Regulatory roles of microRNAs in modulating mitochondrial dynamics, amyloid beta fibrillation, microglial activation, and cholinergic signaling: Implications for alzheimer's disease pathogenesis.

Alzheimer's Disease (AD) remains a formidable challenge due to its complex pathology, notably involving mitochondrial dysfunction and dysregulated microRNA (miRNA) signaling. This study delves into the underexplored realm of miRNAs' impact on mitochondrial dynamics and their interplay with amyloid-beta (Aß) aggregation and tau pathology in AD. Addressing identified gaps, our research utilizes advanced molecular techniques and AD models, alongside patient miRNA profiles, to uncover miRNAs pivotal in mitochondrial regulation. We illuminate novel miRNAs influencing mitochondrial dynamics, Aß, and tau, offering insights into their mechanistic roles in AD progression. Our findings not only enhance understanding of AD's molecular underpinnings but also spotlight miRNAs as promising therapeutic targets. By elucidating miRNAs' roles in mitochondrial dysfunction and their interactions with hallmark AD pathologies, our work proposes innovative strategies for AD therapy, aiming to mitigate disease progression through targeted miRNA modulation. This contribution marks a significant step toward novel AD treatments, emphasizing the potential of miRNAs in addressing this complex disease.

Labral Support Shelf Acetabuloplasty for Late Presenting Perthes Disease: Outcomes in Indian Patients.

Introduction: The treatment of late-presenting Perthes disease with extrusion is controversial and debatable. One of the options available is the labral shelf acetabuloplasty (LSA). Aim: The aim of the study was to evaluate the results of LSA in late-presenting Perthes disease in terms of clinic-radiological outcome measures. Materials and Methods: A retrospective analysis of prospectively collected data of patients with late presenting Perthes disease (Elizabethtown stage 2B onwards) treated by LSA by 2 experienced paediatric orthopaedic surgeons was performed. Data was collected of clinical parameters such as hip range of motion(ROM) and Harris Hip score and radiological parameters such as acetabular height, width and volume, shelf width, Centre Edge angle(CEA) and the lateral extrusion. Results: Thirty-five patients (28 males and 7 females) treated between 2012 to 2019 were analyzed. Majority were in Elizabethtown stage 3A (23) followed by 2B and 3B (12 each). At a mean follow up of 36 months, the hip ROM and the Harris Hip Score (from 65 ± 3.5 to 81.33 ± 7.12) improved significantly and there was a statistically significant improvement in terms of all radiological parameters. Majority of the hips were in Stulberg grade 3 (20) followed by grade 1 and 2 (7 each) and Stulberg 4 (1). There were no major complications in any of the patients of the series. Conclusion: Labral support shelf acetabuloplasty is a valuable surgery for late presenting Perthes disease and helps in maintenance of good coverage and allows restoration of range of motion over time.

One-Bone Forearm Procedure for Severe Recalcitrant Forearm Deformities in Masada IIb Hereditary Multiple Exostoses.

Introduction: Hereditary multiple exostoses (HME) Masada IIB has traditionally been treated by gradual ulnar lengthening with questionable efficacy in reducing the dislocated head. One-bone forearm (OBF) has been used as a reconstructive procedure in forearm deformities with very scarce literature for HME. The study aims to report short-term results of OBF as a definitive procedure for severe forearm deformities in Masada IIB patients with respect to clinical and radiological parameters. Materials and Methods: Four patients with HME Masada IIb were included in this retrospective study. All patients complained of forearm and wrist deformity with an abnormal bony protrusion restricting elbow motion. Indications for OBF were ulnar shortening > 3 cm, dysplastic proximal radius with convex radial head and restricted prono-supination. All patients were examined pre-operatively and post-operatively clinically and radiographically using the Peterson's outcome score. Results: The average age was 13 years (12-14 years). Pre-operative ulnar shortening, carpal slip percentage, and radial articular angle was 3.4 cm, 79.5%, and 47.5°, respectively. All radial heads were dislocated with convex articular surface restricting elbow extension and forearm prono-supination. At the latest follow-up, the mean elbow flexion was 110° with forearm in 10° supination. The mean carpal slip percentage, radial articular angle, and Peterson functional grade was 15%, 22.5°, and 8 points, respectively. The mean follow-up period was 30.25 months with no recurrence. Conclusion: We recommend one bone forearm as a definitive procedure in HME Masada IIB patients with severe forearm deformities with ulnar shortening > 3 cm and dysplastic proximal radius with a dislocated radial head, for faster return to function.

