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PURPOSE: The research outlines anatomical landmarks that may help surgeons in identifying the lateral antebrachial cutaneous nerve (LABCN) to minimize nerve damage during procedures in the cubital fossa. METHODS: Twenty-eight fresh cadaveric upper extremities were dissected. The course of the LABCN was followed from the emerging point at the biceps brachii tendon (BT) to the mid-forearm. The nerve's relationships with the BT, lateral epicondyle (LE), antebrachial vein, and brachioradialis (BR) muscle were measured and documented. RESULTS: The LABCN emerged lateral to the BT in all specimens and crossed medially at the top of the BT in 50% of the cadavers. It was deep to the forearm superficial fascia in all cadavers. At the level of the LE, the nerve was located at a mean of 6.3 ± 3.1 mm medial to the BR. The LABCN aligns with the medial border of the BR at a mean of 68 mm distal to the interepicondylar line. The mean distance from the LE to the LABCN at the interepicondylar line was 24.5 ± 7.2 mm. The LABCN and antebrachial vein are in the same deep fascia plane, on average 47.6 ± 5 mm (37-55) from the LE. At the elbow joint level, 82.1% of the specimens have two branches for the LABCN, whereas 17.9% demonstrated only a single branch. CONCLUSIONS: Lateral antebrachial cutaneous nerve was situated approximately 6.8 cm distal to the interepicondyle line, positioned at the ulnar edge of the BR, and runs parallel with the antebrachial vein deep to the forearm fascia plane. The nerve crossed over the biceps tendon in 50% of the specimens. These findings suggest that the nerve should be identified 6-7 cm distal to the LE, followed by a proximal dissection. CLINICAL RELEVANCE: This study may help surgeons in identifying LABCN, and reducing the potential risk of LABCN injury.
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As cancer therapies increase in effectiveness and patients' life expectancies improve, balancing oncologic efficacy while reducing acute and long-term cardiovascular toxicities has become of paramount importance. To address this pressing need, the Cardiology Oncology Innovation Network (COIN) was formed to bring together domain experts with the overarching goal of collaboratively investigating, applying, and educating widely on various forms of innovation to improve the quality of life and cardiovascular healthcare of patients undergoing and surviving cancer therapies. The COIN mission pillars of innovation, collaboration, and education have been implemented with cross-collaboration among academic institutions, private and public establishments, and industry and technology companies. In this report, we summarize proceedings from the first two annual COIN summits (inaugural in 2020 and subsequent in 2021) including educational sessions on technological innovations for establishing best practices and aligning resources. Herein, we highlight emerging areas for innovation and defining unmet needs to further improve the outcome for cancer patients and survivors of all ages. Additionally, we provide actionable suggestions for advancing innovation, collaboration, and education in cardio-oncology in the digital era.
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BACKGROUND: Bone marrow (BM)- and adipose tissue (AT)-derived mesenchymal stromal cells (MSCs) have shown potential as cell-based therapies for cartilage and bone injuries and are used increasingly in human and veterinary practice to facilitate the treatment of orthopedic conditions. However, human and rodent studies have documented a sharp decline in chondrogenic and osteogenic differentiation potential with increasing donor age, which may be problematic for the important demographic of older orthopedic patients. The aim of this study was to identify the effect of donor age on the chondrogenic and osteogenic differentiation performance of equine BM- and AT-MSCs in vitro. BM- and AT-MSCs and dermal fibroblasts (biological negative control) were harvested from horses in five different age groups (n = 4, N = 60); newborn (0 days), yearling (15-17 months), adult (5-8 years), middle-aged (12-18 years), and geriatric (≥ 22 years). Chondrogenic differentiation performance was assessed quantitatively by measuring pellet size, matrix proteoglycan levels, and gene expression of articular cartilage biomarkers. Osteogenic differentiation performance was assessed quantitatively by measuring alkaline phosphatase activity, calcium deposition, and gene expression of bone biomarkers. RESULTS: Chondrogenic and osteogenic differentiation performance of equine BM- and AT-MSCs declined with increasing donor age. BM-MSCs had a higher chondrogenic differentiation performance. AT-MSCs showed minimal chondrogenic differentiation performance in all age groups. For osteogenesis, alkaline phosphatase activity was also higher in BM-MSCs, but BM-MSCs calcium deposition was affected by donor age earlier than AT-MSCs. Chondrogenic and osteogenic differentiation performance of BM-MSCs exhibited a decline as early as between the newborn and yearling samples. Steady state levels of mRNA encoding growth factors, chondrogenic, and osteogenic biomarkers were lower with increasing donor age in both MSC types. CONCLUSIONS: The data showed that chondrogenic and osteogenic differentiation performance of equine BM-MSCs declined already in yearlings, and that AT-MSCs showed minimal chondrogenic potential, but were affected later by donor age with regards to osteogenesis (calcium deposition). The results highlight the importance of donor age considerations and MSC selection for cell-based treatment of orthopedic injuries and will help inform clinicians on when to implement or potentially cryopreserve cells. Moreover, the study provides molecular targets affected by donor age.
