Role of the NO-GC/cGMP signaling pathway in platelet biomechanics.

Cyclic guanosine monophosphate (cGMP) is a second messenger produced by the NO-sensitive guanylyl cyclase (NO-GC). The NO-GC/cGMP pathway in platelets has been extensively studied. However, its role in regulating the biomechanical properties of platelets has not yet been addressed and remains unknown. We therefore investigated the stiffness of living platelets after treatment with the NO-GC stimulator riociguat or the NO-GC activator cinaciguat using scanning ion conductance microscopy (SICM). Stimulation of human and murine platelets with cGMP-modulating drugs decreased cellular stiffness and downregulated P-selectin, a marker for platelet activation. We also quantified changes in platelet shape using deep learning-based platelet morphometry, finding that platelets become more circular upon treatment with cGMP-modulating drugs. To test for clinical applicability of NO-GC stimulators in the context of increased thrombogenicity risk, we investigated the effect of riociguat on platelets from human immunodeficiency virus (HIV)-positive patients taking abacavir sulfate (ABC)-containing regimens. Our results corroborate a functional role of the NO-GC/cGMP pathway in platelet biomechanics, indicating that biomechanical properties such as stiffness or shape could be used as novel biomarkers in clinical research.

Increased platelet activation and development of thrombosis has been linked to a dysfunctional NO-GC/cGMP signaling pathway. How this pathway affects platelet stiffness, however, has not been studied yet. For the first time, we used novel microscopy techniques to investigate stiffness and shape of platelets in human and murine blood samples treated with cGMP modifying drugs. Stiffness contains information about biomechanical properties of the cytoskeleton, and shape quantifies the spreading behavior of platelets. We showed that the NO-GC/cGMP signaling pathway affects platelet stiffness, shape, and activation in human and murine blood. HIV-positive patients are often treated with medication that may disrupt the NO-GC/cGMP signaling pathway, leading to increased cardiovascular risk. We showed that treatment with cGMP-modifying drugs altered platelet shape and aggregation in blood from HIV-negative volunteers but not from HIV-positive patients treated with medication. Our study suggests that platelet stiffness and shape can be biomarkers for estimating cardiovascular risk.

Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance.

The accumulation of metabolic waste is a leading cause of numerous neurological disorders, yet we still have only limited knowledge of how the brain performs self-cleansing. Here we demonstrate that neural networks synchronize individual action potentials to create large-amplitude, rhythmic and self-perpetuating ionic waves in the interstitial fluid of the brain. These waves are a plausible mechanism to explain the correlated potentiation of the glymphatic flow1,2 through the brain parenchyma. Chemogenetic flattening of these high-energy ionic waves largely impeded cerebrospinal fluid infiltration into and clearance of molecules from the brain parenchyma. Notably, synthesized waves generated through transcranial optogenetic stimulation substantially potentiated cerebrospinal fluid-to-interstitial fluid perfusion. Our study demonstrates that neurons serve as master organizers for brain clearance. This fundamental principle introduces a new theoretical framework for the functioning of macroscopic brain waves.

Investigating the association between knee osteoarthritis symptoms with pain catastrophizing domains between Hispanics and non-Hispanic Whites.

