Effects of Intrathecal Morphine Administration in Patients Undergoing Primary Total Hip Arthroplasty Under Spinal Anesthesia With Quadratus Lumborum Block for Postoperative Analgesia.

Introduction Quadratus lumborum (QL) block has previously been shown to provide improved analgesia in patients undergoing primary total hip arthroplasty (THA) under spinal anesthesia when compared to spinal anesthesia alone. Additionally, recent studies have shown the addition of intrathecal morphine (ITM) to provide superior postoperative analgesia in patients undergoing various surgical interventions including total knee arthroplasty under spinal anesthesia with peripheral nerve blockade. At this time, however, there has not been a study evaluating the effects of intrathecal morphine in patients undergoing THA under spinal anesthesia with QL block. This study aims to assess if the addition of intrathecal morphine can provide adequate or even superior postoperative analgesia in patients undergoing primary THA. Methods This retrospective study included 26 patients in the spinal/QL block/intrathecal morphine (SA+QLB+ITM) group, 31 patients in the spinal/QL block group (SA+QLB), and 28 patients in the spinal only (SA or control) group. Twenty-six patients undergoing primary THA under a combination of spinal anesthesia and peripheral nerve blockade (quadratus lumborum block) were given a dose of 100 mcg of intrathecal morphine. Various parameters were evaluated including Post-Anesthesia Care Unit (PACU) and 24-hour visual analog scale (VAS) scores, time to first opioid use, 24- and 48-hour total opioid use as oral morphine equivalents (OME), 24-hour ambulation distance, and time from block placement to hospital discharge. The results were analyzed and compared to patients undergoing primary THA under spinal anesthesia with QL block (no intrathecal morphine) and compared to a control group of patients undergoing primary THA under spinal anesthesia only. Results The study analysis included 26 patients in the SA+QLB+ITM group, 31 patients in the SA+QLB group, and 28 patients in the SA (control) group. When compared with the control group, the SA+QLB+ITM had lower 24-hour total opioid usage (mean difference 20.80 OME, CI 6.454 to 35.15, p-value 0.0025), longer time to 1st opioid use (mean difference -20.51 hours later, p-value .0052), lower 24-hr VAS (difference 2.421, p-value 0.0012, CI 0.8559 to 3.987), and faster time to discharge (16.00 hr earlier, p-value 0.0459). When compared to the SA+QLB group, the SA+QLB+ITM group only showed a statistically significant difference in faster time to discharge (19.46 hr earlier, p-value 0.0068). However, while there was no statistically significant difference in time to 1st opioid use between the control and SA+QLB group, the difference did become significant when comparing the control to the SA+QLB+ITM group (mean difference -20.51 hours later (p-value .0052). There was no significant difference in either of the three groups in ambulation distance at 24 hours, PACU VAS, or 48-hour total opioid use. Conclusion Our study concludes that the addition of 100 mcg ITM for total hip arthroplasty under spinal anesthesia improved postoperative analgesia compared to the control group. Also, the ITM group did better with respect to delay in first opioid use and decreased hospital stay compared to the control and block-only groups. Our study warrants no more concerns of PONV, pruritus, or respiratory depression with this dose of ITM and requires standard postoperative care.

Identifying fibrogenic cells following salivary gland obstructive injury.

Fibrosis results from excess extracellular matrix accumulation, which alters normal tissue architecture and impedes function. In the salivary gland, fibrosis can be induced by irradiation treatment for cancer therapy, Sjögren's Disease, and other causes; however, it is unclear which stromal cells and signals participate in injury responses and disease progression. As hedgehog signaling has been implicated in fibrosis of the salivary gland and other organs, we examined contributions of the hedgehog effector, Gli1, to fibrotic responses in salivary glands. To experimentally induce a fibrotic response in female murine submandibular salivary glands, we performed ductal ligation surgery. We detected a progressive fibrotic response where both extracellular matrix accumulation and actively remodeled collagen significantly increased at 14 days post-ligation. Macrophages, which participate in extracellular matrix remodeling, and Gli1+ and PDGFRα+ stromal cells, which may deposit extracellular matrix, both increased with injury. Using single-cell RNA-sequencing, Gli1 + cells were not found in discrete clusters at embryonic day 16 but were found in clusters expressing the stromal genes Pdgfra and/or Pdgfrb. In adult mice, Gli1+ cells were similarly heterogeneous but more cells co-expressed PDGFRα and PDGFRß. Using Gli1-CreERT2; ROSA26tdTomato lineage-tracing mice, we found that Gli1-derived cells expand with ductal ligation injury. Although some of the Gli1 lineage-traced tdTomato+ cells expressed vimentin and PDGFRß following injury, there was no increase in the classic myofibroblast marker, smooth muscle alpha-actin. Additionally, there was little change in extracellular matrix area, remodeled collagen area, PDGFRα, PDGFRß, endothelial cells, neurons, or macrophages in Gli1 null salivary glands following injury when compared with controls, suggesting that Gli1 signaling and Gli1+ cells have only a minor contribution to mechanical injury-induced fibrotic changes in the salivary gland. We used scRNA-seq to examine cell populations that expand with ligation and/or showed increased expression of matrisome genes. Some Pdgfra + /Pdgfrb + stromal cell subpopulations expanded in response to ligation, with two stromal cell subpopulations showing increased expression of Col1a1 and a greater diversity of matrisome genes, consistent with these cells being fibrogenic. However, only a few cells in these subpopulations expressed Gli1, consistent with a minor contribution of these cells to extracellular matrix production. Defining the signaling pathways driving fibrotic responses in stromal cell sub-types could reveal future therapeutic targets.

