Is a Failed Spinal Attempt Associated with a Worse Clinical Course Following Primary Total Hip and Knee Arthroplasty?

INTRODUCTION: Spinal anesthesia (SA) is the preferred anesthesia modality for total joint arthroplasty (TJA). However, studies establishing SA as preferential may be subject to selection bias given that general anesthesia (GA) is often selectively utilized on more difficult, higher-risk operations. The optimal comparison group, therefore, is the patient converted to GA due to a failed attempt at SA. The purpose of this study was to determine risk factors and outcomes following failed SA with conversion to GA during primary total hip (THA) or knee arthroplasty (TKA). METHODS: A consecutive cohort of 4,483 patients who underwent primary TJA at our institution was identified (2,004 THA and 2,479 TKA). Of these patients, 3,307 underwent GA (73.8%), 1,056 underwent SA (23.3%), and 130 patients failed SA with conversion to GA (2.90%). Primary outcomes included rescue analgesia requirement in the post-anesthesia care unit (PACU), time to ambulation, pain scores in the PACU, estimated blood loss (EBL), and 90-day complications. RESULTS: Risk factors for SA failure included older age and a higher comorbidity burden. Failure of SA was associated with increased EBL, rescue intravenous (IV) opioid use, and time to ambulation when compared to the successful SA group in both THA and TKA patients (P < 0.001). The anesthesia modality was not associated with significant differences in PACU pain scores. The 90-day complication rate was similar between the failed SA and GA groups. There was a higher incidence of post-operative pain prompting unplanned visits and thromboembolism when comparing failed SA to successful SA in both THA and TKA patients (P < 0.05). CONCLUSION: In our series, patients who had failed SA demonstrated inferior outcomes to patients receiving successful SA and similar outcomes to patients receiving GA who did not have an SA attempt. This emphasizes the importance of success in the initial attempt at SA for optimizing outcomes following TJA.

Altered sacral neural crest development in Pax3 spina bifida mutants underlies deficits of bladder innervation and function.

Mouse models of Spina bifida (SB) have been instrumental for identifying genes, developmental processes, and environmental factors that influence neurulation and neural tube closure. Beyond the prominent neural tube defects, other aspects of the nervous system can be affected in SB with significant changes in essential bodily functions such as urination. SB patients frequently experience bladder dysfunction and SB fetuses exhibit reduced density of bladder nerves and smooth muscle although the developmental origins of these deficits have not been determined. The Pax3 Splotch-delayed (Pax3Sp-d) mouse model of SB is one of a very few mouse SB models that survives to late stages of gestation. Through analysis of Pax3Sp-d mutants we sought to define how altered bladder innervation in SB might arise by tracing sacral neural crest (NC) development, pelvic ganglia neuronal differentiation, and assessing bladder nerve fiber density. In Pax3Sp-d/Sp-d fetal mice we observed delayed migration of Sox10+ NC-derived progenitors (NCPs), deficient pelvic ganglia neurogenesis, and reduced density of bladder wall innervation. We further combined NC-specific deletion of Pax3 with the constitutive Pax3Sp-d allele in an effort to generate viable Pax3 mutants to examine later stages of bladder innervation and postnatal bladder function. Neural crest specific deletion of a Pax3 flox allele, using a Sox10-cre driver, in combination with a constitutive Pax3Sp-d mutation produced postnatal viable offspring that exhibited altered bladder function as well as reduced bladder wall innervation and altered connectivity between accessory ganglia at the bladder neck. Combined, the results show that Pax3 plays critical roles within sacral NC that are essential for initiation of neurogenesis and differentiation of autonomic neurons within pelvic ganglia.

Epithelial DNA methyltransferase-1 regulates cell survival, growth and maturation in developing prostatic buds.