Knee osteoarthritis (KOA) is a chronic disease accompanied by debilitating symptoms including pain, stiffness, and limited physical functionality, which have been shown to be associated with pain catastrophizing. Previous studies have revealed racial discrepancies in pain catastrophizing, notably between Hispanics and non-Hispanics while pointing to potential health disparities. Using a conceptual model, this study aimed to investigate racial differences in associations between KOA symptoms with specific pain catastrophizing domains (rumination, magnification, and helplessness). Patients with KOA (n = 253; 147 Hispanics, 106 non-Hispanic Whites) completed a survey that included measures of knee symptoms, pain catastrophizing, and demographic variables. Structural equation modeling revealed that among Hispanics, each pain catastrophizing domain (rumination, magnification, and helplessness) was associated with at least two symptomatic experiences, including pain severity and difficulty in physical function. Specifically, pain severity was associated with (a) rumination: ß = 0.48, p < 0.001, (b) magnification: ß = 0.31, p = 0.003; and (c) helplessness: ß = 0.39, p < 0.001). Additionally, a lower score in physical function was associated with higher magnification (ß = 0.26, p = 0.01), and helplessness (ß = 0.25, p = 0.01). Among non-Hispanic White patients, pain severity was further associated with two domains of pain catastrophizing, including rumination (ß = 0.39, p < 0.001) and helplessness (ß = 0.35, p = 0.01). In addition, association pathways for demographic variables revealed that older Hispanics experienced greater challenges with higher pain severity (ß = 0.26, p = 0.01) and greater difficulty with physical function (ß = 0.31, p < 0.001) while Hispanics females experienced higher pain (ß = 0.19, p = 0.03). These findings highlight the importance of designing tailored interventions that consider key demographic factors such as age, and gender, to improve physical function that might alleviate pain catastrophizing among Hispanics with KOA.

Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage.

The meningeal lymphatic network enables the drainage of cerebrospinal fluid (CSF) and facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer's disease, impaired meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins in the CNS. Reversing this age-related dysfunction represents a promising strategy to augment CNS waste clearance; however, the mechanisms underlying this decline remain elusive. Here, we demonstrate that age-related alterations in meningeal immunity underlie this lymphatic impairment. Single-cell RNA sequencing of meningeal lymphatic endothelial cells from aged mice revealed their response to IFNγ, which was increased in the aged meninges due to T cell accumulation. Chronic elevation of meningeal IFNγ in young mice via AAV-mediated overexpression attenuated CSF drainage-comparable to the deficits observed in aged mice. Therapeutically, IFNγ neutralization alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable approach to normalize CSF drainage and alleviate the neurological deficits associated with impaired waste removal.

The C-C chemokine receptor 7: An immune molecule that modulates central nervous system function in homeostasis and disease.

The interaction between the central nervous system (CNS) and the peripheral immune system is key for brain function in homeostasis and disease. Recent studies have revealed that the C-C chemokine receptor 7 (CCR7) is expressed in both CNS resident cells and peripheral immune cells, and plays an important role in regulating behavior in homeostasis and neuroinflammation in disease. This review integrates studies examining the role of CCR7 in CNS resident and peripheral immune cells in homeostasis and disease, as well as the pathways of peripheral immune cell migration in and out of the brain via CCR7. A special emphasis is placed on the CCR7-dependent migration of peripheral immune cells into the recently discovered meningeal lymphatic vessels surrounding the brain and nasal lymphatics, its migration into cervical lymph nodes, and the implications that this migration might have for CNS function.

The roles and therapeutic potentialof mesenchymal stem/stromal cells and their extracellular vesicles in tendinopathies.

Tendinopathies encompass a highly prevalent, multi-faceted spectrum of disorders, characterized by activity-related pain, compromised function, and propensity for an extended absence from sport and the workplace. The pathophysiology of tendinopathy continues to evolve. For decades, it has been related primarily to repetitive overload trauma but more recently, the onset of tendinopathy has been attributed to the tissue's failed attempt to heal after subclinical inflammatory and immune challenges (failed healing model). Conventional tendinopathy management produces only short-term symptomatic relief and often results in incomplete repair or healing leading to compromised tendon function. For this reason, there has been increased effort to develop therapeutics to overcome the tissue's failed healing response by targeting the cellular metaplasia and pro-inflammatory extra-cellular environment. On this basis, stem cell-based therapies have been proposed as an alternative therapeutic approach designed to modify the course of the various tendon pathologies. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells often referred to as "medicinal signaling cells" due to their immunomodulatory and anti-inflammatory properties that can produce a pro-regenerative microenvironment in pathological tendons. However, the adoption of MSCs into clinical practice has been limited by FDA regulations and perceived risk of adverse events upon infusion in vivo. The introduction of cell-free approaches, such as the extracellular vesicles of MSCs, has encouraged new perspectives for the treatment of tendinopathies, showing promising short-term results. In this article, we review the most recent advances in MSC-based and MSC-derived therapies for tendinopathies. Preclinical and clinical studies are included with comment on future directions of this rapidly developing therapeutic modality, including the importance of understanding tissue loading and its relationship to any treatment regimen.

