Relaxation of vascular smooth muscle and prevention of blood coagulation are mediated by ligand-induced activation of the human prostacyclin (hIP) receptor, a seven-transmembrane-domain G-protein-coupled receptor (GPCR). In this study, we elucidate the molecular requirements for receptor activation within the region of the ligand-binding pocket, identifying transmembrane residues affecting potency. Eleven of 30 mutated residues in the region of the ligand-binding domain exhibited defective activation (decreased potency). These critical residues localized to four distinct clusters (analysis via a rhodopsin-based human prostacyclin receptor homology model). Residues Y75(2.65) (TMII), F95(3.28) (TMIII), and R279(7.40) (TMVII) comprised the immediate binding-pocket cluster and were shown to be essential for proper receptor activation, compared to equivalent expression levels of the wild-type hIP (WT EC(50) = 1.2 +/- 0.1 nM; Y75(2.65)A EC(50) = 347.3 +/- 62.8 nM, p < 0.001; F95(3.28)A EC(50) = 8.0 +/- 0.6 nM, p < 0.001; R279(7.40)A EC(50) = 130 +/- 63.0 nM, p < 0.001). Residues S20(1.39) (TMI), F24(1.43) (TMI), and F72(2.62) (TMII) were localized to a cluster involving P17(1.36), a critical residue thought to facilitate transmembrane movement during changes in activation conformation. A third cluster formed around amino acid D60(2.50) (TMII), containing the highly conserved (100% of prostanoid receptors) D288(7.49)/P289(7.50) motif located in TMVII. Last, a large hydrophobic cluster composed of aromatic residues F146(4.52) (TMIV), F150(4.56) (TMIV), F184(5.40) (TMV), and Y188(5.44) (TMV) was observed away from the ligand-binding pocket, but still necessary for hIP activation. These results assist in delineating the potential molecular requirements for agonist-induced signaling through the transmembrane domain. Such observations may be generally applicable, as many of these clusters are highly conserved among the prostanoid receptors as well as other class A GPCRs.
Tumoral pseudoangiomatous stromal hyperplasia (PASH) is a rare benign proliferative disease of the breast. The majority of the literature reports of PASH have not contained detailed descriptions of the imaging characteristics of PASH. A 10-year retrospective study of patients with tumoral PASH and a 20-year Ovid MEDLINE® search were performed to determine whether specific imaging and needle biopsy results could characterize PASH preoperatively. We identified 22 patients with tumoral PASH. Seventeen (77%) of 22 women had a palpable lump and 14 (72%) of 21 had a density on mammography. Ultrasound (US) findings included mixed or hypoechoic echogenicity in 83 per cent and ill-defined borders in 62 per cent. Eight (36%) patients had lesions with a Breast Imaging Reporting and Data System (BI-RADS®) classification of 4 or 5. The sensitivity of preoperative core needle biopsy (CNB) to identify PASH was 83 per cent. A review of the literature revealed that 90 per cent of patients with PASH had some malignant imaging characteristics and 95 per cent had a mass on mammography. The imaging characteristics of PASH exhibited marked variability. Excision of PASH after CNB may be considered for patients with symptoms, enlarging lesions, or lesions classified as BI-RADS® 4 or 5. PASH diagnosed by CNB allows selected patients to avoid excision.
Purpose This study aimed to determine whether unrestricted weight-bearing as tolerated (WBAT) following lateral locking plate (LLP) fixation of periprosthetic distal femoral fractures (PDFFs) is associated with increased failure and reoperation, compared with restricted weight-bearing (RWB). Materials and methods In a retrospective cohort study of consecutive patients with unilateral PDFFs undergoing LLP fixation, patients prescribed WBAT were compared with those prescribed 6 weeks of RWB. The primary outcome measure was reoperation. Kaplan–Meier and Cox multivariable analyses were performed. Results There were 43 patients (mean age 80.9 ± 11.7 years, body mass index 26.8 ± 5.7 kg/m2 and 86.0% female): 28 WBAT and 15 RWB. There were more interprosthetic fractures in the RWB group (p = 0.040). Mean follow-up was 3.8 years (range 1.0–10.4). Eight patients (18.6%) underwent reoperation. Kaplan–Meier analysis demonstrated no difference in 2-year survival between WBAT (80.6%, 95% CI 65.3–95.9) and RWB (83.3%, 95% CI 62.1–100.0; p = 0.54). Cox analysis showed increased reoperation risk with medial comminution (hazard ratio 10.7, 95% CI 1.5–80; p = 0.020) and decreased risk with anatomic reduction (hazard ratio 0.11, 95% CI 0.01–1.0; p = 0.046). Immediate weight-bearing did not significantly affect the risk of reoperation compared with RWB (relative risk 1.03, 95% CI 0.61–1.74; p = 0.91). Conclusions LLP fixation failure was associated with medial comminution and non-anatomic reductions, not with postoperative weight-bearing. Medial comminution should be managed with additional fixation. Weight-bearing restrictions additional to this appear unnecessary and should be avoided.
