Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells.

Diabetes mellitus is clinically defined by chronic hyperglycemia. Sex differences in the presentation and outcome of diabetes exist with premenopausal women having a reduced risk of developing diabetes, relative to men, or women after menopause. Accumulating evidence shows a protective role of estrogens, specifically 17-beta estradiol, in the maintenance of pancreatic beta cell health; however, the mechanisms underlying this protection are still unknown. To elucidate these potential mechanisms, we used a pancreatic beta cell line (BTC6) and a mouse model of hyperglycemia-induced atherosclerosis, the ApoE-/-:Ins2+/Akita mouse, exhibiting sexual dimorphism in glucose regulation. In this study we hypothesize that 17-beta estradiol protects pancreatic beta cells by modulating the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. We observed that ovariectomized female and male ApoE-/-:Ins2+/Akita mice show significantly increased expression of apoptotic UPR markers. Sham operated female and ovariectomized female ApoE-/-:Ins2+/Akita mice supplemented with exogenous 17-beta estradiol increased the expression of adaptive UPR markers compared to non-supplemented ovariectomized female ApoE-/-:Ins2+/Akita mice. These findings were consistent to what was observed in cultured BTC6 cells, suggesting that 17-beta estradiol may protect pancreatic beta cells by repressing the apoptotic UPR and enhancing the adaptive UPR activation in response to pancreatic ER stress.

MPFL repair after acute first-time patellar dislocation results in lower redislocation rates and less knee pain compared to rehabilitation: a systematic review and meta-analysis.

PURPOSE: This study aimed to explore the efficacy of medial patellofemoral ligament (MPFL) repair versus nonoperative rehabilitation treatment on the rate of patellar redislocation and functional outcomes in skeletally mature patients with traumatic, first-time patellar dislocations. MATERIALS AND METHODS: MEDLINE, PubMed and EMBASE were searched from database inception to May 2022 for studies examining the management options for acute first-time patellar dislocations. This study was conducted in accordance with PRISMA and R-AMSTAR guidelines. Data on redislocation rates, functional outcomes including the Kujala score for anterior knee pain, and complication rates were extracted. A meta-analysis was used to pool the mean postoperative Kujala score and calculate the proportion of patients sustaining redislocations using a random effects model. Quality assessment of included studies was performed for all included studies using the MINORS and Detsky scores. RESULTS: This review included a total of 25 studies and 1,361 patients. The pooled mean redislocation rate in 15 studies comprising 798 patients in the rehabilitation group was 30% (95% CI 25-36%, I2 = 65%). Moreover, the pooled mean redislocation rate in 10 studies comprising 170 patients undergoing MPFL repair was 7% (95% CI 3-12%, I2 = 30%). The pooled mean postoperative Kujala score in 8 studies comprising 396 patients in the rehabilitation group was 82.5 (95% CI 78.3-86.8, I2 = 91%), compared to a score of 88 (95% CI 87-90, I2 = 76%) in 3 studies comprising 94 patients in the repair group. Range of motion deficits was reported in 3.8% of 893 patients in the rehabilitation group and 2.0% of 205 patients in the repair group. CONCLUSION: MPFL repair resulted in a lower rate of redislocation, less knee pain, and noninferiority with respect to a range of motion deficits compared to nonoperative treatment for the management of acute first-time patellar dislocations. LEVEL OF EVIDENCE: IV.

The Role of Estrogen in Insulin Resistance: A Review of Clinical and Preclinical Data.

Insulin resistance results when peripheral tissues, including adipose, skeletal muscle, and liver, do not respond appropriately to insulin, causing the ineffective uptake of glucose. This represents a risk factor for the development of type 2 diabetes mellitus. Along with abdominal obesity, hypertension, high levels of triglycerides, and low levels of high-density lipoproteins, insulin resistance is a component of a condition known as the metabolic syndrome, which significantly increases the risk of developing cardiometabolic disorders. Accumulating evidence shows that biological sex has a major influence in the development of cardiometabolic disturbances, with females being more protected than males. This protection appears to be driven by female sex hormones (estrogens), as it tends to disappear with the onset of menopause but can be re-established with hormone replacement therapy. This review evaluates current knowledge on the protective role of estrogens in the relevant pathways associated with insulin resistance. The importance of increasing our understanding of sex as a biological variable in cardiometabolic research to promote the development of more effective preventative strategies is emphasized.