Prototype of an IoT-Based Low-Cost Sensor Network for the Hydrological Monitoring of Landslide-Prone Areas.

Steep slopes covered by loose unsaturated pyroclastic deposits widely dispersed in Campania, Southern Italy, are often subjected to shallow landslides that turn into fast debris flows causing a large amount of damage and many casualties, triggered by heavy and persistent precipitation. The slope of Cervinara, located around 40 km northeast of Naples, was involved in a destructive flowslide between 15 and 16 December 1999, triggered by a rain event of 325 mm in 48 h. Hydrometeorological monitoring activities have been carried out near the landslide scarp of 1999 since 2017 to assess the water balance and to identify major hydrological processes involving the cover and the shallow groundwater system developing in the upper part of the underlying limestone fractured bedrock. Since 1 December 2022, a remotely accessible low-cost network has been installed to expand the field hydrological monitoring. The use of a network of low-cost capacitive sensors, communicating within the domain of Internet of Things (IoT) technology, aiming at dispersed monitoring of soil moisture, has been tested. Specifically, the tested prototype network allows measurements of the soil water content at two different points, communicating through a Wi-Fi-based IoT system using ESP32 boards. The ThingSpeakTM IoT platform has been used for remote field data visualization. Based on the obtained results, the prototype of this IoT-based low-cost network shows the potential to expand the amount of hydrological data, suitable for setting up early warning systems in landslide-prone areas.

Nonsteroidal Anti-inflammatory and Corticosteroid Injections for Shoulder Impingement Syndrome: A Systematic Review and Meta-analysis.

CONTEXT: To determine optimal treatment strategies for shoulder impingement syndrome (SIS). OBJECTIVE: To compare subacromial nonsteroidal anti-inflammatory injections (SNIs) and subacromial corticosteroid injections (SCIs) on pain relief and functional improvement in individuals with SIS. Second, to perform a cost analysis of the 2 injections. DATA SOURCES: MEDLINE, SPORTDiscus, CINAHL, Embase, Web of Science, and SCOPUS databases were searched for randomized controlled trials using several keywords. STUDY SELECTION: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were utilized, and 10 studies comparing changes in pain or function in humans with SIS receiving SNIs or SCIs were included. Quality and risk of bias were assessed using the Consolidated Standards of Reporting Trials (CONSORT) 2010 scale and the Cochrane Collaboration tool. STUDY DESIGN: Systematic review and meta-analysis. LEVEL OF EVIDENCE: Level 1. DATA EXTRACTION: Baseline and follow-up scores of the visual analog, Constant-Murley, and University of California Los Angeles shoulder scales were extracted to calculate effect sizes (ESs), represented as Cohen d. Metaregression and publication bias analyses were performed. Procedural and medication costs were extracted from Medicare guidelines. RESULTS: A total of 7 high and 3 good quality studies were included, with a mean score of 21.1. Only 1 study had a high risk of bias. The meta-analyses produced pooled ESs of 0.05 (P = 0.83), 0.12 (P = 0.71), and 0.07 (P = 0.79) for each scale, respectively, with CIs crossing 0. Procedural costs were equal between groups, whereas ketorolac was the least costly medication ($0.47). There was no significant difference in side effects between the 2 injections. CONCLUSION: SNIs are as effective as SCIs for short-term pain relief and improving function in patients with subacromial impingement syndrome. In addition, they are less expensive and cause no major difference in complications, providing a viable, cost-effective alternative for injection therapy in patients with SIS.

Correction of pediatric angular deformities in lower limbs through guided growth using a novel flexible plate system.

