Browsing by Author "Mulenga, Chilando"

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    07. The Mechanism of NGF Signaling In Innervation-dependent Corneal Epithelial Renewal: New Topical Treatment For Neurotrophic Keratopathy
    (Wolters Kluwer, 2024-04-19) Hussain, Arif; Mirmoeini, Kaveh; Mulenga, Chilando; Crabtree, Jordan; Tajdaran, Kiana; Henrique, Mario; Blum, Noam; Shalom-Feuerstein, Ruby; Borschel, Gregory; Feinberg, Konstantin; Surgery, School of Medicine
    Background: Corneal clarity is essential for vision. Limbal stem cells (LSCs), the source of transparent corneal epithelial cells, are located in the basal epithelium of the limbus at the corneal-conjunctival interface, where they interact with corneal sensory nerves. Besides protection, corneal nerves may stimulate LSC activity. Pathological corneal denervation can lead to ulcers, scarring, and opacification due to impaired healing from repetitive wounds. This condition, termed Neurotrophic Keratopathy (NK), a major cause of corneal blindness, and lacks a definitive cure. Corneal nerves release various trophic factors that regulate epithelial renewal. Nerve growth factor (NGF) has shown positive effects on corneal healing and maintenance in vivo. Topical recombinant human NGF is the only FDA-approved treatment for NK. However, NGF is not efficacious in 30% of cases, requires very frequent dosing, and costs $100k per course. Moreover, NGF’s ability to heal corneal ulcers is limited. Prior studies showed NGF stimulates proliferation and maintenance of cultured human LSCs, which express TrkA and p75NTR receptors, but didn’t establish a link between NGF signaling and corneal sensory innervation-mediated trophic regulation of epithelial renewal. Furthermore, the role and molecular mechanism of NGF signaling in LSC activity remains unidentified. We hypothesize that NGF, locally expressed in its mature and premature (proNGF) forms, regulates LSC activity-dependent homeostatic and wound-induced corneal epithelial renewal via differential activation of its receptors TrkA and p75NTR, a process dependent on corneal sensory innervation. Methods: A) We conducted in vivo experiments in wild-type and mutant mice and rats to elucidate the NGF signaling mechanism in corneal innervation-dependent epithelial renewal. We examined the effect of combinations of TrkA and p75NTR agonists and antagonists on the healing of experimentally wounded corneas, both intact and surgically denervated. B) To understand the role and mechanism of NGF signaling in LSC activity and its relevance to humans, we assessed the clonogenicity of cultured human LSCs (hLSCs) by pharmacologically modulating NGF receptors, as described in (A). Results: A) While inactivation of TrkA completely prevents healing of normally innervated cornea, inactivation of p75NTR combined with a single daily dose of NGF induces complete and rapid healing of denervated de-epithelialized corneas. B) NGF or specific p75NTR inhibitor THX-B supported colonies’ formation by hLSCs that were further augmented by combination of the two compounds. Conclusions: Corneal sensory nerve-associated expression of NGF in its both forms (NGF and proNGF) regulates the proliferation and differentiation of LSCs by differentially stimulating the activity of the NGF receptors. Combined pharmacological activation and inhibition of TrkA and p75NTR, respectively, will be applied in the development of a superior NGF-based treatment of NK.
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    The Role of Early Latissimus Dorsi Tendon Transfers for Shoulder Movement and Stability in Neonatal Brachial Plexus Injury
    (Wolters Kluwer, 2023-10-18) Gross, Jeffrey; Bhagat, Neel; Mulenga, Chilando; Singh, Nikhi; Borschel, Gregory; Adkinson, Joshua; Graduate Medical Education, School of Medicine
    INTRODUCTION: Neonatal brachial plexus injury (BPI) is a rare but devastating complication of birth. An upper trunk BPI can result in the loss of shoulder external rotation and abduction and often leads to glenohumeral joint dysplasia (GJD). The latissimus dorsi/teres major tendon transfer (LTT) is a procedure used to restore external rotation and shoulder abduction and potentially reduce the incidence of GJD. Historically, this tendon transfer has been performed when the child is older and has demonstrated impaired shoulder function. In this study, we sought to assess feasibility and short-term outcomes of LTT combined with BPI reconstruction. METHODS: A retrospective review of patients was performed. Inclusion criteria were patients under 18 years of age at Riley Children’s Hospital with BPI who underwent LTT between 2021-2022. RESULTS: Eighteen patients underwent LTT between 2021-2022 at the mean age of 2.2 +/- 2.2 years. Five patients (27.8%) underwent the transfer concurrently with BPI nerve reconstruction, 8 (44.4%) underwent staged LTT, and 5 (27.8%) patients underwent LTT with no previous or concurrent BPI reconstruction. Of the 8 patients that underwent staged repair, 7/8 (88%) had MRI evidence of GJD prior to their tendon transfer. There were no major complications in any subgroup. Average follow-up was 7.54 months. The mean age at surgery for patients undergoing staged LTT was 2.1 years old compared to 6 months in the concurrent group. In the staged cohort, available post-operative mean AMS scores were 3.5 for shoulder abduction, 1.67 for shoulder external rotation. and 4.83 for shoulder forward flexion. In the concurrent cohort, mean AMS scores were 3.2 for shoulder abduction, 1.8 for external rotation, and 3.6 for shoulder forward flexion. CONCLUSIONS: In this study, we found that LTT can be safely and efficiently combined with BPI reconstruction. Patients in the concurrent surgery cohort achieved similar shoulder functional scores as those in the staged surgery cohort, but these scores were achieved at a younger age (i.e.1.5 years earlier) and without a second surgery. In addition, a simultaneous or early approach may provide the very young pediatric patient shoulder stability needed to prevent GJD while also avoiding the need for a second anesthetic exposure. Future studies will focus on comparative assessment of long-term shoulder functional outcomes.