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.

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.