INTRODUCTION: Tension band plates (TBP) for guided growth (GG) are the gold standard treatment for angular deformities around the knee. EPIFLEX® is a novel flexible TBP that adjusts to the patient's bone anatomy. HYPOTHESIS: GG using a flexible TBP produces satisfactory correction rates with minor complications in the pediatric population with angular deformities around the knee. MATERIALS AND METHODS: A retrospective evaluation of 33 patients (60 knees) treated for genu varum and valgum with hemiepiphysiodesis using a flexible TBP between 2017 and 2020 was performed. The study aimed to assess correction and complication rates; patients who completed treatment were included regardless of the follow-up times after implant removal. RESULTS: Thirteen females and 20 males with a median age of 10 years were included. The median treatment duration and follow-up were 10 and 22 months. The median monthly rate of change of mLDFA and mMPTA was 0.67° and 0.57°, respectively. A successful correction was achieved in 90% of the cases. There were no cases of infection or implant failure. Four cases presented overcorrection and two undercorrection; no significant relation with deformity or obesity was found. DISCUSSION: GG using this flexible TBP showed satisfactory correction rates with a low incidence of complications and no implant failure. It provides flexibility through good adaptability to the bone anatomy and mobility of the screws avoiding implant protrusion or breakage. LEVEL OF EVIDENCE: IV; observational descriptive case series.

Erratum to "COVID-19 vaccine-associated granulomatous mass mimicking a sarcoma: A case report" [Radiology Case Reports 17 (2022) 2775-2778].

[This corrects the article DOI: 10.1016/j.radcr.2022.05.035.].

Imaging Findings of Complications After Lateral Extra-Articular Tenodesis of the Knee: A Current Concepts Review.

Background: Despite successful anterior cruciate ligament (ACL) reconstruction, many patients continue to experience persistent anterolateral rotatory instability. Lateral extra-articular tenodesis (LET) is used to address this instability by harvesting a portion of the iliotibial band, passing it underneath the fibular collateral ligament, and attaching it just proximal and posterior to the lateral femoral epicondyle. Based on the most recent clinical evidence, the addition of LET to ACL reconstruction improves clinical outcomes, which has led to an increase in the use of this technique. Purpose: To provide an overview of the postoperative complications of the LET procedure and their associated imaging findings, with a focus on magnetic resonance imaging (MRI). Study Design: Narrative review. Methods: In this scoping review, the authors reviewed available radiographic, computed tomography, and MRI scans of patients who experienced postoperative complications after ACL reconstruction with LET, in which the complication was determined to be from the LET procedure. Images were reviewed and subsequently described by an on-staff musculoskeletal radiologist. Results: The authors found 9 different complications associated with LET: graft failure, hematoma, infection, chronic pain, tunnel convergence, fixation device migration, muscular hernia, peroneal nerve palsy, and knee stiffness. They supplemented these findings with radiographic evidence from 6 patients. Conclusion: As extra-articular reconstruction techniques including LET become more popular among orthopaedic surgeons, it is important that radiologists and surgeons be adept at recognizing the normal imaging findings of LET and associated complications.

Long noncoding RNAs in mesenchymal stromal/stem cells osteogenic differentiation: Implications in osteoarthritis pathogenesis.

This letter focuses on a recently published article that provided an exceptional description of the effect of epigenetic modifications on gene expression patterns related to skeletal system remodeling. Specifically, it discusses a novel modality of epigenetic regulation, the long noncoding RNAs (lncRNAs), and provides evidence of their involvement in mesenchymal stromal/stem cells osteo-/adipo-genic differentiation balance. Despite focus on lncRNAs, there is an emerging cross talk between lncRNAs and miRNAs interaction as a novel mechanism in the regulation of the function of the musculoskeletal system, by controlling bone homeostasis and bone regeneration, as well as the osteogenic differentiation of stem cells. Thus, we touched on some examples to demonstrate this interaction. In addition, we believe there is still much to discover from the effects of lncRNAs on progenitor and non-progenitor cell differentiation. We incorporated data from other published articles to review lncRNAs in normal progenitor cell osteogenic differentiation, determined lncRNAs involved in osteoarthritis pathogenesis in progenitor cells, and provided a review of lncRNAs in non-progenitor cells that are differentially regulated in osteoarthritis. In conclusion, we really enjoyed reading this article and with this information we hope to further our under standing of lncRNAs and mesenchymal stromal/stem cells regulation.

