Society of American Gastrointestinal and Endoscopic Surgeons guidelines development: health equity update to standard operating procedure.

INTRODUCTION: The SAGES Guidelines Committee creates evidence-based clinical practice guidelines. Due to existing health disparities, recommendations made in these guidelines may have different impacts on different populations. The updates to our standard operating procedure described herein will allow us to produce well-designed guidelines that take these disparities into account and potentially reduce health inequities. METHODS: This paper outlines updates to the SAGES Guidelines Committee Standard Operating Procedure in order to incorporate issues of heath equity into our guideline development process with the goal of minimizing downstream health disparities. RESULTS: SAGES has developed an evidence-based, standardized approach to consider issues of health equity throughout the guideline development process to allow physicians to better counsel patients and make research recommendations to better address disparities. CONCLUSION: Societies that promote guidelines within their organization must make an intentional effort to prevent the widening of health disparities as a result of their recommendations. The updates to the Guidelines Committee Standard Operating Procedure will hopefully lead to increased attention to these disparities and provide specific recommendations to reduce them.

Mid-term Outcomes of Nissen Fundoplication Versus Roux-en-y Gastric Bypass for Primary Management of Gastroesophageal Reflux Disease in Patients With Obesity.

INTRODUCTION: The efficacy and outcomes of laparoscopic Nissen fundoplication (LNF) in patients with obesity is controversial. Specifically, concerns regarding long-term outcomes and recurrence in the setting of obesity has led to interest in laparoscopic Roux-en-Y gastric bypass (RYGB). METHODS: In this retrospective cohort study, we studied patients with obesity who underwent either LNF or RYGB for gastroesophageal reflux disease. Baseline demographics, clinical variables, operative outcomes, and symptom severity scores were compared. RESULTS: Baseline demographics, operative outcomes, and quality-of-life scores were similar. Proton pump inhibitor usage, quality-of-life, symptom severity scores, and satisfaction with the operation were similar between groups at mid-term follow-up. DISCUSSION: RYGB and LNF produced similar improvements in disease-specific quality of life with similar rates of complications, side effects, and need for reoperation. This demonstrates that RYGB and LNF represent possible options for surgical management of gastroesophageal reflux disease in obese patients.

S148: Long-term patient-reported outcomes of laparoscopic magnetic sphincter augmentation versus Nissen fundoplication: a 5-year follow-up study.

BACKGROUND: Laparoscopic magnetic sphincter augmentation (MSA) has emerged as an alternative to laparoscopic Nissen fundoplication (LNF) for the management of symptomatic gastroesophageal reflux disease (GERD). While short-term outcomes of MSA compare favorably to those of LNF, direct comparisons of long-term outcomes are lacking. We hypothesized that the long-term patient-reported outcomes of MSA would be similar to those achieved with LNF. METHODS: We tested this hypothesis in a retrospective cohort undergoing primary LNF or MSA between March 2013 and July 2015. The primary outcome was GERD-Health Related Quality of Life (GERD-HRQL) score at long-term follow-up relative to baseline. Secondary outcomes included dysphagia and bloating scores, proton-pump inhibitor (PPI) cessation, reoperations, and overall satisfaction with surgery. RESULTS: 70 patients (25 MSA, 45 LNF) met criteria for study inclusion. MSA patients had lower baseline BMI (median: 27.1 [IQR: 22.7-29.9] versus 30.4 [26.4-32.8], p = 0.02), lower total GERD-HRQL (26 [19-32] versus 34 [25-40], p = 0.02), and dysphagia (2 [0-3] versus 3 [1-4], p = 0.02) scores. Median follow-up interval exceeded 5 years (MSA: 68 [65-74]; LNF: 65 months [62-69]). Total GERD-HRQL improved from 26 to 9 after MSA (p < 0.001) and from 34 to 7.5 after LNF (p < 0.01); these scores did not differ between groups (p = 0.68). Dysphagia (MSA: 1 [0-2]; LNF: 0 [0-2], p = 0.96) and bloating (MSA: 1.5 [0.5-3.0]; LNF: 3.0 [1.0-4.0], p = 0.08) scores did not show any statistically significant differences. Device removal was performed in 4 (16%) MSA patients and reoperation in 3 (7%) LNF patients. Eighty-nine percent of LNF patients reported satisfaction with the procedure, compared to 70% of MSA patients (p = 0.09). CONCLUSIONS: MSA appears to offer similar long-term improvement in disease-specific quality of life as LNF. For MSA, there was a trend toward reduced long-term bloating compared to LNF, but need for reoperation and device removal may be associated with patient dissatisfaction.

