Pantothenate-encapsulated liposomes combined with exercise for effective inhibition of CRM1-mediated PKM2 translocation in Alzheimer's therapy.

Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by metabolic imbalances and neuroinflammation, posing a formidable challenge in medicine due to the lack of effective treatments. Despite considerable research efforts, a cure for AD remains elusive, with current therapies primarily focused on symptom management rather than addressing the disease's underlying causes. This study initially discerned, through Mendelian randomization analysis that elevating pantothenate levels significantly contributes to the prophylaxis of Alzheimer's disease. We explore the therapeutic potential of pantothenate encapsulated in liposomes (Pan@TRF@Liposome NPs), targeting the modulation of CRM1-mediated PKM2 nuclear translocation, a critical mechanism in AD pathology. Additionally, we investigate the synergistic effects of exercise, proposing a combined approach to AD treatment. Exercise-induced metabolic alterations share significant similarities with those associated with dementia, suggesting a potential complementary effect. The Pan@TRF@Liposome NPs exhibit notable biocompatibility, showing no liver or kidney toxicity in vivo, while demonstrating stability and effectiveness in modulating CRM1-mediated PKM2 nuclear translocation, thereby reducing neuroinflammation and neuronal apoptosis. The combined treatment of exercise and Pan@TRF@Liposome NP administration in an AD animal model leads to improved neurofunctional outcomes and cognitive performance. These findings highlight the nanoparticles' role as effective modulators of CRM1-mediated PKM2 nuclear translocation, with significant implications for mitigating neuroinflammation and neuronal apoptosis. Together with exercise, this dual-modality approach could offer new avenues for enhancing cognitive performance and neurofunctional outcomes in AD, marking a promising step forward in developing treatment strategies for this challenging disorder.

Exercise-Induced Reduction of IGF1R Sumoylation Attenuates Neuroinflammation in APP/PS1 Transgenic Mice.

INTRODUCTION: Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues. OBJECTIVES: This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies. METHODS: APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise. RESULTS: Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1ß, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation. CONCLUSION: Moderate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD.

Clinical Utility of the Prenatal BACs-on-Beads™ Assay in Invasive Prenatal Diagnosis.

Background: The prenatal BACs-on-Beads™ (PNBoBs™) assay has been applied worldwide for prenatal diagnosis. However, there are neither guidelines nor consensus on choosing patients, sample types, or clinical pathways for using this technique. Moreover, different perspectives have emerged regarding its clinical value. This study aimed to evaluate its clinical utility in the context of clinical practice located in a prenatal diagnostic center in Xiamen, a city in southeast China. Methods: We tested 2,368 prenatal samples with multiple referral indications using both conventional karyotyping and PNBoBs™. Positive results from PNBoBs™ were verified using current gold-standard approaches. Results: The overall rates for the detection of pathogenic copy number variation (pCNV) by karyotyping and PNBoBs™ were 1.9% (46/2,368) and 2.0% (48/2,368), respectively. The overall detection rate of karyotyping combined with PNBoBs™ for pCNV was 2.3% (54/2,368). A total of 13 cases of copy number variation (CNV)with a normal karyotype were detected by PNBoBs™. Another case with a normal karyotype that was detected as a CNV of sex chromosomes by PNBoBs™ was validated to be maternal cell contamination by short tandem repeat analysis. Conclusion: Karyotyping combined with PNBoBs™ can improve both the yield and efficiency of prenatal diagnosis and is appropriate in the second trimester in all patients without fetal ultrasound anomalies who undergo invasive prenatal diagnosis.

Retears and Concomitant Functional Impairments After Rotator Cuff Repair: Shoulder Activity as a Risk Factor.