Synthesis and Characterization of a New Cationic Lipid: Efficient siRNA Delivery and Anticancer Activity of Survivin-siRNA Lipoplexes for the Treatment of Lung and Breast Cancers.

Survivin has been shown to be widely expressed in most tumor cells, including lung and breast cancers. Due to limited siRNA delivery, it is more challenging to target survivin using knockdown-based techniques. Designing and developing new, bifunctional chemical molecules with both selective anti-proliferative activity and effective siRNA transfection capabilities by targeting a particular gene is important to treat aggressive tumors like triple-negative breast tumors (TNBC). The cationic lipids deliver small interfering RNA (siRNA) and also display inherent anti-cancer activities; therefore, cationic lipid therapies have become very popular for treating malignant cancers. In the current study, we attempted to synthesize a series of acid-containing cationic lipids, anthranilic acid-containing mef lipids, and indoleacetic acid-containing etodo lipids etc. Further, we elucidated their bi-functional activity for their anticancer activity and survivin siRNA-mediated anti-cancer activity. Our results showed that lipoplexes with siRNA-Etodo: Dotap (ED) and siRNA-Mef: Dotap (MD) exhibited homogeneous particle size and positive zeta potential. Further, biological investigations resulted in enhanced survivin siRNA delivery with high stability, improved transfection efficiency, and anti-cancer activity. Additionally, our findings showed that survivin siRNA lipoplexes (ED and MD) in A549 cells and 4T1 cells exhibited stronger survivin knockdown, enhanced apoptosis, and G1 or G2/M phase arrest in both cell types. In vivo results revealed that treatment with survivin complexed lipoplexes significantly reduced tumor growth and tumor weight compared to control. Thus, our novel quaternary amine-based liposome formulations are predicted to open up new possibilities in the development of a simple and widely utilized platform for siRNA delivery and anti-cancer activities.

Splenic artery pathology presentation, operative interventions, and outcomes in 88 patients with vascular Ehlers-Danlos syndrome.

OBJECTIVE: Vascular Ehlers-Danlos syndrome (VEDS) is rare and associated with arteriopathies. The aim of this study is to investigate the presentation, operative interventions, and outcomes of splenic arterial pathology in a population of more than 1500 individuals with genetically confirmed VEDS due to pathogenic COL3A1 variants. METHODS: Cross-sectional analysis of 1547 individuals was performed. The data were assembled by harmonizing data from three overlapping cohorts with genetically confirmed VEDS: the VEDS Collaborative Natural History Study (N = 242), a single-center cohort (N = 75), and the University of Washington Collagen Diagnostic Lab cohort (N = 1231). Duplicates were identified and removed. Patients were selected for analysis if they had splenic artery aneurysm (SAA), pseudoaneurysm, dissection, thrombosis, or rupture. Demographics, COL3A1 variants, interventions, and outcomes were analyzed. Comparisons by splenic artery rupture were made. RESULTS: A total of 88 patients presented between 1992 and 2021 with splenic artery pathology (5.7% of the cohort; mean age at diagnosis, 37 ± 11.1 years; 50% male). One-third were diagnosed with VEDS prior to the splenic artery pathology diagnosis, and 17% were diagnosed post-mortem. Most had a positive family history (61%). Most had COL3A1 variants associated with minimal normal collagen production (71.6%). Median follow up was 8.5 years (interquartile range, 0.9-14.7 years). Initial presentation was rupture in 47% of the cases. Splenic artery rupture overall was 51% (n = 45), including four cases of splenic rupture. There were no major differences in VEDS-related manifestations or COL3A1 variant type by rupture status. SAA was noted in 39% of the cases. Only 12 patients had splenic artery diameter documented in 12 cases with a median diameter of 12 mm (interquartile range, 10.3-19.3 mm). A total of 34 patients (38.6%) underwent 40 splenic arterial interventions: 21 open surgical, 18 embolization, and one unknown procedure. More than one splenic artery intervention was performed in five cases (14.7%). Open repair complications included arteriovenous fistula (n = 1), intestinal or pancreatic injury (n = 1 each), and four intraoperative deaths. There were no deaths or access site complications related to splenic artery embolization. Four patients (23.5%) developed a new SAA in the remaining splenic artery post embolization. All-cause mortality was 35% (n = 31), including 22 related to a ruptured splenic artery. CONCLUSIONS: Splenic arteriopathy in VEDS is associated with variants that affect the structure and secretion of type III collagen and frequently present with rupture. Rupture and open repair are associated with high morbidity and mortality, whereas embolization is associated with favorable outcomes. Suggest repair considerations at SAA diameter of 15 mm. Long-term follow-up is indicated as secondary splenic arteriopathy can occur.