Brachial artery thrombosis secondary to fixation screw pullout: Case report.

The vascular supply of the shoulder and forearm are principal derivates of the ipsilateral subclavian artery. The trajectory of this arterial supply predisposes it to concomitant injuries in the shoulder and clavicular fractures proximally and elbow dislocation distally. Distal bicep tendon tears often occur most commonly in middle-aged men due to trauma to the elbow, typically in weight-bearing situations [1]. To our knowledge, this is the first case of distal biceps tendon tear repair resulting in distal brachial artery injury from displaced hardware due to postoperative re-injury. We present a case of a 41-year-old male who developed a vaso-occluding hematoma at the distal biceps secondary to a displaced fixation screw. The patient required emergency vascular surgery with embolectomy and arterial bypass. Although this patient fully recovered, the clinical course the patient experienced could have been minimized with appropriate postoperative care. This report aims to alert clinicians to the relevant local anatomy and relate it to the proposed mechanism of injury, thereby bringing attention to the importance of postoperative limb protection in at-risk patients. The timing of the injury, and the protracted rate of thrombus formation suggest that the brachial artery's thrombosis was associated with the screw pullout during reinjury of the area. Screw pullout in orthopedics is a rare phenomenon that can lead to significant complications. The risk of reinjury, screw pullout, and other complications such as thrombosis is evidence to support the careful treatment of the area postoperatively.

COVID-19 vaccine-associated ganulomatous mass mimicking a sarcoma: a case report.

Several studies have previously documented the development of complications stemming from injection with one of the various COVID-19 vaccines. No study, however, has discussed the spontaneous development of a soft tissue mass shortly after a COVID-19 vaccine injection. We report on 66-year-old female with concerns of a growing shoulder mass, 2 weeks after receiving a COVID-19 vaccine booster. Initial work-up with X-ray and MRI was concerning for a soft tissue neoplasm, specifically a soft tissue sarcoma. Subsequent ultrasound guided biopsy demonstrated a benign granulomatous lesion. No further management was required as the lesion spontaneously resolved during a 3-month follow-up period.

Changing sensitivity to cold weather in Texas power demand.

We estimate the effect of heightened temperature sensitivity on electricity demand in Texas during the February 2021 blackout event. Using 20 years of hourly data, we estimate the relationship between temperature and electricity demand; finding demand has become more responsive to cold temperatures over time. This is consistent with the fact electric heating has similarly increased over the past 20 years in Texas. We find during the February 2021 event, average electricity demand was 8% higher, and approximately 10,000 MW higher during the peak hour, than it would have been had temperature sensitivity remained unchanged at early 2000s levels. Our results highlight that Texas's increased sensitivity to cold weather extremes is not limited to the supply side, but the demand side as well. These findings have implications to other regions that are seeking to reduce carbon emissions through the electrification of heating.

Aberrant Expression of Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) in Warthin Tumors.