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Células Madre Mesenquimatosas , Osteogénesis , Caballos , Humanos , Animales , Médula Ósea , Fosfatasa Alcalina , Calcio/metabolismo , Células Cultivadas , Diferenciación Celular , Células de la Médula ÓseaRESUMEN
PURPOSE OF REVIEW: Cardiovascular disease (CVD) and cancer are the first and second most common causes of death within the USA. It is well established that a diagnosis of cancer increases risk and predisposes the patient to CVD, and vice versa. Despite these associations, cancer is not yet incorporated into current CVD risk calculators, necessitating additional CV risk markers for improved stratification in this at-risk population. In this review, we consider the utility of breast arterial calcification (BAC), coronary artery calcification (CAC), clonal hematopoiesis of indeterminate potential (CHIP), and cancer and cancer treatment in CVD risk assessment. RECENT FINDINGS: There is evidence supporting the use of BAC, CAC, CHIP, and cancer and cancer treatment for improved CV risk stratification in patients with cancer and those who are being screened for cancer. BAC has been shown to predict CAC, coronary atherosclerotic plaque on coronary CTA, coronary artery stenosis on coronary angiography, and CVD events and accordingly enhances CVD risk stratification beyond the atherosclerotic CVD (ASCVD) risk pooled cohort equation. Additionally, CAC visualized on CT utilized for lung cancer screening, radiation planning, and cancer staging is predictive of coronary artery disease (CAD). Furthermore, CHIP can also be utilized in risk stratification, as the presence of CHIP carries a 40% increase in CV risk independent of traditional CV risk factors. Finally, cancer and many oncologic therapies confer a lifelong increased risk of CVD. We propose an emerging set of tools to be incorporated into the routine continuum of CVD risk assessment in individuals who have been treated for cancer or who are being screened for cancer development. In this review, we discuss BAC, CAC, CHIP, and cancer and cancer treatment as emerging risk markers in cardiovascular health assessment. Their effectiveness in predicting and influencing the burden of CVD will be discussed, along with suggestions on their incorporation into preventive cardio-oncology practice. Future research will focus on short- and long-term CVD outcomes in these populations.