Identifying Fibrogenic Cells Following Salivary Gland Obstructive Injury.

Fibrosis results from excess extracellular matrix accumulation, which alters normal tissue architecture and impedes function. In the salivary gland, fibrosis can be induced by irradiation treatment for cancer therapy, Sjögren's Disease, and other causes; however, it is unclear which stromal cells and signals participate in injury responses and disease progression. As hedgehog signaling has been implicated in fibrosis of the salivary gland and other organs, we examined contributions of the hedgehog effector, Gli1, to fibrotic responses in salivary glands. To experimentally induce a fibrotic response in female murine submandibular salivary glands, we performed ductal ligation surgery. We detected a progressive fibrotic response where both extracellular matrix accumulation and actively remodeled collagen trended upwards at 7 days and significantly increased at 14 days post- ligation. Macrophages, which participate in extracellular matrix remodeling, Gli1 + and PDGFRα + stromal cells, which may deposit extracellular matrix, both increased with injury. Using single-cell RNA-sequencing, we found that a majority of Gli1 + cells at embryonic day 16 also express Pdgfra and/or Pdgfrb. However, in adult mice, only a small subset of Gli1 + cells express PDGFRα and/or PDGFRß at the protein level. Using lineage-tracing mice, we found that Gli1-derived cells expand with ductal ligation injury. Although some of the Gli1 lineage-traced tdTomato + cells expressed vimentin and PDGFRß following injury, there was no increase in the classic myofibroblast marker, smooth muscle alpha-actin. Additionally, there was little change in extracellular matrix area, remodeled collagen area, PDGFRα, PDGFRß, endothelial cells, neurons, or macrophages in Gli1 null salivary glands following injury when compared with controls, suggesting that Gli1 signaling and Gli1 + cells have only a minor contribution to mechanical injury-induced fibrotic changes in the salivary gland. We used scRNA-seq to examine cell populations that expand with ligation and/or showed increased expression of matrisome genes. Pdgfra + /Pdgfrb + stromal cell subpopulations both expanded in response to ligation, showed increased expression and a greater diversity of matrisome genes expressed, consistent with these cells being fibrogenic. Defining the signaling pathways driving fibrotic responses in stromal cell sub-types could reveal future therapeutic targets.

Comparison of the Utilization of Tranexamic Acid and Tourniquet Use in Total Knee Arthroplasty: A Retrospective Case Series.