QIC: A Pilot Quality Improvement Curriculum Utilizing Interactive, Team-based Workshops.

BACKGROUND: Incorporation of quality improvement (QI) training is essential to meet the milestones set forth by the Accreditation Council for Graduate Medical Education. However, there is no standardized curriculum. OBJECTIVE: We aimed to create a QI curriculum through the integration of didactics and team-based learning via the completion of resident-led QI projects. METHODS: An institutional review board-approved QI curriculum consisting of four interactive workshops was developed. The workshops introduced the various components of QI, with a focus on Plan-Do-Study-Act. Anonymous and voluntary precurriculum and postcurriculum surveys were administered during the study period in 2018. RESULTS: Fifty surgical residents participated in the curriculum, and four QI projects were completed, with 23 residents completing both precurriculum and postcurriculum surveys. Following the curriculum, residents were more confident in their ability to design a QI project (5.7 ± 2.6 versus 7.1 ± 1.9, P = 0.02), write a problem statement (6.7 ± 2.5 versus 7.8 ± 1.1, P = 0.04), and write an aim statement (6.7 ± 2.6 versus 7.8 ± 1.2, P = 0.04). Residents also improved in perceived ability to lead a QI project (5.6 ± 2.9 versus 6.9 ± 1.9, P = 0.05), knowing the steps to complete a QI project (6.0 ± 2.8 versus 7.4 ± 1.7, P = 0.04), and familiarity with QI terminology (5.6 ± 2.6 versus 7.0 ± 1.9, P = 0.03). CONCLUSIONS: We found that the curriculum was a success and was well received. In addition, there was an improvement in perceived competency and confidence surrounding some of the steps necessary to complete a QI endeavor.

Enhanced recovery after surgery pathway for patients undergoing abdominal wall reconstruction.

BACKGROUND: Pathways of enhanced recovery after surgery represent a standardized, multimodal approach to postoperative care with the goal of accelerating recovery without increasing morbidity. We hypothesized that implementation of an enhanced recovery after surgery pathway for abdominal wall reconstruction would result in a decreased duration of stay. METHODS: We compared 100 historic controls to 100 consecutive patients undergoing abdominal wall reconstruction with use of a newly implemented, enhanced recovery after surgery pathway to detect a difference in duration of stay of 1 day. Groups were compared on demographics and clinical characteristics using χ2, Fisher exact, Mann-Whitney U test, and 2 sample t tests as appropriate for the data. RESULTS: There was no change in duration of stay with the enhanced recovery after surgery protocol (median 5 vs 5 days, P = .78). There was no difference in time to regular diet (median 3 vs 3 days, P = .14). There was a trend toward decreased time epidurals or patient-controlled analgesia used (median 3 vs 3 day, P = .01). There was no increase in readmission rates. In a subgroup analysis, factors associated with a duration of stay <4 days were hernia width 9.5 ± 7.2 cm (P = .009), operative time 2.5 ± 0.9 hours (P = .001), and preoperative quality-of-life scores (HerQles) 59.5 ± 11.7 (P = .008). CONCLUSION: Our enhanced recovery after surgery study group did not show a decrease in duration of stay. Although smaller hernia defects, lesser operative times, and better baseline quality-of-life scores were associated with shorter duration of stay, the benefits of enhanced recovery after surgery seem limited in patients with the more complex hernia repairs.

Validation of a novel patient-reported outcome measure for parathyroid and thyroid disease (PROMPT).

BACKGROUND: Patient-reported outcome measures are being used increasingly to assess disease severity and response to surgery. The purpose of this study was to create and validate a patient-reported outcome measure for symptoms of thyroid enlargement and hyperparathyroidism, 2 conditions where the presence of preoperative symptoms and response to surgery is often questioned. METHODS: A questionnaire reviewing common symptoms was developed from a literature review and expert opinion. Internal validity, reliability, and initial responsiveness to surgery were evaluated. RESULTS: Patient-Reported Outcome Measure for Parathyroid and Thyroid Disease (PROMPT) consists of 30 items: 10 compressive items and 20 hyperparathyroidism items; we evaluated 302 surveys collected over 10 months. PROMPT showed high internal consistency for compressive and hyperparathyroid constructs (Cronbach's α 0.84 and 0.95). Constructs were scored from 0-100, with greater scores corresponding to increased severity of symptoms. Preoperatively, patients with a goiter demonstrated greater compressive scores compared with other thyroid patients and hyperparathyroid patients (goiter, 47.5; nodule/other, 38.4; hyperparathyroid, 29.8; P < .0001). PROMPT demonstrated high test-retest reliability with acceptable intraclass correlation coefficients for both compressive score and hyperparathyroid score (0.840 and 0.646). Hyperparathyroid scores improved 2 weeks after (48.6 postop, 44.0 preop, P = .0470). CONCLUSION: We validated a novel measure for symptoms of hyperparathyroidism and goiter. PROMPT demonstrates high internal consistency, test-retest reliability, and preliminary analysis, which suggests that it is sensitive to change after surgery.