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Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Neoplasias Pulmonares , Calcificación Vascular , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/terapia , Detección Precoz del Cáncer , Humanos , Neoplasias Pulmonares/complicaciones , Medición de Riesgo , Factores de Riesgo , Calcificación Vascular/diagnóstico por imagen , Calcificación Vascular/epidemiologíaRESUMEN
Mechanisms of rhythm generation have been extensively studied in motor systems that control locomotion over terrain in limbed animals; however, much less is known about rhythm generation in soft-bodied terrestrial animals. Here we explored how muscarinic acetylcholine receptor (mAChR)-modulated rhythm-generating networks are distributed in the central nervous system (CNS) of soft-bodied Drosophila larvae. We measured fictive motor patterns in isolated CNS preparations, using a combination of Ca2+ imaging and electrophysiology while manipulating mAChR signaling pharmacologically. Bath application of the mAChR agonist oxotremorine potentiated bilaterally asymmetric activity in anterior thoracic regions and promoted bursting in posterior abdominal regions. Application of the mAChR antagonist scopolamine suppressed rhythm generation in these regions and blocked the effects of oxotremorine. Oxotremorine triggered fictive forward crawling in preparations without brain lobes. Oxotremorine also potentiated rhythmic activity in isolated posterior abdominal CNS segments as well as isolated anterior brain and thoracic regions, but it did not induce rhythmic activity in isolated anterior abdominal segments. Bath application of scopolamine to reduced preparations lowered baseline Ca2+ levels and abolished rhythmic activity. Overall, these results suggest that mAChR signaling plays a role in enabling rhythm generation at multiple sites in the larval CNS. This work furthers our understanding of motor control in soft-bodied locomotion and provides a foundation for study of rhythm-generating networks in an emerging genetically tractable locomotor system.NEW & NOTEWORTHY Using a combination of pharmacology, electrophysiology, and Ca2+ imaging, we find that signaling through mACh receptors plays a critical role in rhythmogenesis in different regions of the Drosophila larval CNS. mAChR-dependent rhythm generators reside in distal regions of the larval CNS and provide functional substrates for central pattern-generating networks (CPGs) underlying headsweep behavior and forward locomotion. This provides new insights into locomotor CPG operation in soft-bodied animals that navigate over terrain.
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Proteínas de Drosophila , Drosophila , Locomoción , Receptores Muscarínicos , Acetilcolina/farmacología , Animales , Proteínas de Drosophila/fisiología , Larva/fisiología , Locomoción/fisiología , Oxotremorina/farmacología , Receptores Muscarínicos/fisiología , Escopolamina/farmacologíaRESUMEN
Study objective: Cancer and heart disease are leading causes of mortality, and cardio-oncology is emerging as a new field addressing the cardiovascular toxicities related to cancer and cancer therapy. Interdisciplinary research platforms that incorporate digital health to optimize cardiovascular health and wellness in cancer survivors are therefore needed as we advance in the digital era. Our goal was to develop the Connected Health Innovation Research Program (C.H.I.R.P.) to serve as a foundation for future integration and assessments of adoption and clinical efficacy of digital health tools for cardiovascular health and wellness in the general population and in oncology patients. Design/setting/participants: Partner companies were identified through the American Medical Association innovation platform, as well as LinkedIn and direct contact by our team. Company leaders met with our team to discuss features of their technology or software. Non-disclosure agreements were signed and data were discussed and obtained for descriptive or statistical analysis. Results: A suite of companies with technologies focused on wellness, biometrics tracking, audio companions, oxygen saturation, weight trends, sleep patterns, heart rate variability, electrocardiogram patterns, blood pressure patterns, real-time metabolism tracking, instructional video modules, or integration of these technologies into electronic health records was collated. We formed an interdisciplinary research team and established an academia-industry collaborative foundation for connecting patients with wellness digital health technologies. Conclusions: A suite of software and device technologies accessible to the cardiology and oncology population has been established and will facilitate retrospective, prospective, and case research studies assessing adoption and clinical efficacy of digital health tools in cardiology/oncology.