INTRODUCTION: Total knee arthroplasty (TKA) carries a high risk for significant blood loss due to bone cuts and extensive soft tissue involvement in the knee region. The use of tranexamic acid (TXA) or a tourniquet are two methods commonly employed to prevent significant blood loss and avoid the need for blood transfusion. TXA has been shown to reduce both intraoperative and postoperative bleeding as well as the probability that a patient will require a blood transfusion. The purpose of this study is to compare the efficacy of TXA and tourniquet use, both alone and in combination, in reducing blood loss during TKA. METHODS: Data for this retrospective cohort study were obtained by searching records of patients who underwent TKA at a tertiary care center from January 2019 to October 2020. Data from 526 subjects were available. A chart review was conducted to determine if the patient received TXA only, tourniquet only, or both TXA and tourniquet during the TKA procedure. Primary outcomes for this study including procedure length in minutes, estimated blood loss in cubic centimeters, and total infusion pressor (phenylephrine) administered intraoperatively in milligrams were recorded for the study. Data were summarized using means and standard errors. Statistical methods used for analysis include one-way ANOVA, probability plots, the Shapiro-Wilk test for normality, the Kruskal-Wallis test, and Tukey's test. RESULTS: Data were available for 526 subjects. 122 subjects received tourniquet only (Tourniquet group), 104 received intravenous (IV) TXA only, 264 received both tourniquet and IV TXA (Tourniquet + TXA), and 36 received neither tourniquet nor TXA (None). The groups did not significantly differ in procedure length (p = 0.140) or infusion pressor total (p > 0.20). The groups did significantly differ in estimated blood loss (p < 0.001). Subjects who did not receive either TXA or tourniquet had significantly more blood loss than the Tourniquet and Tourniquet + TXA groups. Similarly, the TXA group had significantly more blood loss than both the Tourniquet and Tourniquet + TXA groups. CONCLUSION: This study supports the conclusion that the use of a tourniquet is superior to the use of TXA in reducing intraoperative blood loss during TKA. All groups that underwent TKA using a tourniquet, either alone or in combination with TXA, exhibited significantly lower levels of blood loss compared to the control (no intervention) group.

Extra-short humeral heads reduce glenohumeral joint overstuffing compared with short heads in anatomic total shoulder arthroplasty.

BACKGROUND: Rotator cuff tears and glenoid loosening remain the two most common causes for revision after anatomic total shoulder arthroplasty. Oversizing of the humeral head leads to increased contact force across the glenohumeral joint and is hypothesized to contribute to clinical and radiographic failure. The purpose of this study is to compare the rate of radiographic overstuffing between standard short humeral heads and newer extra-short heads with decreased lateral offset. METHODS: Fifty-five consecutive anatomic total shoulder arthroplasties performed using extra-short humeral heads were retrospectively reviewed and compared with age- and sex-matched controls receiving standard short heads. A total of 110 postoperative radiographs were analyzed using the Iannotti's perfect circle method to compare the prosthesis' center of rotation (COR) with the native humeral head COR. A difference in the COR of >3.0 mm was considered malpositioned. Malpositioning medially was considered overstuffed, and malpositioning laterally was considered understuffed. The direction of displacement of malpositioned prostheses was categorized using a quadrant system. Furthermore, we used a novel method to evaluate medial and superior overstuffing by measuring the displacement between the anatomic and prosthetic head positions along perpendicular axes. RESULTS: Using the Iannotti's perfect circle method, 56% of heads were malpositioned. Overstuffing occurred more frequently with short heads compared with extra-short heads (47% vs. 4%, P < .001). Conversely, understuffing occurred more frequently with extra-short heads (47% vs. 15%, P = .001). Malpositioned extra-short heads were most frequently placed in the inferomedial quadrant (93% vs. 24%, P < .001), whereas malpositioned short heads were most commonly placed in the superomedial quadrant (56% vs. 7%, P < .001). Our novel measurement method demonstrated that extra-short heads reduced medial overstuffing (2.8 ± 2.8 mm vs. 0.3 ± 2.0 mm, P < .001). Both extra-short and short heads had similar rates of superior malpositioning (1.6 ± 2.2 mm vs. 1.4 ± 1.5 mm, P = .683). CONCLUSION: Routine use of extra-short humeral head sizes reduces the rate of medial glenohumeral joint overstuffing but not superior malpositioning. This is hypothesized to improve clinical outcomes, but future studies are needed to assess the relationship between improved humeral head fit and clinical outcomes.

Arthroscopically Assisted Surgical Decompression and Fibular Strut Grafting for Proximal Humerus Avascular Necrosis: Surgical Technique.

Avascular necrosis is a relatively common entity that affects the proximal humerus and can lead to substantial morbidity. It often occurs in younger patients for whom the traditional treatment of shoulder arthroplasty is not optimal. Fibular strut grafting to prevent humeral head collapse has been described as a viable treatment option. However, it is technically challenging to direct the fibular strut graft into the center of the bony infarct, where it will be most effective. This paper describes a technique of arthroscopically assisted fibular strut grafting for avascular necrosis of the humerus. This is a minimally invasive technique with low morbidity and an accurate way of placing the graft into the infarcted segment.

ROCK inhibitor increases proacinar cells in adult salivary gland organoids.