Percutaneous thrombectomy of upper extremity and thoracic central veins using Inari ClotTriever System: Experience in 14 patients.

Objective: In the present report, we have described the technical and clinical outcomes of percutaneous thrombectomy in the deep veins of the upper extremity and thorax using the ClotTriever system (Inari Medical, Irvine, CA). Methods: Fourteen patients with symptomatic deep venous occlusive disease in the upper extremity deep veins and thoracic central veins who had undergone thrombectomy using the ClotTriever system between October 2020 and January 2022 were reviewed. The technical results, adverse events, imaging follow-up data, and clinical outcomes were recorded. Results: Fourteen patients (seven men and seven women; mean age, 53.6 ± 13.3 years) constituted the study cohort. Of the 14 patients, 9 (64.3%) had had DVT due to intravascular invasion or external compression from known malignancy, 2 (14.3%) had had infected thrombi and/or vegetation due to Staphylococcus aureus refractory to intravenous antibiotic therapy, and 3 (21.4%) had had a benign etiology for thrombus formation. The presenting symptoms included upper extremity and/or facial swelling (n = 14), upper extremity pain (n = 6), fever (n = 2), and dyspnea (n = 1). Thrombectomy with the ClotTriever system was successfully completed in all 14 patients. Seven patients (50.0%) had required additional venous stent reconstruction after thrombectomy to address the underlying stenosis. No major adverse events were noted. All the patients had experienced resolution of the presenting symptoms. Conclusions: For the management of symptomatic deep venous occlusive disease of the upper extremity deep veins and thoracic central veins, thrombectomy using the ClotTriever system was feasible with excellent technical and clinical success.

Kissing Viabahn VBX stent graft reconstruction of thoracic central veins for management of superior vena cava syndrome.

OBJECTIVE: In the present study, we evaluated the technical and clinical outcomes of thoracic central vein reconstruction for superior vena cava (SVC) syndrome using kissing Viabahn VBX stent grafts (W.L. Gore & Associates, Flagstaff, AZ). METHODS: All adult patients with SVC syndrome who had undergone attempted bilateral brachiocephalic vein-to-SVC reconstruction using kissing VBX stent grafts at an academic hospital between August 2019 and February 2021 were reviewed. The technical results, adverse events, imaging follow-up findings, and clinical outcomes were recorded. Patency over time was assessed using Kaplan-Meier analysis. RESULTS: A total of 28 patients (16 women and 12 men; mean age, 52.0 years) constituted the study cohort. Of the 28 patients, 17 (60.7%) had had benign and 11 (39.3%) malignant etiologies. The presenting symptoms included neck swelling (n = 17; 60.7%), bilateral upper extremity swelling (n = 15; 53.6%), dyspnea (n = 7; 25%), unilateral upper extremity swelling (n = 4; 14.3%), and dysphagia (n = 1; 3.6%). SVC reconstruction with VBX stent grafts in a kissing configuration was successfully completed in 27 of the 28 patients (96.4%). Four major adverse events were noted in the benign etiology subgroup (23.5%), including intraprocedural hemopericardium (n = 3) and delayed pneumothorax (n = 1). Of the 28 patients, 27 (96.4%) had experienced resolution of their presenting symptoms. The mean clinical follow-up for the living patients was 358.8 ± 77.2 days (range, 78-645 days). The mean imaging follow-up for the living patients was 272.6 ± 91 days (range, 26-594 days). The primary, primary-assisted, and secondary patency rates at 12 months were 71.8%, 88.8%, and 100%, respectively. CONCLUSIONS: For the management of SVC syndrome, thoracic central vein reconstruction with kissing VBX stent grafts was feasible with a high rate of symptom resolution and acceptable patency. However, this technique should not be recommended for those with benign SVC syndrome owing to the high risk of cardiac tamponade.