DNA methyltransferase 1 (DNMT1) is required for embryogenesis but roles in late forming organ systems including the prostate, which emerges from the urethral epithelium, have not been fully examined. We used a targeted genetic approach involving a Shhcre recombinase to demonstrate requirement of epithelial DNA methyltransferase-1 (Dnmt1) in mouse prostate morphogenesis. Dnmt1 mutant urethral cells exhibit DNA hypomethylation, DNA damage, p53 accumulation and undergo cell cycle arrest and apoptosis. Urethral epithelial cells are disorganized in Dnmt1 mutants, leading to impaired prostate growth and maturation and failed glandular development. We evaluated oriented cell division as a mechanism of bud elongation and widening by demonstrating that mitotic spindle axes typically form parallel or perpendicular to prostatic bud elongation axes. We then deployed a ShhcreERT allele to delete Dnmt1 from a subset of urethral epithelial cells, creating mosaic mutants with which to interrogate the requirement for cell division in specific prostatic bud epithelial populations. DNMT1- cell distribution within prostatic buds is not random as would be expected in a process where DNMT1 was not required. Instead, replication competent DNMT1 + cells primarily accumulate in prostatic bud margins and tips while replication impeded DNMT1- cells accumulate in prostatic bud cores. Together, these results highlight the role of DNMT1 in regulating epithelial bud formation by maintaining cell cycle progression and survival of rapidly dividing urethral epithelial cells, which can be extended to the study of other developing epithelial organs. In addition, our results show that prostatic buds consist of two epithelial cell populations with distinct molecular and functional characteristics that could potentially contribute to specialized lineages in the adult prostate.

A folic acid-enriched diet attenuates prostate involution in response to androgen deprivation.

BACKGROUND: Serum folate concentrations in the United States have risen since dietary folic acid fortification was first mandated in 1998. Although maternal folic acid offers protection against neural tube defects in conceptuses, its impact on other organ systems and life stages have not been fully examined. Here, we used a mouse model to investigate the impact of a Folic acid (FA) enriched diet on prostate homeostasis and response to androgen deprivation. METHODS: Male mice were fed a control diet (4 mg FA/kg feed) or a folic acid supplemented diet (24 mg FA/kg feed) beginning at conception and continuing through early adulthood, when mice were castrated. RESULTS: We made the surprising observation that dietary FA supplementation confers partial resistance to castration-mediated prostate involution. At 3, 10, and 14 days post-castration, FA enriched diet fed mice had larger prostates as assessed by wet weight, taller prostatic luminal epithelial cells, and more abundant RNAs encoding prostate secretory proteins than castrated control diet fed mice. Diet did not significantly affect prostate weights of intact mice or serum testosterone concentrations of castrated mice. RNA-Seq analysis revealed that the FA enriched diet was associated with a unique prostate gene expression signature, affecting several signaling and metabolic pathways. CONCLUSIONS: Continuous exposure to a FA enriched diet slows prostate involution in response to androgen deprivation. Prostates from FA diet mice have increased secretory gene expression and increased luminal cell heights. The influence of dietary FA supplementation on the prostate response to androgen deprivation raises a future need to consider how dietary folic acid supplementation affects efficacy of androgen-reducing therapies for treating prostate disease.

In vivo replacement of damaged bladder urothelium by Wolffian duct epithelial cells.

The bladder's remarkable regenerative capacity had been thought to derive exclusively from its own progenitors. While examining consequences of DNA methyltransferase 1 (Dnmt1) inactivation in mouse embryonic bladder epithelium, we made the surprising discovery that Wolffian duct epithelial cells can support bladder regeneration. Conditional Dnmt1 inactivation in mouse urethral and bladder epithelium triggers widespread apoptosis, depletes basal and intermediate bladder cells, and disrupts uroplakin protein expression. These events coincide with Wolffian duct epithelial cell recruitment into Dnmt1 mutant urethra and bladder where they are reprogrammed to express bladder markers, including FOXA1, keratin 5, P63, and uroplakin. This is evidence that Wolffian duct epithelial cells are summoned in vivo to replace damaged bladder epithelium and function as a reservoir of cells for bladder regeneration.