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Osteoarthritis (OA) may result from impaired ability of synovial macrophages to resolve joint inflammation. Increasing macrophage counts in inflamed joints through injection with bone marrow mononuclear cells (BMNC) induces lasting resolution of synovial inflammation. To uncover mechanisms by which BMNC may affect resolution, in this study, differential transcriptional signatures of BMNC in response to normal (SF) and inflamed synovial fluid (ISF) were analyzed. We demonstrate the temporal behavior of co-expressed gene networks associated with traits from related in vivo and in vitro studies. We also identified activated and inhibited signaling pathways and upstream regulators, further determining their protein expression in the synovium of inflamed joints treated with BMNC or DPBS controls. BMNC responded to ISF with an early pro-inflammatory response characterized by a short spike in the expression of a NF-ÆB- and mitogen-related gene network. This response was associated with sustained increased expression of two gene networks comprising known drivers of resolution (IL-10, IGF-1, PPARG, isoprenoid biosynthesis). These networks were common to SF and ISF, but more highly expressed in ISF. Most highly activated pathways in ISF included the mevalonate pathway and PPAR-γ signaling, with pro-resolving functional annotations that improve mitochondrial metabolism and deactivate NF-ÆB signaling. Lower expression of mevalonate kinase and phospho-PPARγ in synovium from inflamed joints treated with BMNC, and equivalent IL-1ß staining between BMNC- and DPBS-treated joints, associates with accomplished resolution in BMNC-treated joints and emphasize the intricate balance of pro- and anti-inflammatory mechanisms required for resolution. Combined, our data suggest that BMNC-mediated resolution is characterized by constitutively expressed homeostatic mechanisms, whose expression are enhanced following inflammatory stimulus. These mechanisms translate into macrophage proliferation optimizing their capacity to counteract inflammatory damage and improving their general and mitochondrial metabolism to endure oxidative stress while driving tissue repair. Such effect is largely achieved through the synthesis of several lipids that mediate recovery of homeostasis. Our study reveals candidate mechanisms by which BMNC provide lasting improvement in patients with OA and suggests further investigation on the effects of PPAR-γ signaling enhancement for the treatment of arthritic conditions.
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Células de la Médula Ósea/inmunología , Leucocitos Mononucleares/inmunología , Osteoartritis/complicaciones , Osteoartritis/inmunología , Sinovitis/complicaciones , Sinovitis/inmunología , Transcriptoma/genética , Animales , Articulaciones del Carpo/inmunología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Genómica/métodos , Caballos , Lipopolisacáridos/efectos adversos , Macrófagos/inmunología , Masculino , Osteoartritis/genética , Líquido Sinovial/inmunología , Sinovitis/inducido químicamente , Sinovitis/genéticaRESUMEN
Within developing synovial joints, interzone and anlagen cells progress through divergent chondrogenic pathways to generate stable articular cartilage and transient hypertrophic anlagen cartilage, respectively. Understanding the comparative cell biology between interzone and anlagen cells may provide novel insights into emergent cell-based therapies to support articular cartilage regeneration. The aim of this study was to assess the kinetics of gene expression profiles in these skeletal cell lines after inducing chondrogenesis in culture. Interzone and anlagen cells from seven equine fetuses were isolated and grown in a TGF-ß1 chondrogenic inductive medium. Total RNA was isolated at ten time points (0, 1.5, 3, 6, 12, 24, 48, 96, 168, and 336 h), and gene expression for 93 targeted gene loci was measured in a microfluidic RT-qPCR system. Differential transcriptional responses were observed as early as 1.5 h after the initiation of chondrogenesis. Genes with functional annotations that include transcription regulation responded to the chondrogenic stimulation earlier (1.5-96 h) than genes involved in signal transduction (1.5-336 h) and the extracellular matrix biology (3-336 h). Between interzone and anlagen cell cultures, expression levels of 73 out of the 93 targeted genes were not initially different at 0 h, but 47 out of the 73 genes became differentially expressed under the chondrogenic stimulation. While interzone and anlagen cells are both chondrogenic, they display clear differences in response to the same TGF-ß1 chondrogenic stimulation. This study provides new molecular insight into a timed sequence of the divergent developmental fates of interzone and anlagen cells in culture over 14 days.