Salisphere-derived adult epithelial cells have been used to improve saliva production of irradiated mouse salivary glands. Importantly, optimization of the cellular composition of salispheres could improve their regenerative capabilities. The Rho Kinase (ROCK) inhibitor, Y27632, has been used to increase the proliferation and reduce apoptosis of progenitor cells grown in vitro. In this study, we investigated whether Y27632 could be used to improve expansion of adult submandibular salivary epithelial progenitor cells or to affect their differentiation potential in different media contexts. Application of Y27632 in medium used previously to grow salispheres promoted expansion of Kit+ and Mist1+ cells, while in simple serum-containing medium Y27632 increased the number of cells that expressed the K5 basal progenitor marker. Salispheres derived from Mist1CreERT2; R26TdTomato mice grown in salisphere media with Y27632 included Mist1-derived cells. When these salispheres were incorporated into 3D organoids, inclusion of Y27632 in the salisphere stage increased the contribution of Mist1-derived cells expressing the proacinar/acinar marker, Aquaporin 5 (AQP5), in response to FGF2-dependent mesenchymal signals. Optimization of the cellular composition of salispheres and organoids can be used to improve the application of adult salivary progenitor cells in regenerative medicine strategies.

Arthroscopic All-Inside Biceps Tenodesis: Technique and Outcomes.

The long head of the biceps tendon (LHBT) is a frequent source of disorders and pathology in the shoulder. Significant evidence is available on the management of disorders of the LHBT in the literature, and the LHBT is frequently addressed intraoperatively when involved in shoulder pathology. An all-arthroscopic, intra-articular biceps tenodesis with suture anchor fixation has several advantages that have not been well described previously, and it does not add significant morbidity to arthroscopic surgery to treat the rotator cuff or other sources of pain. Intra-articular LHBT tenodesis in the bicipital groove thus has advantages of less surgical time and a decreased bone footprint.

RARα and RARγ reciprocally control K5+ progenitor cell expansion in developing salivary glands.

Understanding the mechanisms of controlled expansion and differentiation of basal progenitor cell populations during organogenesis is essential for developing targeted regenerative therapies. Since the cytokeratin 5-positive (K5+) basal epithelial cell population in the salivary gland is regulated by retinoic acid signaling, we interrogated how isoform-specific retinoic acid receptor (RAR) signaling impacts the K5+ cell population during salivary gland organogenesis to identify RAR isoform-specific mechanisms that could be exploited in future regenerative therapies. In this study, we utilized RAR isoform-specific inhibitors and agonists with murine submandibular salivary gland organ explants. We determined that RARα and RARγ have opposing effects on K5+ cell cycle progression and cell distribution. RARα negatively regulates K5+ cells in both whole organ explants and in isolated epithelial rudiments. In contrast, RARγ is necessary but not sufficient to positively maintain K5+ cells, as agonism of RARγ alone failed to significantly expand the population. Although retinoids are known to stimulate differentiation, K5 levels were not inversely correlated with differentiated ductal cytokeratins. Instead, RARα agonism and RARγ inhibition, corresponding with reduced K5, resulted in premature lumenization, as marked by prominin-1. With lineage tracing, we demonstrated that K5+ cells have the capacity to become prominin-1+ cells. We conclude that RARα and RARγ reciprocally control K5+ progenitor cells endogenously in the developing submandibular salivary epithelium, in a cell cycle-dependent manner, controlling lumenization independently of keratinizing differentiation. Based on these data, isoform-specific targeting RARα may be more effective than pan-RAR inhibitors for regenerative therapies that seek to expand the K5+ progenitor cell pool. SUMMARY STATEMENT: RARα and RARγ reciprocally control K5+ progenitor cell proliferation and distribution in the developing submandibular salivary epithelium in a cell cycle-dependent manner while regulating lumenization independently of keratinizing differentiation.

Acute porphyria in a patient with Arnold Chiari malformation.

BACKGROUND: Acute porphyria and Arnold Chiari malformation are both uncommon genetic disorders without known association. The insidious onset, non-specific clinical manifestations, and precipitating factors often cause diagnosis of acute porphyria to be missed, particularly in patients with comorbidities. CASE REPORT: A women with Arnold Chiari malformation type II who was treated with oxybutynin and antibiotics, including Bactrim for neurogenic bladder and recurrent urinary tract infection, presented with non-specific abdominal pain, constipation, and diarrhea. After receiving Flagyl for C. difficile colitis, the patient developed psychosis, ascending paralysis, and metabolic derangements. She underwent extensive neurological workup due to her congenital neurological abnormalities, most of which were unremarkable. As a differential diagnosis of Guillain Barré syndrome, acute porphyria was then considered and ultimately proved to be the diagnosis. After hematin administration and intense rehabilitation, the patient slowly recovered from the full-blown acute porphyria attack. CONCLUSIONS: This case report, for the first time, documents acute porphyria attack as a result of a sequential combination of 3 common medications. This is the first case report of the concomitant presence of both acute porphyria and Arnold Chiari malformation, 2 genetic disorders with unclear association.