Utilization of Quality Improvement Methodology to Standardize Communication of Outside Hospital Transfers in a General Surgery Program.

OBJECTIVE: There is no standardized method of communication regarding the arrival of outside hospital (OSH) transfers at our institution. We utilized quality improvement methodologies to enhance sign-out, benefiting both resident workflow and patient care. DESIGN: A dynamic census log of pending OSH transfers was created. Total number of OSH transfers (with or without prior notification), time to admission orders, and resident self-reported preparedness in receiving/triaging OSH admissions were measured before and after implementation of the census log tool. SETTING: Quaternary referral hospital in Cleveland, Ohio. PARTICIPANTS: The census log was made available to General Surgery residents on receiving surgical teams. After the data collection period, it was made available to all residents in the program. RESULTS: A total of 93 patients were transferred to receiving surgical teams during our 13-week study period. Resident notification of the OSH transfer prior to patient's arrival increased from 44.7% pre- to 70.3% postimplementation of the tool (p = 0.03). When residents received prior notification of pending transfers, time to place admission orders decreased from 81.2 ± 79.9 minutes to 40.4 ± 36.8 minutes (p = 0.0029). Junior residents' self-reported preparedness in admitting an OSH transfer did not significantly differ when they received prior notification versus when they did not. In contrast, senior residents' self-reported higher levels of preparedness in the instances where they received prior notification of a pending transfer. CONCLUSIONS: In light of the recent Clinical Learning Environment Review program set forth by the Accreditation Council for Graduate Medical Education, trainees are expected to engage in improvement processes as it relates to patient safety and transitions of care. The development and implementation of our tool demonstrate that quality improvement methodologies can be effectively applied to resident workflow challenges, improving both trainee education and patient care.

Surgical Management of Parastomal Hernias.

Parastomal hernias are a common complication after ostomy formation that can require surgical repair when they become symptomatic. Operative planning and a thorough understanding of the anatomy of the abdominal wall are important. Simple fascial repair is associated with an unacceptably high recurrence rate and should be used as a temporary measure only. Stoma relocation has a high recurrence rate. Prophylactic mesh can and should be used. At this time, the use of mesh is considered the standard of care in the repair of parastomal hernias.

Addressing Professionalism, Social, and Communication Competencies in Surgical Residency Via Integrated Humanities Workshops: A Pilot Curriculum.

OBJECTIVE: We aimed to conduct professionalism and social competencies (PSC) training by integrating humanities into structured workshops, and to assess reception of this curriculum by first-year surgical residents. DESIGN: An IRB-approved, pilot curriculum consisting of 4 interactive workshops for surgical interns was developed. The workshops were scheduled quarterly, often in small group format, and supplemental readings were assigned. Humanities media utilized to illustrate PSC included survival scenarios, reflective writing, television portrayals, and social media. Emphasis was placed on recognizing personal values and experiences that influence judgment and decision-making, using social media responsibly, identifying and overcoming communication barriers related to generational changes in training (especially technology and work-life balance), and tackling stereotypes of surgeons. Anonymous and voluntary pre- and postcurriculum surveys were administered. Univariate analysis of responses was performed with JMP Pro v12 using Fisher's exact, χ2, and Students' t-tests for categorical and continuous variables. SETTING: The study took place at the Cleveland Clinic in Cleveland, OH, within the general surgery program. PARTICIPANTS: Surgical interns at the Cleveland Clinic were included in the study. A total of 16 surgical interns completed the curriculum. RESULTS: Sixteen surgical interns participated in the curriculum: 69% were domestic medical school graduates (DG) and 31% were international medical school graduates (IMG). Overall, the majority (81%) of residents had received PSC courses during medical school: 100% of DG compared to 40% of IMG (p = 0.02). Before beginning the curriculum, 86% responded that additional PSC training would be useful during residency, which increased to 94% upon completion (p = 0.58). Mean number of responses supporting the usefulness of PSC training increased from 1.5 ± 0.2 before the curriculum to 1.75 ± 0.2 upon completion (p = 0.4). When describing public and medical student perceptions of surgeons, 60% and 83% of adjectives used were negative, respectively. When describing perceptions of female surgeons, 88% of adjectives used were negative. CONCLUSIONS: Most interns received prior PSC coursework; however, the majority still desired additional training during residency. After completion, a greater percentage of interns responded that PSC training was important and choose more reasons in favor of the curriculum. Formalized didactics should be strongly considered, especially in programs with IMG. Future areas of investigation include expanding the cohort to additional years of residency; potentially identifying unique PSC needs for each postgraduate year.