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Osteoarthritis (OA) is the most prevalent joint disease causing major disability and medical expenditures. Synovitis is a central feature of OA and is primarily driven by macrophages. Synovial macrophages not only drive inflammation but also its resolution, through a coordinated, simultaneous expression of pro- and anti-inflammatory mechanisms that are essential to counteract damage and recover homeostasis. Current OA therapies are largely based on anti-inflammatory principles and therefore block pro-inflammatory mechanisms such as prostaglandin E2 and Nuclear factor-kappa B signaling pathways. However, such mechanisms are also innately required for mounting a pro-resolving response, and their blockage often results in chronic low-grade inflammation. Following minor injury, macrophages shield the damaged area and drive tissue repair. If the damage is more extensive, macrophages incite inflammation recruiting more macrophages from the bone marrow to maximize tissue repair and ultimately resolve inflammation. However, sustained damage and inflammation often overwhelms pro-resolving mechanisms of synovial macrophages leading to the chronic inflammation and related tissue degeneration observed in OA. Recently, experimental and clinical studies have shown that joint injection with autologous bone marrow mononuclear cells replenishes inflamed joints with macrophage and hematopoietic progenitors, enhancing mechanisms of inflammation resolution, providing remarkable and long-lasting effects. Besides creating an ideal environment for resolution with high concentrations of interleukin-10 and anabolic growth factors, macrophage progenitors also have a direct role in tissue repair. Macrophages constitute a large part of the early granulation tissue, and further transdifferentiate from myeloid into a mesenchymal phenotype. These cells, characterized as fibrocytes, are essential for repairing osteochondral defects. Ongoing "omics" studies focused on identifying key drivers of macrophage-mediated resolution of joint inflammation and those required for efficient osteochondral repair, have the potential to uncover ways for developing engineered macrophages or off-the-shelf pro-resolving therapies that can benefit patients suffering from many types of arthropaties, not only OA.
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BACKGROUND: As cardiovascular disease is a leading cause of death in cancer survivors, the new subspecialty of Cardio-Oncology has emerged to address prevention, monitoring, and management of cardiovascular toxicities to cancer therapies. During the coronavirus disease of 2019 (COVID-19) pandemic, we developed a Virtual-Hybrid Approach to build a de novo Cardio-Oncology Clinic. METHODS: We conceptualized a Virtual-Hybrid Approach including three arms: information seeking in locations with existing Cardio-Oncology clinics, information gathering at the location for a new clinic, and information sharing to report clinic-building outcomes. A retrospective review of outcomes included collection and synthesis of data from our first 3 months (at pandemic peak) on types of appointments, cancers, drugs, and cardiotoxicities. Data were presented using descriptive statistics. RESULTS: A de-novo Cardio-Oncology clinic was developed structured from the ground up to integrate virtual and in-person care in a hybrid and innovative model, using the three arms of the Virtual-Hybrid Approach. First, we garnered in-person and virtual preparation through hands-on experiences, training, and discussions in existing Cardio-Oncology Clinics and conferences. Next, we gleaned information through virtual inquiry and niche-building. With partners throughout the institution, a virtual referral process was established for outpatient referrals and inpatient e-consult referrals to actualize a hybrid care spectrum for our patients administered by a multidisciplinary hybrid care team of clinicians, ancillary support staff, and clinical pharmacists. Among the multi-subspecialty clinic sessions, approximately 50% were in Cardio-Oncology, 20% in Preventive Cardiology, and 30% in General Cardiology. In the hybrid model, the Heart & Vascular Center had started to re-open, allowing for 65% of our visits to be in person. In additional analyses, the most frequent cardiovascular diagnosis was cardiomyopathy (34%), the most common cancer drug leading to referral was trastuzumab (29%), and the most prevalent cancer type was breast cancer (42%). CONCLUSION: This Virtual-Hybrid Approach and retrospective review provides guidance and information regarding initiating a brand-new Cardio-Oncology Clinic during the pandemic for cancer patients/survivors. This report also furnishes virtual resources for patients, virtual tools for oncologists, cardiologists, and administrators tasked with starting new clinics during the pandemic, and innovative future directions for this digital pandemic to post-pandemic era.