Inferior Vena Cava Obstruction Complicating Remote Venovenous Extracorporeal Membrane Oxygenation Bridge to Lung Transplantation.

Extracorporeal membrane oxygenation (ECMO) increasingly is being used to support acute respiratory failure and for bridging to lung transplantation. Bleeding and thrombosis are common complications in the acute setting, but the literature describing long-term ECMO complications is limited, and no previous reports have been made of delayed central venous strictures resulting from remote ECMO bridging. Herein, we describe a patient who demonstrated complete inferior vena cava obstruction resulting from venovenous ECMO bridge to lung transplantation 5 years previously. The severe stricture and secondary thrombosis were managed with inferior vena cava angioplasty, stenting, thrombectomy, and thrombolysis, leading to clinical improvement. This case highlights the need for awareness and monitoring for long-term vascular complications in a growing population of patients who have received ECMO support.

Design and In Vitro Evaluation of Novel Cationic Lipids for siRNA Delivery in Breast Cancer Cell Lines.

Breast cancer is the most common cause of cancer mortality in Western nations, with a terrible prognosis. Many studies show that siRNA plays a role in the development of tumors by acting as a tumor suppressor and apoptosis inhibitor or both. siRNAs may be used as diagnostic and prognostic biomarkers in breast cancer. Antisurvivin siRNA was chosen as a therapeutic target in breast cancer treatment because it directly targets survivin, an inhibitor of apoptosis protein, that causes cell death. However, siRNA-based treatment has significant limitations, including a lack of tissue selectivity, a lack of effective delivery mechanisms, low cellular absorption, and the possibility of systemic toxicity. To address some of these issues, we provide a siRNA delivery method based on cationic lipids. In the recent past, cationic liposomes have displayed that they offer a remarkable perspective in proficient siRNA delivery. The presence of a positive charge plays a vital role in firm extracellular siRNA binding along with active intracellular siRNA separation and low biological adversities. Consequently, the methods for developing innovative cationic lipids through rendering and utilization of appropriate positive charges would certainly be helpful for benign and effective siRNA delivery. In the current study, an effort was made to synthesize a 3,4-dimethoxyaniline lipid (DMA) to improve the effectiveness and protection of successful siRNA delivery. DMA cationic lipid successfully delivered survivin siRNA that reduced the survivin mRNA expression, indicating the possibility of utilizing siRNA therapeutics for breast cancer. It is expected that this innovative quaternary amine-based liposome can open up new avenues in the process of developing an easy and extensively used platform for siRNA delivery. Cationic lipoplexes, a potential carrier system for siRNA-based therapies in the treatment of breast cancer, were proven by our data.

Lower-Limb Ischemia at Birth Because of Spontaneous Arterial Thrombosis: A Case Report.