MPFL reconstruction results in lower redislocation rates and higher functional outcomes than rehabilitation: a systematic review and meta-analysis.

PURPOSE: To determine the effect of early MPFL reconstruction versus rehabilitation on the rate of recurrent patellar dislocations and functional outcomes in skeletally mature patients with traumatic, first-time patellar dislocation. METHODS: Three online databases MEDLINE, PubMed and EMBASE were searched from database inception (1946, 1966, and 1974, respectively) to August 20th, 2021 for literature addressing the management of patients sustaining acute first-time patellar dislocations. Data on redislocation rates, functional outcomes using the Kujala score, and complication rates were recorded. A meta-analysis was used to pool the mean postoperative Kujala score, as well as calculate the proportion of patients sustaining redislocation episodes using a random effects model. Quality assessment of included studies was performed for all included studies using the MINORS and Detsky scores. RESULTS: A total of 19 studies and 1,165 patients were included in this review. The pooled mean redislocation rate in 14 studies comprising 734 patients in the rehabilitation group was 30% (95% CI 25-36%, I2 = 67%). Moreover, the pooled mean redislocation rate in 5 studies comprising 318 patients undergoing early MPFL reconstruction was 7% (95% CI 2-17%, I2 = 70%). The pooled mean postoperative Kujala anterior knee pain score in 7 studies comprising 332 patients in the rehabilitation group was 81 (95% CI 78-85, I2 = 78%), compared to a score of 87 (95% CI 85-89, I2 = 0%, Fig. 4) in 3 studies comprising 54 patients in the reconstruction group. CONCLUSION: Management of acute first-time patellar dislocations with MPFL reconstruction resulted in a lower rate of redislocation of 7% in the reconstruction group vs 30% in the rehabilitation group and a higher Kujala score compared to the rehabilitation group. The information this review provides will help surgeons guide their decision to choose early MPFL reconstruction versus rehabilitation when treating patients with first-time patellar dislocations and may guide future studies on the topic. LEVEL OF EVIDENCE: IV.

Quadriceps tendon autograft for pediatric anterior cruciate ligament reconstruction results in promising postoperative function and rates of return to sports: A systematic review.

PURPOSE: To assess the performance of the quadriceps tendon (QT) autograft in pediatric anterior cruciate ligament reconstruction (ACLR). METHODS: A systematic search of MEDLINE, PubMed, and EMBASE was conducted on March 1, 2021. Studies of all levels of evidence reporting outcomes and/or complications after QT autograft ACLR in pediatric patients (≤ 18 years old) were eligible for inclusion. Study demographics, patient demographics, reported outcomes, and complications were abstracted. Screening and data abstraction were designed in accordance with PRISMA and R-AMSTAR guidelines. Descriptive statistics were presented when applicable, with data for heterogeneous outcomes presented in narrative summary fashion. RESULTS: A total of 14 studies examining 596 patients (46.3% female), mean age 15.4 years, were included in this systematic review. Mean postoperative Lysholm scores ranged from 94.0 to 99.5. Mean postoperative IKDC subjective scores ranged from 75.9 to 94.0. Limb symmetry index ranged from 96.8 ± 10.4 to 100.4 ± 7.6% across multiple hop tests. Return to sports (RTS) rates ranged from 88.9 to 91.7%. Eleven studies reported postoperative complications, whereby 16 patients (4.8%) experienced contralateral complications and injuries. Forty-six patients (9.4%) experienced ipsilateral complications, including ten graft failures (2.5%) and two growth disturbances (0.6%). CONCLUSIONS: QT autograft ACLR in the pediatric population retains the potential of regaining a preinjury level of knee stability, and yields promising postoperative function and rates of RTS, yielding comparable outcomes relative to HT autograft and the reference-standard BPTB ACLR that have previously been described in the literature. Moreover, use of the QT autograft is associated with low rates of postoperative complications, including graft failure and growth disturbances in this active and high-risk patient population in observational studies to date. Therefore, clinical equipoise exists to further appraise the influence of QT autograft on postoperative outcomes compared to aforementioned autograft options in a randomized control trial fashion. LEVEL OF EVIDENCE: IV.