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OBJECTIVE: Articular cartilage in mammals has limited intrinsic capacity to repair structural defects, a fact that contributes to the chronic and progressive nature of osteoarthritis. In contrast, Mexican axolotl salamanders have demonstrated the remarkable ability to spontaneously and completely repair large joint cartilage lesions, a healing process that involves interzone cells in the intraarticular space. Furthermore, interzone tissue transplanted into skeletal defects in the axolotl salamander demonstrates a multi-differentiation potential. Cellular and molecular mechanisms of this repair process remain unclear. The objective of this study was to examine whether paracrine mitogenic signals are an important variable in the interaction between interzone cells and the skeletal microenvironment. DESIGN: The paracrine regulation of the proliferation of equine interzone cells was evaluated in an in vitro co-culture system. Cell viability and proliferation were measured in equine fetal interzone cells after exposure to conditioned medium from skeletal and nonskeletal primary cell lines. Steady-state expression was determined for genes encoding 37 putative mitogens secreted by cells that generated the conditioned medium. RESULTS: All experimental groups of conditioned media elicited a mitogenic response in interzone cells. Fetal anlage chondrocytes (P < 0.0001) and dermal fibroblasts (P < 0.0001) conditioned medium showed a significantly higher mitogenic potential compared with interzone cells. Conditioned medium from bone marrow-derived cells elicited a significantly higher proliferative response relative to that from young adult articular chondrocytes (P < 0.0001) or dermal fibroblasts (P < 0.0001). Sixteen genes had expression patterns consistent with the functional proliferation assays. CONCLUSIONS: The results indicate a mitogenic effect of skeletal paracrine signals on interzone cells.
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Cartílago Articular , Animales , Diferenciación Celular , Proliferación Celular , Condrocitos/metabolismo , Caballos , MamíferosRESUMEN
Background: Bone marrow (BM)- and adipose tissue (AT)-derived mesenchymal stem cells (MSCs) are used increasingly for autologous cell therapy in equine practice to treat musculoskeletal and other injuries. Current recommendations often call for 10-100 million MSCs per treatment, necessitating the expansion of primary cells in culture prior to therapeutic use. Of concern, human and rodent studies have shown a decline of both MSC recovery from sampled tissue and in vitro proliferative capacity with increasing donor age. This may be problematic for applications of autologous cell-based therapies in the important equine demographic of older patients. Objectives: To investigate the effect of donor age on the cellular proliferation of equine BM- and AT-MSCs. Study Design: In vitro study. Methods: BM- and AT-MSCs and dermal fibroblasts (biological control) were harvested from horses in five different age groups (n = 4, N = 60); newborn (0 days), yearling (15-17 months), adult (5-8 years), middle-aged (12-18 years), and geriatric (≥22 years). Proliferation of the cells was tested using an EdU incorporation assay and steady state mRNA levels measured for targeted proliferation, aging, and senescence biomarkers. Results: The cellular proliferation of equine BM- and AT-MSCs declined significantly in the geriatric cohort relative to the younger age groups. Proliferation levels in the two MSC types were equally affected by donor age. Analysis of steady state mRNA levels showed an up-regulation in tumor suppressors, apoptotic genes, and multiple growth factors in MSCs from old horses, and a down-regulation of some pro-cycling genes with a few differences between cell types. Main Limitations: Potential age-dependent differences in cell function parameters relevant to cell-therapy application were not investigated. Conclusions: The cellular proliferation of equine BM- and AT-MSCs declined at advanced donor ages. High levels of in vitro proliferation were observed in both MSC types from horses in the age groups below 18 years of age.
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Long non-coding RNAs (lncRNAs) are untranslated regulatory transcripts longer than 200 nucleotides that can play a role in transcriptional, post-translational, and epigenetic regulation. Traditionally, RNA-sequencing (RNA-seq) libraries have been created by isolating transcriptomic RNA via poly-A+ selection. In the past 10 years, methods to perform ribosomal RNA (rRNA) depletion of total RNA have been developed as an alternative, aiming for better coverage of whole transcriptomic RNA, both polyadenylated and non-polyadenylated transcripts. The purpose of this study was to determine which library preparation method is optimal for lncRNA investigations in the horse. Using liver and cerebral parietal lobe tissues from two healthy Thoroughbred mares, RNA-seq libraries were prepared using standard poly-A+ selection and rRNA-depletion methods. Averaging the two biologic replicates, poly-A+ selection yielded 327 and 773 more unique lncRNA transcripts for liver and parietal lobe, respectively. More lncRNA were found to be unique to poly-A+ selected libraries, and rRNA-depletion identified small nucleolar RNA (snoRNA) to have a higher relative expression than in the poly-A+ selected libraries. Overall, poly-A+ selection provides a more thorough identification of total lncRNA in equine tissues while rRNA-depletion may allow for easier detection of snoRNAs.