BACKGROUND: Most patients return successfully to shoulder involving sports or activity after rotator cuff repairs. It has not been decided yet whether postoperative participation in shoulder activity adds to the risk of retear. PURPOSE/HYPOTHESIS: The purpose was to verify whether patients who participate in shoulder activities after rotator cuff repair have a higher risk of structural failure than nonactive patients and to investigate the relationship between postoperative shoulder function and tendon integrity in active and nonactive patients. The hypotheses were that (1) active patients have a higher retear rate than nonactive patients and (2) structural failure is associated with worse functional outcomes in active patients. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A cohort study was performed using 145 patients who underwent arthroscopic rotator cuff repair from 2015 to 2017. Functional assessments and magnetic resonance imaging were performed at least 24 months postoperatively. Shoulder activities since 6 months after surgery were rated in 4 categories (sports, job, activities of daily life, and weight of general lifting) as sedentary, light, moderate, or strenuous. The activity level of each patient was defined by the highest rated category. Patients who were involved in light, moderate, and strenuous activity were identified as active for the present study, and the rest were defined as sedentary. The proportion of retears between groups and the functional conditions between retorn and intact tendons were compared. RESULTS: A total of 48 patients were enrolled in the active group, and 97 were enrolled in the sedentary group. The active group demonstrated a significantly higher retear rate than the sedentary group (27.1% vs 11.3%, respectively; P = .016; risk ratio, 2.39 [95% CI, 1.16-4.93]). In the active group, patients with retears showed higher visual analog scale scores for pain, decreased abduction strength, and lower shoulder functional scores (American Shoulder and Elbow Surgeons score, Fudan University Shoulder Score, and Constant-Murley score) than those with healed tendons, whereas in the sedentary group, functional outcomes were generally similar across patients with and without retears. CONCLUSION: Shoulder activity after the early postoperative period was associated with a high risk of retears in patients who underwent rotator cuff repair. A correlation between inhibited function and structural failure was detected but only in active patients, while sedentary patients with retears retained functional improvements similar to those with intact tendons.

Arthroscopic Superior Capsular Reconstruction Using "Sandwich" Patch Technique for Irreparable Rotator Cuff Tears.

The technique of superior capsular reconstruction (SCR) using fascia lata autograft, described by Mihata et al. in 2012, has been an acceptable and effective method for treating irreparable massive rotator cuff tears, especially in cases with severe fatty infiltration and tendon retraction. After the SCR procedure of Mihata et al., it was found that some graft failure occurred with thinning and elongation during the follow-up time, which was called graft "creep." To avoid graft creep and reduce graft failure rates after SCR, we created an arthroscopic SCR technique with a "sandwich" patch augmented with polyethylene terephthalate scaffold interspaced between 2 folded layers of fascia lata autograft.

Double-row rotator cuff repairs lead to more intensive pain during the early postoperative period but have a lower risk of residual pain than single-row repairs.

PURPOSE: The purpose of this study is to compare pain patterns and identify factors associated with residual shoulder pain after rotator cuff repairs using double-row and single-row techniques. METHODS: A cohort study was performed using patients who underwent arthroscopic rotator cuff repairs at our center in 2015. Patients were allocated according to the repair technique into an single-row (SR) group or a double-row (DR) group. Visual Analog Scale (VAS) scores for pain were assessed at 1 week, 3 months, 6 months, 12 months and 24 months after surgery. Functional and radiographic assessments were performed at least 24 months postoperatively. The proportion of patients with residual pain and factors associated with residual shoulder pain (VAS > 0 at the final follow-up) were analyzed in both groups. RESULTS: Fifty-two patients were enrolled in the SR group, and 53 were enrolled in the DR group. The DR group appeared to have higher levels of pain 1 week (P < 0.001) and 3 months (P = 0.041) postoperatively, while at other time points, the pain intensity of the two groups was comparable. Fourteen (26.4%) and 25 (48.1%) patients in the DR and the SR groups, respectively, developed residual shoulder pain, (P = 0.022; RR 1.82). The univariate analysis and multiple regression revealed that a poorer quality of tendon tissue is related to residual pain in the SR group, whereas tendon retraction is associated with residual pain in the DR group. The rate of re-tear was similar between the two groups and between patients with and without residual pain. CONCLUSIONS: The DR repair technique results in a greater intensity of pain than that of SR repair during the first 3 months after surgery; however, patients who underwent DR repair presented a significantly lower proportion of residual shoulder pain and better tendon quality after 2 years. Poorer tendon quality and larger tendon retraction as determined intraoperatively were risk factors for residual pain. These results highlight the necessity of promoting healing on the grounds of residual pain prevention. LEVEL OF EVIDENCE: II.

Effect of Nearly Isometric ACL Reconstruction on Graft-Tunnel Motion: A Quantitative Clinical Study.