A Comparison of Robotic Versus Laparoscopic Adrenalectomy in Patients With Primary Hyperaldosteronism.

BACKGROUND: Over the last decade, robotic approaches have been described for removing adrenal tumors. Although there are reports comparing robotic and laparoscopic techniques in general, there are limited data on outcomes in patients with primary hyperaldosteronism (PHA). The aim of this study is to compare the safety and efficacy of robotic adrenalectomy (RA) versus laparoscopic adrenalectomy (LA) for PHA. MATERIALS AND METHODS: The records of 20 patients who underwent RA for PHA were compared with 16 patients who underwent LA between 2000 and 2014. Data were retrospectively reviewed from a prospectively maintained, IRB-approved adrenal database. Statistical analysis was performed using t test and the Fisher exact analysis. Continuous variables are reported as mean±SEM. RESULTS: Demographic and clinical parameters were similar between the groups. There were no conversions to open in either group. Estimated blood loss, length of stay, and complication rates were comparable. Operative time was shorter in the robotic versus laparoscopic group (130±8.94 vs. 159±11.1 min, P=0.0487). In follow-up, the improvement in patients' blood pressure after adrenalectomy, as assessed by the reduction in the number of antihypertensive medications, was similar between the 2 groups. However, 1 patient in the RA and 1 patient in the LA group were not cured, as determined by postoperative aldosterone:renin levels. The biochemical cure rate between the groups was similar (P=0.529). CONCLUSIONS: To our knowledge, this is the first study comparing robotic versus laparoscopic resection of PHA. Our results show that the robotic approach was similar to laparoscopic regarding safety and efficacy. Operative time was shorter with the robotic approach, which could be related to more efficient dissection with wristed instrumentation.

Pancreatic metastasis from an osseous solitary fibrous tumour.

A 73-year-old man presented with a right-sided chest wall mass that showed an epitheloid neoplasm with mild cytologic atypia on core needle biopsy. He underwent surgical resection, and final pathology revealed solitary fibrous tumour/hemangiopericytoma with negative margins. Three years after surgical resection, the patient presented with fatigue, abdominal pain, weight loss and mildly elevated liver function tests. Further workup revealed a 1.2 cm hypervascular mass in the neck of the pancreas. This case report summarises the surgical treatment and outcomes for a patient who presented with this rare tumour.

The utility of indocyanine green fluorescence imaging during robotic adrenalectomy.

BACKGROUND AND OBJECTIVES: Indocyanine green (ICG) has been used for medical imaging since 1950s, but has more recently become available for use in minimally invasive surgery owing to improvements in technology. This study investigates the use of ICG florescence to guide an accurate dissection by delineating the borders of adrenal tumors during robotic adrenalectomy (RA). METHODS: This prospective study compared conventional robotic view with ICG fluorescence imaging in 40 consecutive patients undergoing RA. Independent, non-blinded observers assessed how accurately ICG fluorescence delineated the borders of adrenal tumors compared to conventional robotic view. RESULTS: A total of 40 patients underwent 43 adrenalectomies. ICG imaging was superior, equivalent, or inferior to conventional robotic view in 46.5% (n = 20), 25.6% (n = 11), and 27.9% (n = 12) of the procedures. On univariate analysis, the only parameter that predicted the superiority of ICG imaging over conventional robotic view was the tumor type, with adrenocortical tumors being delineated more accurately on ICG imaging compared to conventional robotic view. CONCLUSIONS: This study demonstrates the utility of ICG to guide the dissection and removal of adrenal tumors during RA. A simple reproducible method is reported, with a detailed description of the utility based on tumor type, approach and side. J. Surg. Oncol. 2016;114:153-156. © 2016 Wiley Periodicals, Inc.

A phase I/II trial of bortezomib combined concurrently with gemcitabine for relapsed or refractory DLBCL and peripheral T-cell lymphomas.

