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Previously, we reported that chemokine (C-C motif) receptor 2 (CCR2) heteromerizes with α

It is known that catecholamines regulate innate immune functions. The underlying mechanisms, however, are not well understood. Here we show that at least 20 members of the human chemokine receptor (CR) family heteromerize with one or more members of the α1-adrenergic receptor (AR) family in recombinant systems and that such heteromeric complexes are detectable in human monocytes and the monocytic leukemia cell line THP-1. Ligand binding to α1-ARs inhibited migration toward agonists of the CR heteromerization partners of α1B/D-ARs with high potency and 50 to 77% efficacy but did not affect migration induced by a noninteracting CR. Incomplete siRNA knockdown of α1B/D-ARs in THP-1 cells partially inhibited migration toward agonists of their CR heteromerization partners. Complete α1B-AR knockout via CRISPR-Cas9 gene editing in THP-1 cells (THP-1_ADRA1BKO) resulted in 82% reduction of α1D-AR expression and did not affect CR expression. Migration of THP-1_ADRA1BKO cells toward agonists of CR heteromerization partners of α1B/D-ARs was reduced by 82 to 95%. Our findings indicate that CR:α1B/D-AR heteromers are essential for normal function of CR heteromerization partners, provide a mechanism underlying neuroendocrine control of leukocyte trafficking, and offer opportunities to modulate leukocyte and/or cancer cell trafficking in disease processes.

SignificanceHere we show that most chemokine receptors (CRs) form heteromeric complexes with α1-adrenergic receptors (ARs) in recombinant systems and that such heteromers are detectable in human monocytes and in the human monocytic leukemia cell line THP-1. Furthermore, we provide evidence that α1B/D-ARs control the function of their CR heteromerization partners. Our findings suggest that heteromeric complexes between α1B/D-ARs and CRs are necessary for normal function of CR heteromerization partners, indicate receptor heteromerization as a molecular mechanism by which stress hormones regulate leukocyte trafficking in health and disease, and offer opportunities to modulate leukocyte and/or cancer cell trafficking in disease processes.

Background: Achalasia and other esophageal motility disorders are incurable diseases for which palliation and symptom relief are the goals. One of the many ways these diseases are treated is with either a Heller myotomy or, now more commonly, per-oral endoscopic myotomy (POEM). Unfortunately, symptoms persistence or recurrence is common. This review presents our current approach to these complex patients. Methods: Review of the literature pertaining to approaches to recurrent or persistent symptoms after myotomy for esophageal motility disorders and elucidation of our multidisciplinary approach to this patient group. Results: There are a myriad of causes of recurrent or persistent symptoms. These include incomplete myotomy, periesophageal scarring, reflux-induced stricture, obstructing fundoplication, functional dysphagia, and end-stage achalasia. Therapeutic options include redo myotomy (either Heller or POEM), botulinum toxin injection, pneumatic, balloon or Savary dilation, adhesiolysis, and fundoplication reversal or esophagectomy. Choice of approach is best done through multidisciplinary consensus. Conclusions: A multidisciplinary approach to patients with persistent and recurrent symptoms after myotomy can best tailor the therapeutic approach based on symptom causation.

Many surgical disciplines have demonstrated superior outcomes when procedures are performed at "high-volume". Esophagomyotomy is commonly performed for achalasia, however it's unclear what constitutes "high-volume" for this procedure, and if individual procedure volume and outcome are related. We identified physicians performing esophagomyotomy, stratified them by individual case volume, and examined their outcomes with the hypothesis that high-volume surgeons will be associated with improved outcomes as compared to low-volume surgeons.The 2015-2019 Florida Agency for Health Care Administration (AHCA) inpatient dataset was queried for esophagomyotomy. Surgeons who performed ≥ 10 procedures during the study period were placed into the high-volume cohort, and those performing 10 into the low-volume cohort. Groups were compared by length of stay, discharge disposition, and postoperative complications. Patient demographics were evaluated using student's t test and chi square test, p 0.05 considered significant.Six hundred and sixty-two procedures performed by 135 surgeons were identified. The mean number of esophagomyotomies per surgeon was 4.9 (Range 1-147). The high-volume group (n = 12) performed 362 of the 662 procedures (55%), while the low-volume group (n = 123) performed the remaining 300 (45%). Patients of high-volume physicians had decreased length of stay (1.4 ± 0.8 days vs 4.9 ± 6.7 days, p = 0.01) and were more likely to be discharged to home following surgery (92.8% vs 86.0, p = 0.04). High volume physicians also had statistically significant differences in rates of urinary tract infection (1.4% vs 4.0%, p = 0.034), postoperative malnutrition (5.8% vs 11.0%, p = 0.015), and postoperative fluid and electrolyte disorders (5.5% vs 13.3%, p 0.0001).Surgeons who perform higher volumes of esophagomyotomies are associated with decreased length of stay, higher likelihood of patient discharge to home, and decreased rates of some postoperative complications. This research should prompt further inquiry into defining what constitutes a high-volume center in foregut surgery and their role in improving patient outcomes.