CASE: A full-term neonate presented with right lower extremity ischemia at birth because of spontaneous thrombosis of the right common iliac artery. He was initially managed with supportive treatment, anticoagulation, and dressings; however, advanced gangrenous changes precluded salvage of the ischemic limb. A guillotine amputation was performed at day 15 of life, and the stump went on to heal well by secondary intention. CONCLUSION: Thromboembolic events occurring in infancy are well-recognized phenomena; however, it is far rarer to encounter a neonate born with "congenital gangrene". We discuss the etiology, approach to diagnosis, and treatment of this rare but devastating condition.

Role of Imaging in Renal Cell Carcinoma: A Multidisciplinary Perspective.

With the expansion in cross-sectional imaging over the past few decades, there has been an increase in the number of incidentally detected renal masses and an increase in the incidence of renal cell carcinomas (RCCs). The complete characterization of an indeterminate renal mass on CT or MR images is challenging, and the authors provide a critical review of the best imaging methods and essential, important, and optional reporting elements used to describe the indeterminate renal mass. While surgical staging remains the standard of care for RCC, the role of renal mass CT or MRI in staging RCC is reviewed, specifically with reference to areas that may be overlooked at imaging such as detection of invasion through the renal capsule or perirenal (Gerota) fascia. Treatment options for localized RCC are expanding, and a multidisciplinary group of experts presents an overview of the role of advanced medical imaging in surgery, percutaneous ablation, transarterial embolization, active surveillance, and stereotactic body radiation therapy. Finally, the arsenal of treatments for advanced renal cancer continues to grow to improve response to therapy while limiting treatment side effects. Imaging findings are important in deciding the best treatment options and to monitor response to therapy. However, evaluating response has increased in complexity. The unique imaging findings associated with antiangiogenic targeted therapy and immunotherapy are discussed. An invited commentary by Remer is available online. Online supplemental material is available for this article. ©RSNA, 2021.

Preparation of cement spacer in treatment of segmental bone defects in children by the induced membrane technique: A technical note.

The Masquelet Induced Membrane Technique (IMT) is one of the tools in the surgeon's armamentarium for the management of segmental bone defects. The first stage of the IMT includes the insertion of a cement spacer, which is typically fashioned by the free-hand technique. We propose a novel technique for preparation of the cement spacer using a split syringe barrel as a mould. This technique produces a uniformly cylindrical spacer with minimum cement spillage, while also minimizing thermal damage to the surrounding soft tissues. It is a simple and cost-effective method that can be adapted for use in any long bone in children.

Modified Dunn Osteotomy for Moderate and Severe Slipped Capital Femoral Epiphysis - A retrospective study of thirty hips.

BACKGROUND: Modified Dunn procedure has become popular for the treatment of severe cases of slipped capital femoral epiphysis (SCFE). We assessed the outcomes in a consecutive series of thirty Indian adolescents treated by the modified Dunn procedure. MATERIALS AND METHODS: All patients treated by the modified Dunn procedure by a single senior Paediatric Orthopaedic surgeon over six years were retrospectively reviewed. Only moderate and severe slips undergoing modified Dunn procedure were included. Clinical records and radiographs were reviewed to obtain demographic information; to classify the slips by duration of symptoms, severity and physeal stability; and to assess the outcomes by Harris Hip Score, radiological changes and rate of complications. RESULTS: Thirty consecutive hips with 19 stable and 11 unstable slips were included. Mean age was 13.05 years, 25 boys and 5 girls; six were acute slips, six chronic and eighteen acute-on-chronic. There were 20 moderate and 10 severe slips. Slip angle correction was on average 43.63° ± 8.42° (p < 0.001). At a mean follow-up of 25.36 months, the slip angle averaged 9.9° ± 3.78°, and alpha angle was 33.63° ± 4.14. The average Harris Hip Score was 81.833 ± 7.12 points, with six excellent, 17 good, six fair and one poor result. Osteonecrosis occurred in two hips (6.6%). One hip had post-operative subluxation which was corrected. CONCLUSION: This study adds to the evidence that the modified Dunn procedure is safe, reliable and reproducible. It should be the first choice for the treatment of moderate and severe SCFE.

Developmental Dysplasia of Hip and Post-natal Positioning: Role of Swaddling and Baby-Wearing.