Bone Grafting the Patellar Defect After Bone-Patellar Tendon-Bone Anterior Cruciate Ligament Reconstruction Decreases Anterior Knee Morbidity: A Systematic Review.

PURPOSE: The aim of this systematic review was to evaluate the impact of bone grafting of patellar defects on reported anterior knee morbidity and subjective outcomes after bone-patellar tendon-bone autograft reconstruction of the anterior cruciate ligament. METHODS: A systematic electronic search of MEDLINE, Embase, Web of Science, and the Cochrane Library was carried out. All English-language prospective randomized clinical trials published from January 1, 2000, to July 24, 2020, were eligible for inclusion. All studies addressing patellar defect grafting were eligible for inclusion regardless of the timing of surgery, graft type, surgical technique, or rehabilitation protocol. RESULTS: A total of 39 studies with 1,955 patients were included for analysis. There were 796 patients in the no patellar grafting (NPG) group, with a mean age range of 22.7 to 33.0 years, and 1,159 patients in the patellar grafting (PG) group, with a mean age range of 17.8 to 34.7 years. The visual analog scale pain score ranged from 1.2 to 5.1 in the NPG group compared with 0.3 to 3.7 in the PG group. The proportion of patients with anterior knee pain ranged from 19% to 81% in the NPG group and from 15% to 32% in the PG group. Moderate to severe kneeling pain was reported in 22% to 57% of patients in the NPG group and 10% of those in the PG group. The percentage of patients with at least 3° of extension loss ranged from 4% to 43% in the NPG group and from 2% to 11% in the PG group. CONCLUSIONS: PG favors decreased anterior knee pain, kneeling pain, and extension loss compared with non-grafted defects; however, the functional outcomes are comparable. Owing to the heterogeneity in reporting, statistical conclusions could not be drawn. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies.

The incidence of tibial tunnel coalition is higher than femoral tunnel coalition in double-bundle anterior cruciate ligament reconstruction using hamstring autografts: A systematic review.

INTRODUCTION: Intra-operative and postoperative coalition of tunnels may occur in double-bundle (DB) anterior cruciate ligament reconstruction (ACLR). However, the incidence and effect on clinical outcomes of tunnel coalition following primary DB ACLR using a hamstring autograft has yet be analyzed, and thus remains unknown. The objective of this systematic review was to identify the incidence of tunnel coalition upon DB ACLR using hamstring autografts and to elucidate any clinical outcomes and/or complications that tunnel coalition may have postoperatively. HYPOTHESIS: The incidence of tunnel coalition would increase in respect to time from the index surgery, and that tunnel coalition would be related to poorer clinical outcomes compared to non-coalition cases. METHODS: Three databases (PubMed, EMBASE, Cochrane Library) were searched in accordance with PRISMA and R-AMSTAR guidelines on June 15, 2020. Relevant studies were screened in duplicate and data regarding patient demographics, incidence of femoral and tibial tunnel coalition, and outcomes were extracted. Coalition rate was also compared between follow up at 1 month or less defined as "shorter-term", and 6 months or greater as "longer-term". Coalition is defined as the missing of a bony bridge between the two tunnels. RESULTS: Thirty-six studies examining 1,574 patients, mean age 29.1 years, were included in this study. 29 studies (1,110 knees) reported the incidence of femoral coalition with a pooled rate of coalition of 8% (95% CI=4-12%). 28 studies (1,129 knees) reported an incidence of tibial coalition with a pooled rate of coalition of 21% (95% CI=13-30%). The incidence of tibial coalition was significantly higher than the incidence of femoral coalition across 21 comparative studies (OR=3.37, 95% CI=1.41-8.09, p=0.0065). Only two studies (111 knees) compared tunnel coalition and non-coalition groups for clinical outcome and no significant differences were observed with regards to Lysholm score, Tegner activity scale, and knee laxity measured with a KT-1000 arthrometer. DISCUSSION: The rate of tibial tunnel coalition in DB ACLR is higher than femoral tunnel coalition, particularly at longer-term follow-up. Despite the higher radiographic evidence of coalition, the clinical effects of such remain to be ascertained, and further comparative studies are required to facilitate this understanding. LEVEL OF EVIDENCE: IV, systematic review.