Effect of pisiform excision or pisotriquetral arthrodesis as a treatment for pisotriquetral arthritis: a biomechanical study.

PURPOSE: To determine whether flexor carpi ulnaris (FCU) forces and tendon displacements change after pisotriquetral arthrodesis or after pisiform excision. METHODS: Nine cadaver wrists were moved through 4 variations of a dart throw motion, each having an oblique plane of motion, but with different ranges of motion and different antagonistic forces. The FCU tendon force and movement were measured in the intact wrist, following pisotriquetral arthrodesis, and following pisiform excision. Changes in force and tendon movement were compared using a repeated measures analysis of variance. RESULTS: After excision of the pisiform, a significantly greater FCU force was required during the 2 variations of the dart throw motion having a larger range of motion and during the smaller motion having a larger antagonistic force. Pisotriquetral arthrodesis did not cause a significant increase in the peak FCU force. Excision of the pisiform caused the FCU tendon to significantly retract during all wrist motions as compared to the intact wrist or after pisotriquetral arthrodesis. CONCLUSIONS: Greater FCU forces are required to move the wrist when the pisiform with its moment arm function has been removed. This occurs during large oblique plane wrist motions and also in a smaller motion when greater antagonistic forces are applied. Excision of the pisiform also allows the FCU to move proximally, again because its moment arm function has been eliminated. CLINICAL RELEVANCE: Excision of the pisiform requires greater FCU forces during large wrist motions and during motions that include large gripping forces such that excision may be a concern in high-demand patients with pisotriquetral arthritis. Although pisotriquetral arthrodesis does not alter the mechanical advantage of the FCU, its use in high-demand patients with pisotriquetral osteoarthritis cannot yet be recommended until the effects of that arthrodesis on midcarpal kinematics are further clarified.

Inhibition of HDM2 and activation of p53 by ribosomal protein L23.

The importance of coordinating cell growth with proliferation has been recognized for a long time. The molecular basis of this relationship, however, is poorly understood. Here we show that the ribosomal protein L23 interacts with HDM2. The interaction involves the central acidic domain of HDM2 and an N-terminal domain of L23. L23 and L11, another HDM2-interacting ribosomal protein, can simultaneously yet distinctly interact with HDM2 together to form a ternary complex. We show that, when overexpressed, L23 inhibits HDM2-induced p53 polyubiquitination and degradation and causes a p53-dependent cell cycle arrest. On the other hand, knocking down L23 causes nucleolar stress and triggers translocation of B23 from the nucleolus to the nucleoplasm, leading to stabilization and activation of p53. Our data suggest that cells may maintain a steady-state level of L23 during normal growth; alternating the levels of L23 in response to changing growth conditions could impinge on the HDM2-p53 pathway by interrupting the integrity of the nucleolus.

Nucleocytoplasmic shuttling of p53 is essential for MDM2-mediated cytoplasmic degradation but not ubiquitination.

As a shuttling protein, p53 is constantly transported through the nuclear pore complex. p53 nucleocytoplasmic transport is carried out by a bipartite nuclear localization signal (NLS) located at its C-terminal domain and two nuclear export signals (NES) located in its N- and C-terminal regions, respectively. The role of nucleocytoplasmic shuttling in p53 ubiquitination and degradation has been a subject of debate. Here we show that the two basic amino acid groups in the p53 bipartite NLS function collaboratively to import p53. Mutations disrupting individual amino acids in the NLS, although causing accumulation of p53 in the cytoplasm to various degrees, reduce but do not eliminate the NLS activity, and these mutants remain sensitive to MDM2 degradation. However, disrupting both parts of the bipartite NLS completely blocks p53 from entering the nucleus and causes p53 to become resistant to MDM2-mediated degradation. Similarly, mutations disrupting four conserved hydrophobic amino acids in the p53 C-terminal NES block p53 export and prohibit it from MDM2 degradation. We also show that colocalization of a nonshuttling p53 with MDM2 either in the nucleus or in the cytoplasm is sufficient for MDM2-induced p53 polyubiquitination but not degradation. Our data provide new insight into the mechanism and regulation of p53 nucleocytoplasmic shuttling and degradation.