There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL). We conducted a phase I/II trial with bortezomib (dose-escalated to 1·6 mg/m(2) ) given concurrently with gemcitabine (800 mg/m(2) ) days 1 + 8 q21 d. Of 32 patients, 16 each had relapsed/refractory PTCL and DLBCL. Median prior therapies were 3 and 35% had failed transplant. Among the first 18 patients, 67% experienced grade 3/4 neutropenia and/or grade 3/4 thrombocytopenia resulting in repeated treatment delays (relative dose intensity: 46%). Thus, the study was amended to give bortezomib and gemcitabine days 1 + 15 q28 d, which resulted in markedly improved tolerability. Among all patients, the overall response rate (ORR) was 24% with 19% complete remission (CR; intent-to-treat (ITT) ORR 16%, CR 13%), which met criteria for futility. The ORR for DLBCL was 10% (CR 10%) vs. 36% for PTCL (CR 27%). Among 6 PTCL patients treated on the modified schedule, ORR by ITT was 50% (CR 30%). Altogether, concurrent bortezomib/gemcitabine given days 1 + 8 q21 d was not tolerable, while modification to a bi-monthly schedule allowed consistent treatment delivery. Whereas efficacy of this combination was low in heavily pre-treated DLBCL, there was a signal of activity in relapsed/refractory PTCL utilizing the modified schedule.

Neurophenotyping genetically modified mice for social behavior.

Sociability in mice is a multidimensional adaptive and functional response. Due to its complexity, it is important that researchers use well-defined behavioral assays that are easily replicated with clearly defined ethograms. In the Mouse Behavioral and Neuroendocrine Analysis Core Facility at Duke University, we have developed a broad series of tests that examine different components of neonatal and adult social behaviors that include sociability, sexual behavior, aggressive and territorial responses, and maternal behaviors. While the purpose of this chapter is not to provide an exhaustive description of all mouse social tests available, we provide investigators with a description of basic procedures and considerations necessary to develop a successful social behavior testing program within their laboratories.

Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3.

SHANK3 is a synaptic scaffolding protein enriched in the postsynaptic density (PSD) of excitatory synapses. Small microdeletions and point mutations in SHANK3 have been identified in a small subgroup of individuals with autism spectrum disorder (ASD) and intellectual disability. SHANK3 also plays a key role in the chromosome 22q13.3 microdeletion syndrome (Phelan-McDermid syndrome), which includes ASD and cognitive dysfunction as major clinical features. To evaluate the role of Shank3 in vivo, we disrupted major isoforms of the gene in mice by deleting exons 4-9. Isoform-specific Shank3(e4-9) homozygous mutant mice display abnormal social behaviors, communication patterns, repetitive behaviors and learning and memory. Shank3(e4-9) male mice display more severe impairments than females in motor coordination. Shank3(e4-9) mice have reduced levels of Homer1b/c, GKAP and GluA1 at the PSD, and show attenuated activity-dependent redistribution of GluA1-containing AMPA receptors. Subtle morphological alterations in dendritic spines are also observed. Although synaptic transmission is normal in CA1 hippocampus, long-term potentiation is deficient in Shank3(e4-9) mice. We conclude that loss of major Shank3 species produces biochemical, cellular and morphological changes, leading to behavioral abnormalities in mice that bear similarities to human ASD patients with SHANK3 mutations.

Teaching evidence-based medicine pediatric psychopharmacology: integrating psychopharmacologic treatment into the broad spectrum of care.

Pediatric psychopharmacology is taught at the Duke University Hospital Child and Adolescent Psychiatry Residency Training Program within the context of an evidence-based medicine model. The basic goal of the course is to develop competence in the psychopharmacologic management of psychiatric problems of children and adolescents as part of a biopsychosocial/developmental model of care. Associated with this over-arching goal is the demonstration of specific attitudes, knowledge, and skills. This article discusses the educational model with examples and each of these goals in depth.

Fgf9 induces proliferation and nuclear localization of FGFR2 in Sertoli precursors during male sex determination.

Recently, we demonstrated that loss of Fgf9 results in a block of testis development and a male to female sex-reversed phenotype; however, the function of Fgf9 in sex determination was unknown. We now show that Fgf9 is necessary for two steps of testis development just downstream of the male sex-determining gene, Sry: (1) for the proliferation of a population of cells that give rise to Sertoli progenitors; and (2) for the nuclear localization of an FGF receptor (FGFR2) in Sertoli cell precursors. The nuclear localization of FGFR2 coincides with the initiation of Sry expression and the nuclear localization of SOX9 during the early differentiation of Sertoli cells and the determination of male fate.