Aims Debate continues regarding the optimum management of periprosthetic distal femoral fractures (PDFFs). This study aims to determine which operative treatment is associated with the lowest perioperative morbidity and mortality when treating low (Su type II and III) PDFFs comparing lateral locking plate fixation (LLP-ORIF) or distal femoral arthroplasty (DFA). Methods This was a retrospective cohort study of 60 consecutive unilateral (PDFFs) of Su types II (40/60) and III (20/60) in patients aged ≥ 60 years: 33 underwent LLP-ORIF (mean age 81.3 years (SD 10.5), BMI 26.7 (SD 5.5); 29/33 female); and 27 underwent DFA (mean age 78.8 years (SD 8.3); BMI 26.7 (SD 6.6); 19/27 female). The primary outcome measure was reoperation. Secondary outcomes included perioperative complications, calculated blood loss, transfusion requirements, functional mobility status, length of acute hospital stay, discharge destination and mortality. Kaplan-Meier survival analysis was performed. Cox multivariate regression analysis was performed to identify risk factors for reoperation after LLP-ORIF. Results Follow-up was at mean 3.8 years (1.0 to 10.4). One-year mortality was 13% (8/60). Reoperation was more common following LLP-ORIF: 7/33 versus 0/27 (p = 0.008). Five-year survival for reoperation was significantly better following DFA; 100% compared to 70.8% (95% confidence interval (CI) 51.8% to 89.8%, p = 0.006). There was no difference for the endpoint mechanical failure (including radiological loosening); ORIF 74.5% (56.3 to 92.7), and DFA 78.2% (52.3 to 100, p = 0.182). Reoperation following LLP-ORIF was independently associated with medial comminution; hazard ratio (HR) 10.7 (1.45 to 79.5, p = 0.020). Anatomical reduction was protective against reoperation; HR 0.11 (0.013 to 0.96, p = 0.046). When inadequately fixed fractures were excluded, there was no difference in five-year survival for either reoperation (p = 0.156) or mechanical failure (p = 0.453). Conclusion Absolute reoperation rates are higher following LLP fixation of low PDFFs compared to DFA. Where LLP-ORIF was well performed with augmentation of medial comminution, there was no difference in survival compared to DFA. Though necessary in very low fractures, DFA should be used with caution in patients with greater life expectancies due to the risk of longer term aseptic loosening. Cite this article: Bone Joint J 2021;103-B(4):635–643.
Aims The aim of this study was to determine satisfaction rates after hip and knee arthroplasty in patients who did not respond to postoperative patient-reported outcome measures (PROMs), characteristics of non-responders, and contact preferences to maximize response rates. Methods A prospective cohort study of patients planned to undergo hip arthroplasty (n = 713) and knee arthroplasty (n = 737) at a UK university teaching hospital who had completed preoperative PROMs questionnaires, including the EuroQol five-dimension health-related quality of life score, and Oxford Hip Score (OHS) and Oxford Knee Score (OKS). Follow-up questionnaires were sent by post at one year, including satisfaction scoring. Attempts were made to contact patients who did not initially respond. Univariate, logistic regression, and receiver operator curve analysis was performed. Results At one year, 667 hip patients (93.5%) and 685 knee patients (92.9%) had undergone surgery and were alive. No response was received from 151/667 hip patients (22.6%), 83 (55.0%) of whom were ultimately contacted); or from 108/685 knee patients (15.8%), 91 (84.3%) of whom were ultimately contacted. There was no difference in satisfaction after arthroplasty between initial non-responders and responders for hips (74/81 satisfied vs 476/516 satisfied; p = 0.847) or knees (81/93 satisfied vs 470/561 satisfied; p = 0.480). Initial non-response and persistent non-response was associated with younger age, higher BMIs, and worse preoperative PROMs for both hip and knee patients (p < 0.050). Being in employment was associated with persistent non-response for hip patients (p = 0.047). Multivariate analysis demonstrated that younger age (p < 0.038), higher BMI (p = 0.018), and poorer preoperative OHS (p = 0.031) were independently associated with persistent non-response to hip PROMs. No independent associations were identified for knees. Using a threshold of > 66.4 years predicted a preference for contact by post (area under the curve 0.723 (95% confidence interval (CI) 0.647 to 0.799; p < 0.001, though this CI crosses the 0.7 limit considered reliable). Conclusion The majority of initial non-responders were ultimately contactable with effort. Satisfaction rates were not inferior in patients who did not initially respond to PROMs. Cite this article: Bone Jt Open 2022;3(4):275–283.
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