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The first equine reference genome was completed in 2007 and published in 2009. This major accomplishment has enabled equine science to advance in ways that broadly parallel the transformative impact that genomics has had on many animal species including humans. A conceptual overview of reference genomes, genome annotation, and the major implications for equine science is presented. The relationship between genomic sequencing and the accelerating application of precision P4 medicine is discussed in the context of human and equine patients. Emergent technologies built on the foundation of genomic sequencing and rapidly gaining traction in research and clinical settings are introduced.
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Enfermedades de los Caballos/genética , Enfermedades de los Caballos/terapia , Caballos/genética , Medicina de Precisión/veterinaria , Animales , Genómica/métodos , Humanos , Valores de ReferenciaRESUMEN
OBJECTIVE: Expression of the de-adhesive extracellular matrix protein tenascin-C (TNC) is associated with the early postnatal development of articular cartilage which is both load-dependent and associated with chondrocyte differentiation. We assessed morphological changes in the articular cartilage of TNC deficient mice at postnatal ages of 1, 4 and 8 weeks compared to age-matched wildtype mice. RESULTS: Cartilage integrity was assessed based on hematoxylin and eosin stained-sections from the tibial bone using a modified Mankin score. Chondrocyte density and cartilage thickness were assessed morphometrically. TNC expression was localized based on immunostaining. At 8 weeks of age, the formed tangential/transitional zone of the articular cartilage was 27% thicker and the density of chondrocytes in the articular cartilage was 55% lower in wildtype than the TNC-deficient mice. TNC protein expression was associated with chondrocytes. No relevant changes were found in mice at 1 and 4 weeks of age. The findings indicate a role of tenascin-C in the post-natal maturation of the extracellular matrix in articular cartilage. This might be a compensatory mechanism to strengthen resilience against mechanical stress.
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Cartílago Articular/metabolismo , Tenascina/metabolismo , Envejecimiento/patología , Animales , Cartílago Articular/patología , Recuento de Células , Genotipo , Ratones , Tenascina/deficienciaRESUMEN
Synovial inflammation is a central feature of osteoarthritis (OA), elicited when local regulatory macrophages (M2-like) become overwhelmed, activating an inflammatory response (M1-like). Bone marrow mononuclear cells (BMNC) are a source of naïve macrophages capable of reducing joint inflammation and producing molecules essential for cartilage metabolism. This study investigated the response of BMNC to normal (SF) and inflamed synovial fluid (ISF). Equine BMNC cultured in autologous SF or ISF (n = 8 horses) developed into macrophage-rich cultures with phenotypes similar to cells native to normal SF and became more confluent in ISF (~100%) than SF (~25%). BMNC cultured in SF or ISF were neither M1- nor M2-like, but exhibited aspects of both phenotypes and a regulatory immune response, characterized by increasing counts of IL-10+ macrophages, decreasing IL-1ß concentrations and progressively increasing IL-10 and IGF-1 concentrations. Changes were more marked in ISF and suggest that homeostatic mechanisms were preserved over time and were potentially favored by progressive cell proliferation. Collectively, our data suggest that intra-articular BMNC could increase synovial macrophage counts, potentiating the macrophage- and IL-10-associated mechanisms of joint homeostasis lost during the progression of OA, preserving the production of cytokines involved in tissue repair (PGE2 , IL-10) generally impaired by frequently used corticosteroids.