INTRODUCTION: Traditional swaddling, which implies restrictive immobilisation of the infant's lower limbs with the hips in forced extension and adduction, has been shown to be a risk factor for Developmental Dysplasia of Hip (DDH). METHODS: We reviewed the literature regarding the correlation between DDH and post-natal positioning by swaddling and baby-wearing, to draw awareness of healthcare professionals towards an important risk factor for DDH that has often been overlooked. RESULTS: There is overwhelming evidence in the literature, by both experimental and clinical studies, that proves the close association between improper post-natal positioning of the baby's hips in extension-adduction and an increased incidence of DDH. On the other hand, "hip safe" swaddling which allows unrestricted flexion-abduction movements of the infants' hips, and the use of baby-wearing devices which keep the lower limbs in an attitude of hip flexion-abduction and knee flexion, is optimal for hip development. Populations which practice these "hip-safe" techniques of infant immobilisation have a lower incidence of DDH as compared to those which practice restrictive immobilisation. Furthermore, populations which have adopted "hip-safe" positioning have demonstrated a significant decrease in the incidence of DDH. Understanding this association is vital, since this is a modifiable risk factor, rectification of which can decrease the incidence of DDH. CONCLUSION: Policy makers and governments must design educational campaigns tailored to their respective populations to increase awareness regarding the benefits of "hip-safe" techniques of infant positioning, since this simple intervention has the potential of decreasing the incidence of DDH.

Technique and Interpretation of Arthrogram for Developmental Dysplasia of the Hip.

Closed reduction, arthrography and hip spica application is the treatment of choice for DDH between 6 and 18 months. There is a lot of controversy about what exactly constitutes an "acceptable" closed reduction and arthrogram and the arthrography findings are often difficult to interpret. In this video, the authors describe the technique to perform the arthrogram as well as the interpretation of the same. Various static parameters such as the femoral head coverage, the medial dye pool and the hourglass constriction are shown. In addition, the validity of the safe zone is discussed. With this video technique article, the authors hope that it becomes easy for the budding paediatric orthopaedic surgeon to perform and interpret the DDH arthrogram with ease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43465-021-00493-4.

Transforaminal intrathecal delivery of nusinersen for older children and adults with spinal muscular atrophy and complex spinal anatomy: an analysis of 200 consecutive injections.

BACKGROUND: Nusinersen is the only approved treatment for all spinal muscular atrophy (SMA) subtypes and is delivered intrathecally. Distorted spinal anatomy and instrumentation preclude standard approaches for intrathecal access, necessitating alternative techniques for delivery. The purpose of this study is to report technical success and adverse events of transforaminal intrathecal delivery of nusinersen. METHODS: 28 patients, mean age 24.1±9.8 years (range 10.0-51.0 years), with intermediate or late onset SMA, underwent a combined 200 transforaminal nusinersen injections. All patients had osseous fusion or spinal instrumentation precluding standard posterior access routes. Patients who underwent nusinersen injections using a technique other than transforaminal lumbar puncture (n=113) were excluded. Technical success, adverse events (AEs) and radiation exposure were recorded. RESULTS: 200 (100%) procedures were technically successful; 6 (3%) required a second level of attempt for access. 187 (93.5%) interventions were completed using cone beam computed tomography (CBCT) with two-axis fluoroscopic navigational overlay. 13 (6.5%) procedures were performed with fluoroscopic-guidance only at subsequent sessions. There were 8 (4.0%) mild AEs and 2 (0.5%) severe AEs; one patient received antibiotics for possible traversal of the large bowel but did not develop meningitis, and one patient developed aseptic meningitis. Mean air kerma was 74.5±161.3 mGy (range 5.2-1693.0 mGy). CONCLUSION: Transforaminal intrathecal delivery of nusinersen is feasible and safe for gaining access in patients with distorted spinal anatomy. The use of CBCT delineates anatomy and optimizes needle trajectory during the initial encounter, and may be used selectively for subsequent procedures.