BACKGROUND: In anterior cruciate ligament (ACL) reconstruction, minimizing the graft-tunnel motion (GTM) will promote graft-to-bone healing and avoid graft loosening or tearing as well as potential bone tunnel enlargement. A nearly isometric state of the graft can be achieved by placing the tunnel properly to theoretically gain better graft-to-bone healing. However, little clinical evidence is available to quantify the relation between GTM and tunnel position. PURPOSE: To find the proper zones for the femoral and tibial tunnel apertures that minimize the GTM, referred to as the "nearly isometric zone," through use of intraoperative GTM measurement and 3-dimensional computed tomography (3D-CT). STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 100 patients were enrolled in this study. Nearly isometric ACL reconstruction was performed, and an intra-articular GTM measuring device was designed to measure and record the amplitude of GTM while the knee was flexed from 0° to 120°. Postoperatively, the patients underwent multislice CT, and the images were used to create 3D-CT models. After tibial aperture examination, 5 patients were excluded due to the divergence of tibial aperture, and therefore 95 patients remained in the study. Patients were divided into 2 groups according to whether the lateral intercondylar ridge was absent or present. The Bernard-Hertel grid coordinates (h, t) of the femoral tunnel were then quantified. RESULTS: The maximal GTM (mGTM) was a mean ± SD of 1.06 ± 0.66 mm (range, 0.0-3.0 mm). The mGTM in patients with a lateral intercondylar ridge was significantly lower than that in patients without a lateral intercondylar ridge (0.81 ± 0.39 vs 1.59 ± 0.73 mm, respectively; P < .0001). The average h and t were 0.227 ± 0.079 and 0.429 ± 0.770, respectively. Notably, in 1 patient, the mGTM was 0 mm whereas the coordinates (h, t) of the femoral tunnel were 0.250 and 0.255. The overall GTM slowly increased before 90° but increased significantly after the knee was bent 105° (P = .010). Correlation analysis showed that the t coordiinate had significant correlation with mGTM (R = 0.581; P < .001). A gradient pattern was created to show the nearly isometric blue zone (mGTM <0.5 mm), which was found to overlap with the IDEAL (isometric, direct insertion, eccentric, anatomic, low tension-flexion pattern) position. CONCLUSION: A method of measuring intraoperative GTM and quantifying femoral tunnel position on postoperative 3D-CT was successfully developed. The presence of a lateral condylar ridge can significantly reduce mGTM. A nearly isometric zone was described that was consistent with the IDEAL concept.

Enhance the biocompatibility and osseointegration of polyethylene terephthalate ligament by plasma spraying with hydroxyapatite in vitro and in vivo.

PURPOSE: This study was designed to evaluate the biocompatibility and osseointegration of polyethylene terephthalate ligament after coating with hydroxyapatite (PET/HA) by using the plasma spraying technique in vitro and in vivo. METHODS: In this study, PET/HA sheets were prepared by using the plasma spraying technique. The characterization, the viability of bone marrow stromal cells (BMSCs), and the mRNA expression of bone formation-related genes were evaluated in vitro. The osseointegration in vivo was investigated in the rabbit anterior cruciate ligament (ACL) reconstruction model by micro-computed tomography (micro-CT) analysis, histological evaluation, and biomechanical tests. RESULTS: Scanning electron microscopy (SEM) results showed that the surface of polyethylene terephthalate (PET) becomes rough after spraying with hydroxyapatite (HA) nanoparticles, and the water contact angle was 75.4°±10.4° in the PET/HA-plasma group compared to 105.3°±10.9° in the control group (p<0.05). The cell counting kit-8 counting results showed that the number of BMSCs significantly increased in the PET/HA-plasma group (p<0.05). Reverse transcription polymerase chain reaction (RT-PCR) results showed that there was an upregulated mRNA expression of bone formation-related genes in the PET/HA-plasma group (p<0.05). Micro-CT results showed that the transactional area of tibial tunnels and femoral tunnels was smaller in the PET/HA-plasma group (p<0.05). The histological evaluation scores of the PET/HA-plasma group were significantly superior to those of the PET control group at 8 and 12 weeks (p<0.05). The biomechanical tests showed an increased maximum load to failure and stiffness in the PET/HA-plasma group compared to those in the control group at 8 and 12 weeks. CONCLUSION: Both in vitro and in vivo results demonstrated in this study suggest that the biocompatibility and osseointegration of PET/HA ligament were significantly improved by increasing the proliferation of cells and upregulating the expression of bone formation-related genes. In a word, the PET/HA-plasma ligament is a promising candidate for ACL reconstruction in future.

A polygon-shaped complex appearance of medial patellofemoral ligament with dynamic functional insertion based on an outside-in and inside-out dissection technique.