Fibroblast growth factor receptor 3 signaling regulates the onset of oligodendrocyte terminal differentiation.

Fibroblast growth factor receptor (FGFR) signaling is essential for nervous system development. We have shown that, in the normal postnatal brain, the spatial and temporal expression pattern of FGFR3 parallels the appearance of differentiated oligodendrocytes and that in culture FGFR3 is expressed maximally at the critical stage in the lineage at which oligodendrocyte late progenitors (Pro-OLs) enter terminal differentiation. Therefore, FGFR3 expression is positioned ideally to have an impact on oligodendrocyte differentiation. In support of this we show that, during the onset and active phase of myelination in FGFR3-deficient mice, there are reduced numbers of differentiated oligodendrocytes in the forebrain, cerebellum, hindbrain, and spinal cord. Furthermore, myelination is delayed in parallel. Delay of oligodendrocyte differentiation also is observed in primary cell culture from this mutant. On the other hand, no differences are observed in the survival or proliferation of oligodendrocyte progenitors. This suggests that the decrease in the number of differentiated oligodendrocytes is attributable to a delay in the timing of their differentiation process. Astrocytes also express FGFR3, and in mice lacking FGFR3 there is an enhancement of the astrocytic marker glial fibrillary acidic protein expression in a region-specific manner. Thus our findings suggest that there are cell type- and region-specific functions for FGFR3 signaling and in particular emphasize a prominent role for FGFR3 as part of a system regulating the onset of oligodendrocyte terminal differentiation.

Fgfr3 expression by astrocytes and their precursors: evidence that astrocytes and oligodendrocytes originate in distinct neuroepithelial domains.

The postnatal central nervous system (CNS) contains many scattered cells that express fibroblast growth factor receptor 3 transcripts (Fgfr3). They first appear in the ventricular zone (VZ) of the embryonic spinal cord in mid-gestation and then distribute into both grey and white matter - suggesting that they are glial cells, not neurones. The Fgfr3(+) cells are interspersed with but distinct from platelet-derived growth factor receptor alpha (Pdgfra)-positive oligodendrocyte progenitors. This fits with the observation that Fgfr3 expression is preferentially excluded from the pMN domain of the ventral VZ where Pdgfra(+) oligodendrocyte progenitors--and motoneurones--originate. Many glial fibrillary acidic protein (Gfap)- positive astrocytes co-express Fgfr3 in vitro and in vivo. Fgfr3(+) cells within and outside the VZ also express the astroglial marker glutamine synthetase (Glns). We conclude that (1) Fgfr3 marks astrocytes and their neuroepithelial precursors in the developing CNS and (2) astrocytes and oligodendrocytes originate in complementary domains of the VZ. Production of astrocytes from cultured neuroepithelial cells is hedgehog independent, whereas oligodendrocyte development requires hedgehog signalling, adding further support to the idea that astrocytes and oligodendrocytes can develop independently. In addition, we found that mice with a targeted deletion in the Fgfr3 locus strongly upregulate Gfap in grey matter (protoplasmic) astrocytes, implying that signalling through Fgfr3 normally represses Gfap expression in vivo.

Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18.

Gain of function mutations in fibroblast growth factor (FGF) receptors cause chondrodysplasia and craniosynostosis syndromes. The ligands interacting with FGF receptors (FGFRs) in developing bone have remained elusive, and the mechanisms by which FGF signaling regulates endochondral, periosteal, and intramembranous bone growth are not known. Here we show that Fgf18 is expressed in the perichondrium and that mice homozygous for a targeted disruption of Fgf18 exhibit a growth plate phenotype similar to that observed in mice lacking Fgfr3 and an ossification defect at sites that express Fgfr2. Mice lacking either Fgf18 or Fgfr3 exhibited expanded zones of proliferating and hypertrophic chondrocytes and increased chondrocyte proliferation, differentiation, and Indian hedgehog signaling. These data suggest that FGF18 acts as a physiological ligand for FGFR3. In addition, mice lacking Fgf18 display delayed ossification and decreased expression of osteogenic markers, phenotypes not seen in mice lacking Fgfr3. These data demonstrate that FGF18 signals through another FGFR to regulate osteoblast growth. Signaling to multiple FGFRs positions FGF18 to coordinate chondrogenesis in the growth plate with osteogenesis in cortical and trabecular bone.