN: Prospective cohort study. SETTING: A Level 1 trauma center. PATIENTS/PARTICIPANTS: One hundred thirty-two patients with tibial shaft fracture (OTA 42-A, B, C) were enrolled into the Center's prospective orthopaedic trauma database between January 2005 and February 2010. Functional outcome data were collected at baseline, 6 months, 1 year, and 5 years. INTERVENTION: Enrolled patients were treated acutely with intramedullary nailing of their tibia. MAIN OUTCOME MEASUREMENTS: Evaluation was performed using the Short Form-36 and Short Musculoskeletal Function Assessment (SMFA). RESULTS: Mean SF-36 physical component scores improved between 6 and 12 months (P = 0.0008) and between 1 and 5 years (P = 0.0029). Similarly, mean SMFA dysfunction index scores improved between 6 and 12 months (P = 0.0254) and between 1 and 5 years (P = 0.0106). In both scores, the rate or slope of this improvement is flatter between 1 and 5 years than it is between 6 and 12 months. Furthermore, SF-36 and SMFA scores did not reach baseline at 5 years (SF-36 P < 0.0001, SMFA P = 0.0026). A significant proportion of patients were still achieving a minimal clinically important difference in function between 1 and 5 years (SF-36 = 54%, SMFA = 44%). CONCLUSIONS: The trajectory of functional recovery after tibial shaft fracture is characterized by an initial decline in function, followed by improvement between 6 and 12 months. There is still further improvement beyond 1 year, but this is of flatter trajectory. The 5-year results indicate that function does not improve to baseline by 5 years after injury. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.