PURPOSE: To describe the unclarified characteristics of medial patellofemoral ligament and its relation to neighboring structures. METHODS: Sixteen fresh-frozen human knees were dissected in using outside-in and inside-out combined technique. The patellar side attachment was observed from the inside view and femoral side from outside view. RESULTS: The medial patellofemoral ligament was described a complex and multiconnected structure. The femoral side included the upper and lower portion, of which the upper portion attached on the femur with mean width 7.5 ± 1.1 mm and its superficial fibers extended to the adductor magnus tendon and the medial gastrocnemius tendon, and of which the lower portion appeared a right-triangle connected to the MCL without bony attachment. From inside view, the patellar attachment consisted of the bony and non-bony parts. The width of bony attachment was measured mean 16.3 ± 3.8 mm, and the non-bony attachment was found attached on the vastus intermedius tendon with mean width 21.7 ± 4.8 mm. The average thickness was 0.4 ± 0.1 mm and the length were inside assessed mean 67.9 ± 6.1 mm. CONCLUSION: The medial patellofemoral ligament which dissected a complicated structure with bony and non-bony attachment and multi-connected to neighboring structures on both patella and femur side appears as a polygon-shaped complex structure.

Posterior cruciate ligament is twisted and flat structure: new prospective on anatomical morphology.

PURPOSE: This cadaveric study aimed to elucidate PCL morphology by observing the anatomical relationship with other structures and the fibre layers of the PCL in cross section for remnant preserving PCL reconstruction. METHODS: Seventeen fresh-frozen cadaveric knees were studied, using the clock-face method to analyse the anatomical relationship between the PCL and Humphrey's ligament. The width and thickness of the PCL, Humphrey's and Wrisberg's ligaments were measured. The PCL was cut sharply perpendicular to the tibia shaft, and the fibre layers were observed in cross section. RESULTS: The PCL was located between 12 and 4 o'clock in the right knee (8 and 12 o'clock in the left), while Humphrey's ligament was located between 2 and 4 o'clock in the right knee (8 and 10 o'clock in the left). Humphrey's ligament at femoral insertion, midsubstance and lateral meniscus insertion averaged 8.7 ± 2.3, 5.9 ± 2.1 and 6.1 ± 2.0 mm, respectively, while the thickness at each level averaged 2.0 ± 1.2, 1.6 ± 0.6 and 1.9 ± 0.6 mm. The width of the PCL at midsubstance and at medial meniscus level averaged 13.3 ± 2.0 and 11.0 ± 1.6 mm, respectively, while the thickness of the PCL averaged 5.4 ± 0.8 and 5.5 ± 1.4 mm. In cross section, multiple, interconnected layers were observed which could not be divided. The main layers at each level were aligned from the posterolateral to the anteromedial aspect and formed a C-shape at the medial meniscus level. CONCLUSION: The PCL at midsubstance is flat. PCL appears as a twisted ribbon composed of many small fibres without clearly separate bundles. When remnant preserving PCL reconstruction is performed, it is necessary to take account of not only PCL morphology but also the ligaments of Humphrey and Wrisberg. These findings may affect the PCL footprint and the graft shape in the future remnant preserving PCL reconstruction.

A Long Preoperative Duration of Symptoms Is Associated With Worse Functional Outcomes After 1-Stage Arthroscopic Treatment of Rotator Cuff Tears With Shoulder Stiffness.

BACKGROUND: Rotator cuff tears with shoulder stiffness remain a difficult issue. Despite the reported satisfactory results of 1-stage surgery, little information is available regarding the factors that affect clinical outcomes. Purpose/Hypothesis: To evaluate the 1-stage arthroscopic treatment of rotator cuff tears with shoulder stiffness and to present the influence of duration of symptoms (DOS) on postoperative functional outcomes. The hypothesis was that a long preoperative DOS is related to worse functional outcomes. HYPOTHESIS: A long preoperative DOS is related to worse functional outcomes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A cohort study was performed with consecutive patients who underwent 1-stage surgery between January 2012 and July 2014. Forty-four patients were enrolled in the long DOS group (DOS ≥6 months or LDOS), and 38 were enrolled in the short DOS group (DOS <6 months or SDOS). There were no significant differences in the other variables between the groups. The patients were followed for a mean of 33.8 months, and the functional and radiographic outcomes were compared. RESULTS: Both groups achieved apparent functional postoperative improvements in terms of range of motion, pain, strength, and functional scores ( P < .001 for all). Despite the overall improvements, the patients in the SDOS group had significantly better outcomes according to all functional instruments. The mean postoperative abduction and external rotation at the side in the SDOS group were higher than in the LDOS group (abduction: 162.2° vs 152.8°, respectively [ P = .002]; external rotation: 64.7° vs 56.9°, respectively [ P = .004]). The mean postoperative functional scores in the SDOS group were all higher than in the LDOS group (American Shoulder and Elbow Surgeons [ASES] score: 91.1 vs 81.9, respectively; Constant-Murley score: 76.9 vs 71.8, respectively; Fudan University Shoulder Score [FUSS], 90.6 vs 81.1, respectively), and the mean postoperative visual analog scale (VAS) score for pain in the SDOS group was lower (0.7 vs 1.8, respectively) ( P < .001 for all). The difference in the retear rates was not significant, with 7 retears in the SDOS group and 4 in the LDOS group ( P = .216). CONCLUSION: One-stage surgery effectively achieved overall improvements. A preoperative DOS of ≥6 months led to poorer functional outcomes, which suggests that surgeons should propose a surgical treatment for this condition before symptoms persist for 6 months.

