Stereotactic Navigation Improves Outcomes of Orbital Decompression Surgery for Thyroid Associated Orbitopathy.

PURPOSE: To test whether intraoperative stereotactic navigation during orbital decompression surgery resulted in quantifiable surgical benefit. METHODS: This retrospective cohort study examined all consecutive patients who underwent primary orbital decompression surgery for thyroid associated orbitopathy performed by a single surgeon (A.K.) during the periods of 2012-2014 (non-navigated), and 2017-2018 (navigated). The study was HIPAA-compliant, was approved by the Institutional Review Board, and adhered to the tenets of the Helsinki declaration. Recorded parameters included patient age, sex, race, decompression technique (side of operation and walls decompressed), estimated blood loss (EBL), intraoperative complications, times that patient entered and exited the operating room (OR), times of surgical incision and dressing completion, pre- and postoperative best corrected visual acuity (BCVA), proptosis, diplopia, postoperative change in strabismus deviation, and need for subsequent strabismus surgery. Recorded times were used to calculate operating time (initial incision to dressing) and maintenance time (time between OR entry and initial incision and time between dressings and OR exit). The total maintenance time was averaged over total number of operations. Student t test was used to compare surgical times, maintenance times, EBL, and proptosis reduction. Fisher exact test was used to compare BCVA change, strabismus deviation change, resolution or onset of diplopia, and need for corrective strabismus surgery. RESULTS: Twenty-two patients underwent primary orbital decompression surgery without navigation, and 23 patients underwent navigation-guided primary orbital decompression surgery. There were no intraoperative complications in either group. The average operative time was shorter in the navigated group for a unilateral balanced decompression (n = 10 vs. 19; 125.8 ± 13.6 vs. 141.3 ± 19.4 min; p-value = 0.019), and a unilateral lateral wall only decompression (n = 13 vs. 3; 80.5 ± 12.8 vs. 93.0 ± 6.1 min; p-value = 0.041). The average maintenance time per surgery was not significantly different between the non-navigated group (51.3 ± 12.7 min) and the navigated group (50.5 ± 6.4 min). There was no significant difference between the navigated and non-navigated groups in average EBL per surgery. There was no significant difference in BCVA change. Average proptosis reduction was larger in the navigated group, but this was not significant. There was a significantly lower proportion of patients who required corrective strabismus surgery following decompression in the navigated group than in the non-navigated group (39.1% vs. 77.3%, p-value = 0.012). CONCLUSIONS: Intraoperative stereotactic navigation during orbital decompression surgery has the potential to provide the surgeon with superior spatial awareness to improve patient outcomes. This study found that use of intraoperative navigation reduced operative time (even without factoring in a resident teaching component) while also reducing the need for subsequent strabismus surgery. This study is limited by its size but illustrates that use of intraoperative navigation guidance has substantive benefits in orbital decompression surgery.

A graded neonatal mouse model of necrotizing enterocolitis demonstrates that mild enterocolitis is sufficient to activate microglia and increase cerebral cytokine expression.

Background: Necrotizing enterocolitis (NEC) is an inflammatory gastrointestinal process that afflicts approximately 10% of preterm infants born in the United States each year, with a mortality rate of 30%. NEC severity is graded using Bell's classification system, from stage I mild NEC to stage III severe NEC. Over half of NEC survivors present with neurodevelopmental impairment during adolescence, a long-term complication that is poorly understood but can occur even after mild NEC. Although multiple animal models exist, none allow the experimenter to control nor represent the gradient of symptom severities seen in NEC patients. We bridge this knowledge gap by developing a graded murine model of NEC and studying its relationship with neuroinflammation across a range of NEC severities. Methods: Postnatal day 3 (P3) C57BL/6 mice were fed a formula containing different concentrations (0% control, 0.25%, 1%, 2%, and 3%) of dextran sodium sulfate (DSS). P3 mice were fed every 3 hours for 72-hours. We collected data on weight gain and behavior (activity, response, body color) during feeding. At the end of the experiment, we collected tissues (intestine, liver, plasma, brain) for immunohistochemistry, immunofluorescence, and cytokine and chemokine analysis. Results: Throughout NEC induction, mice fed higher concentrations of DSS died sooner, lost weight faster, and became sick or lethargic earlier. Intestinal characteristics (dilation, color, friability) were worse in mice fed with higher DSS concentrations. Histology revealed small intestinal disarray among mice fed all DSS concentrations, while higher DSS concentrations resulted in reduced small intestinal cellular proliferation and increased hepatic and systemic inflammation. In the brain, IL-2, G-CSF, and CXCL1 concentrations increased with higher DSS concentrations. Although the number of neurons and microglia in the CA1 hippocampal region did not differ, microglial branching was significantly reduced in DSS-fed mice. Conclusion: We characterize a novel graded model of NEC that recapitulates the full range of NEC severities. We show that mild NEC is sufficient to initiate neuroinflammation and microglia activation. This model will facilitate studies on the neurodevelopmental effects of NEC.

Twist3 is required for dedifferentiation during extraocular muscle regeneration in adult zebrafish.

Severely damaged adult zebrafish extraocular muscles (EOMs) regenerate through dedifferentiation of residual myocytes involving a muscle-to-mesenchyme transition. Members of the Twist family of basic helix-loop-helix transcription factors (TFs) are key regulators of the epithelial-mesenchymal transition (EMT) and are also involved in craniofacial development in humans and animal models. During zebrafish embryogenesis, twist family members (twist1a, twist1b, twist2, and twist3) function to regulate craniofacial skeletal development. Because of their roles as master regulators of stem cell biology, we hypothesized that twist TFs regulate adult EOM repair and regeneration. In this study, utilizing an adult zebrafish EOM regeneration model, we demonstrate that inhibiting twist3 function using translation-blocking morpholino oligonucleotides (MOs) impairs muscle regeneration by reducing myocyte dedifferentiation and proliferation in the regenerating muscle. This supports our hypothesis that twist TFs are involved in the early steps of dedifferentiation and highlights the importance of twist3 during EOM regeneration.

Extraocular muscle regeneration in zebrafish requires late signals from Insulin-like growth factors.

Insulin-like growth factors (Igfs) are key regulators of key biological processes such as embryonic development, growth, and tissue repair and regeneration. The role of Igf in myogenesis is well documented and, in zebrafish, promotes fin and heart regeneration. However, the mechanism of action of Igf in muscle repair and regeneration is not well understood. Using adult zebrafish extraocular muscle (EOM) regeneration as an experimental model, we show that Igf1 receptor blockage using either chemical inhibitors (BMS754807 and NVP-AEW541) or translation-blocking morpholino oligonucleotides (MOs) reduced EOM regeneration. Zebrafish EOMs regeneration depends on myocyte dedifferentiation, which is driven by early epigenetic reprogramming and requires autophagy activation and cell cycle reentry. Inhibition of Igf signaling had no effect on either autophagy activation or cell proliferation, indicating that Igf signaling was not involved in the early reprogramming steps of regeneration. Instead, blocking Igf signaling produced hypercellularity of regenerating EOMs and diminished myosin expression, resulting in lack of mature differentiated muscle fibers even many days after injury, indicating that Igf was involved in late re-differentiation steps. Although it is considered the main mediator of myogenic Igf actions, Akt activation decreased in regenerating EOMs, suggesting that alternative signaling pathways mediate Igf activity in muscle regeneration. In conclusion, Igf signaling is critical for re-differentiation of reprogrammed myoblasts during late steps of zebrafish EOM regeneration, suggesting a regulatory mechanism for determining regenerated muscle size and timing of differentiation, and a potential target for regenerative therapy.