Dendritic cells are the principal antigen-presenting cells (APCs) in the host defense mechanism. An altered dendritic cell response increases the risk of susceptibility of infections, such as Mycobacterium tuberculosis (M. tb), and the survival of the human immunodeficiency virus (HIV). The altered response of dendritic cells leads to decreased activity of T-helper-1 (Th1), Th2, Regulatory T cells (Tregs), and Th17 cells in tuberculosis (TB) infections due to a diminishment of cytokine release from these APCs, while HIV infection leads to DC maturation, allowing DCs to migrate to lymph nodes and the sub-mucosa where they then transfer HIV to CD4 T cells, although there is controversy around this topic. Increases in the levels of the antioxidant glutathione (GSH) plays a critical role in maintaining dendritic cell redox homeostasis, leading to an adequate immune response with sufficient cytokine release and a subsequent robust immune response. Thus, an understanding of the intricate pathways involved in the dendritic cell response are needed to prevent co-infections and co-morbidities in individuals with TB and HIV.

Lysosomes function not only as degradatory compartments but also as dynamic intracellular calcium ion stores. The transient receptor potential mucolipin 1 (TRPML1) channel mediates lysosomal Ca 2+ release, thereby participating in multiple cellular functions. The pentameric Ragulator complex, which plays a critical role in the activation of mTORC1, is also involved in lysosomal trafficking and is anchored to lysosomes through its LAMTOR1 subunit. Here, we report that the Ragulator restricts lysosomal trafficking in dendrites of hippocampal neurons via LAMTOR1-mediated tonic inhibition of TRPML1 activity, independently of mTORC1. LAMTOR1 directly interacts with TRPML1 through its N-terminal domain. Eliminating this inhibition in hippocampal neurons by LAMTOR1 deletion or by disrupting LAMTOR1-TRPML1 binding increases TRPML1-mediated Ca 2+ release and facilitates dendritic lysosomal trafficking powered by dynein. LAMTOR1 deletion in the hippocampal CA1 region of adult mice results in alterations in synaptic plasticity, and in impaired object-recognition memory and contextual fear conditioning, due to TRPML1 activation. Mechanistically, changes in synaptic plasticity are associated with increased GluA1 dephosphorylation by calcineurin and lysosomal degradation. Thus, LAMTOR1-mediated inhibition of TRPML1 is critical for regulating dendritic lysosomal motility, synaptic plasticity, and learning.

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Category: Trauma Introduction/Purpose: Opioid pain medications are frequently prescribed after orthopedic surgery as effective tools for pain relief, but with adverse consequences such as addiction and overdose. Postoperative pain control can vary depending on patient opioid prescription history and pain expectations. There are limited studies regarding pain and anxiety levels following orthopedic foot and ankle trauma surgery, with a lack of formal guidelines in prescribing opioid medications to this patient population. The overall purpose of this study was to gain an understanding of postoperative pain and anxiety in patients undergoing outpatient foot and ankle trauma surgery. This study additionally sought to identify any risk factors that may predispose a patient to increased postoperative pain and anxiety, resulting in a potentially increased pain medication requirement. Methods: A subanalysis of 50 patients from a prospective, observational study was performed, examining adult patients undergoing outpatient foot and ankle trauma surgery performed by trauma fellowship-trained senior investigators. Patients were enrolled and given pertinent reference materials including access to an automated texting survey platform to collect data regarding their postoperative pain, anxiety, and opioid medication use. Patients were stratified by procedure type (irrigation & debridement/hardware removal, foot/syndesmosis ORIF, ankle ORIF, pilon ORIF) and by receiving perioperative regional anesthetic block versus local anesthetic. Pain and anxiety were measured with the Numeric Rating Scale for Pain (scale of 1-10) and the Visual Facial Anxiety Scale (scale of 1-5), respectively. The primary outcome measured was the number of days on average for a patient to discontinue opioid medication. Secondary endpoints consisted of pain level < 4, anxiety level < 2, patient-specific and surgery-related factors that may affect these variables. Results: Postoperatively, it took an average of 9.6 days until opioids were discontinued, 8.2 days for pain to subside below 4, and 6.6 days until anxiety reduced under 2. Foot/syndesmosis ORIF and older age were associated with prolonged pain medication use (p<0.05). Drug use and older age limited the chance of obtaining a pain score under 4 (p<0.05). Psychiatric history and older age decreased the odds of obtaining an anxiety score under 2 (p<0.05). White race improved the chance of obtaining an anxiety score under 2 and tapering off pain medications (p<0.05). When stratified by procedure type or analgesic adjuvants (regional block vs local), there were no significant differences in pain and anxiety scores. Conclusion: Our study shows that regardless of procedure type or analgesic adjuvant used, it takes approximately eight days for postoperative pain levels to decrease to 4 out of 10 and six days for anxiety levels to decrease to 2 out of 5, with patients requiring opioid pain medications for an average of 10 days. Risk factors such as older age, prior drug use, and psychiatric history increased postoperative pain, anxiety, and use of opioid pain medications. This data may be utilized by orthopedic surgeons in providing safe, effective, and evidence-based pain management prescribing practices in anticipating postoperative pain and anxiety.

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