The Warthin tumor represents the second most frequent benign tumor of the parotid gland and is characterized by the presence of oncocytes rich in structurally and functionally altered mitochondria. Next to its role in metabolism, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is also implicated in cellular mitophagy. Immunohistochemistry was carried out on Warthin tumor and normal control (parotid gland with striated ducts) tissues, using anti-GAPDH specific antibodies followed by digital image analysis. Laser capture microdissection was used to isolate the oncocytic tumor cell and normal control striated duct compartments for RNA extraction and qPCR. Warthin tumor oncocytes exhibited a markedly spotted GAPDH staining pattern exhibiting cells with cytoplasmic and nuclear, only nuclear or none GAPDH staining. A significantly lower (p < 0.0001) total GAPDH signal was detected in Warthin tumor oncocytes. Similarly, significantly lower (p < 0.005) GAPDH mRNA levels were seen in oncocytes compared with normal ductal cells. To exclude the possibility of this GAPDH staining pattern being a general feature of oncocytic neoplasms of different organs, we tested a cohort of renal oncocytoma and oncocytic chromophobe carcinoma; none showed this type of staining. The observed progressive GAPDH loss in Warthin tumor oncocytes could be implicated in the pathogenesis of Warthin tumors.

Características de las fracturas de fémur proximal / Characteristics of proximal femoral fractures

Introducción: Las fracturas de cadera ocurren en la cabeza, el cuello y la región intertrocantérica. El tratamiento obedece al tipo, la localización, la edad del paciente y las comorbilidades. Objetivo: Describir las características y los factores relacionados con las fracturas de cadera en pacientes atendidos en el Hospital de San José de Bogotá entre enero del 2014 y junio del 2016. Métodos: Estudio serie de casos. Se incluyó a adultos con fractura primaria e historia clínica completa. Se excluyó a aquellos con antecedente de manejo quirúrgico de fractura de fémur proximal ipsolateral y las fracturas patológicas. La información se obtuvo de las historias clínicas. Resultados: Se incluyó a 96 pacientes, 66,7% mujeres, mediana de edad 81 an˜ os (RIC 29-93 an˜ os), con comorbilidades (69,8%) como hipertensión arterial (58,3%), enfermedad coronaria (16,7%), diabetes mellitus (8,3%), consumo de tabaco (9,4%), Alzheimer (14,6%) y osteoporosis (4,2%). La fractura más común fue la intertrocantérica (69,8%) teniendo como origen la caída de su altura (93,8%). El tratamiento más frecuente fue osteosíntesis (50%) seguida por artroplastia (43,8%). El clavo céfalo-medular largo fue el más utilizado en osteosíntesis (77,1%). Las complicaciones principales fueron muerte postoperatoria en el 5,2%, aflojamiento y reintervenciones en el 3,1%, úlceras por presión, neumonía, tromboembolismo pulmonar y fracturas periimplante en el 2,1%. Conclusiones: La fractura de cadera es una patología común en pacientes ancianos, se relaciona con alta morbimortalidad. Es imprescindible un manejo temprano de esta patología, así como contar con programas de prevención.

Introduction: Hip fractures may occur in the femoral head, neck or intertrocantheric line. Treatment is based on, type and location of the fracture and patient's age and comorbidities. Objective: To describe hip fracture characteristics and risk factors in patients seen at Hospital de San José of Bogotá between January 2014 and June 2016. Methods: A case series study. Adults with primary fractures and a complete medical record were included. Those with prior surgical management of ipsilateral proximal femoral and pathologic fractures were excluded. Data collection was based on clinical records. Results: 96 patients were included, 66.7% females, mean age 81 years (IQR 29 ­ 93 years), and comorbidities such as hypertension (58.3%), coronary artery disease (16.7%), diabetes mellitus (8.3%), tobacco smoking (9.4%), Alzheimer's (14.6%) and osteoporosis (4.2%) present in 69.8%. Intertrochanteric fracture (69.8%) caused by a fall from own height (93.8%) was the commonest fracture. The most widely used treatment was fixation (50%) followed by arthroplasty (43.8%). Osteosynthesis by an intramedullary long proximal femoral nail was the most common fixation method used (77.1%). Major complications were postoperative mortality (5.2%), component loosening and reoperations (3.1%), pressure ulcers, pneumonia, pulmonary thromboembolism and periprosthetic fractures in 2.1%. Conclusions: Hip fractures associated with significant morbidity and mortality are common in elders. It is essential to provide timely treatment and to count on prevention programs regarding this pathology.