Comparison of tendon-bone healing between autografts and allografts after anterior cruciate ligament reconstruction using magnetic resonance imaging.

PURPOSE: The purpose of the study is to compare tendon-bone healing between autograft tendons and allograft tendons after anterior cruciate ligament (ACL) reconstruction using 3.0T magnetic resonance imaging. METHODS: A total of 36 participants (18 with autograft and 18 with allograft reconstruction) underwent MRI scans at least 2 years after the ACL reconstruction operation. Oblique axial images were obtained on three-dimensional dual-echo steady-state images and imported into solid modelling software for three-dimensional model reconstruction of the bone tunnel. The graft signal intensity in the tunnel, tendon-bone interface, tunnel morphology, and tunnel area was analysed using the Siemens software packages to determine the tendon-bone healing between the groups. RESULTS: For the tunnel morphology, both groups exhibited bone tunnel enlargement either at the femoral or tibial tunnel aperture. For the tendon-bone interface, one patient in the autograft group and two patients in the allograft group exhibited a significant fibrous scar tissue bands at the tendon-bone interface. The graft signal/noise quotient values of the allograft group were higher than the autograft group. However, there was no significant difference in the tunnel area between the allograft group and the autograft group. CONCLUSIONS: Although the autograft tendons exhibited a better remodelling effect than did the allograft tendons in the bone tunnel, there was no significant difference in the tendon-bone healing between the autograft tendons and the allograft tendons postoperatively. These findings indicate that the biomechanical effect of graft motion may play a significant role in the tunnel aperture. LEVEL OF EVIDENCE: III.

The development and evaluation of a new shoulder scoring system based on the view of patients and physicians: the Fudan University shoulder score.

PURPOSE: Existing patient self-reported shoulder scoring systems fail to express physicians' points of view, and understanding the wording can sometimes lead to confusion in Easterners. We sought to develop a valid, reliable, and responsive shoulder scoring system that combines the points of view of physicians and patients and is easily understood for worldwide applicability. METHODS: Six steps were followed to develop the scale: (1) investigation, identification of a specific population, and patient and physician interviews; (2) item generation, according to existing shoulder scales, a literature review, and patient and physician interviews; (3) item reduction, by combining and adjusting items; (4) formatting of the questionnaire, designed using both subjective and objective scales, with a 100-point score range; (5) pretesting, to eliminate confusion and misunderstanding of items, and (6) preliminary evaluation. Pearson correlation coefficients were calculated to assess validity (compared with American Shoulder and Elbow Surgeons, Constant-Murley, and University of California, Los Angeles scores), intraclass correlation coefficients were calculated to assess reliability (with a 2-week test-retest interval), and the standardized response mean was calculated to assess responsiveness (comparing preoperative and postoperative scores in patients). RESULTS: The final scoring system was designed to have a 100-point score range, with higher scores indicating better function. It consisted of self-report assessment by patients (61 points in total) and objective assessment by physicians (39 points in total). Updated scales, including a night pain subscale, patient-physician satisfaction, and 2-dimensional visual analog scale tool, were incorporated in our system. Compared with the other 3 scoring systems (American Shoulder and Elbow Surgeons, Constant-Murley, and University of California, Los Angeles scores), the new scoring system has shown favorable validity, with a Pearson correlation coefficient greater than 0.7. In addition, the intraclass correlation coefficient was greater than 0.9 during a 2-week test-retest interval, indicating high reliability, and the standardized response mean of the new system was greater than that of the other 3 scoring systems, indicating sensitive responsiveness. CONCLUSIONS: A new shoulder scoring system has been developed based on patients' and physicians' points of view and worldwide applicability and was verified to be valid, reliable, and responsive. The new scoring system includes a 2-dimensional visual analog scale, night pain subscale, and patient-physician satisfaction scale, which are not included in the existing scoring systems. LEVEL OF EVIDENCE: Level III, development of diagnostic criteria.