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PURPOSE: To report the efficacy of the oral hypoxia-inducible factor 2α inhibitor belzutifan in participants with von Hippel-Lindau disease-associated retinal hemangioblastomas in the LITESPARK-004 study. DESIGN: Subgroup analysis of the phase 2, single-arm, open-label LITESPARK-004 study. PARTICIPANTS: Adults with 1 or more von Hippel-Lindau disease-associated measurable renal cell carcinoma tumors not requiring immediate surgical intervention were eligible. METHODS: Participants received oral belzutifan 120 mg once daily until disease progression or unacceptable treatment-related toxicity. MAIN OUTCOME MEASURES: Efficacy of belzutifan in retinal hemangioblastomas was a secondary end point, measured as response (improved, stable, or progressed) by independent reading center-certified graders based on color fundus imaging performed every 12 weeks using the investigator's preferred imaging standards. Additional assessments, where available, included OCT and ultra-widefield fluorescein angiography. RESULTS: Among 61 participants in LITESPARK-004, 12 had 1 or more evaluable active retinal hemangioblastomas in 16 eyes at baseline per independent reading center. As of April 1, 2022, the median follow-up for participants with ocular von Hippel-Lindau disease at baseline was 37.3 months. All 16 eyes were graded as improved, with a response rate of 100.0% (95% confidence interval, 79.4%-100%). No new retinal hemangioblastomas or ocular disease progression were reported as of data cutoff date. Eight participants underwent additional multimodal eye assessments performed at the National Institutes of Health study site. Among this subgroup, 10 of 24 hemangioblastomas in 8 eyes of 6 participants measured 500 µm or more in greatest linear dimension at baseline and were analyzed further. All 10 hemangioblastomas had a mean area reduction of 15% or more by month 12 and of 30% or more by month 24. CONCLUSIONS: Belzutifan showed promising activity against ocular von Hippel-Lindau disease, including capacity to control retinal hemangioblastomas, with effects sustained for more than 2 years while treatment is ongoing. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Retinal artery occlusion (RAO) is a devastating condition with no effective treatment. The management of RAO could potentially be improved through an in-depth understanding of the molecular alterations in the condition. This study combined advanced proteomic techniques and an experimental model to uncover the retinal large-scale protein profile of RAO. In 13 pigs, RAO was induced with an argon laser and confirmed by fluorescein angiography. Left eyes serving as controls received a sham laser without inducing occlusion. Retinal samples were collected after one, three, or six days and analyzed with liquid chromatography-tandem mass spectrometry. In RAO, 36 proteins were differentially regulated on day one, 86 on day three, and 557 on day six. Upregulated proteins included clusterin, vitronectin, and vimentin, with several proteins increasing over time with a maximum on day six, including clusterin, vimentin, osteopontin, annexin-A, signal transducer, and the activator of transcription 3. On day six, RAO resulted in the upregulation of proteins involved in cellular response to stress, hemostasis, innate immune response, and cytokine signaling. Downregulated proteins were involved in transmission across chemical synapses and visual phototransduction. This study identified the upregulation of multiple inflammatory proteins in RAO and the downregulation of proteins involved in visual pathways.
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Clusterina , Oclusión de la Arteria Retiniana , Animales , Porcinos , Vimentina/genética , Proteómica/métodos , RetinaRESUMEN
Retinal vein occlusion (RVO) is a frequent visually disabling condition. The management of RVO continues to challenge clinicians. Macular edema secondary to RVO is often recurrent, and patients typically require intravitreal injections for several years. Understanding molecular mechanisms in RVO is a key element in improving the treatment of the condition. Studying the molecular mechanisms in RVO at the retinal level is possible using animal models of experimental RVO. Most studies of experimental RVO have been sporadic, using only a few animals per experiment. Here, we report on 10 years of experience of the use of argon laser-induced experimental RVO in 108 porcine eyes from 65 animals, including 65 eyes with experimental branch retinal vein occlusion (BRVO) and 43 eyes with experimental central retinal vein occlusion (CRVO). Reproducibility and methods for evaluating and controlling ischemia in experimental RVO are reviewed. Methods for studying protein changes in RVO are discussed in detail, including proteomic analysis, Western blotting, and immunohistochemistry. Experimental RVO has brought significant insights into molecular changes in RVO. Testing intravitreal interventions in experimental RVO may be a significant step in developing personalized therapeutic approaches for patients with RVO.
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Oclusión de la Vena Retiniana , Animales , Porcinos , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/tratamiento farmacológico , Proteómica , Reproducibilidad de los Resultados , Retina , Rayos Láser , Tomografía de Coherencia ÓpticaRESUMEN
Central retinal vein occlusion (CRVO) is a visually disabling condition resulting from a thrombus in the major outflow vessel of the eye. The inflammatory response in CRVO is effectively treated with a dexamethasone (DEX) intravitreal implant. Uncovering the proteome changes following DEX implant intervention in CRVO may identify key proteins that mediate the beneficial effects of DEX. In six Göttingen minipigs, CRVO was induced in both eyes with an argon laser using a well-established experimental model. The right eyes were treated with a DEX intravitreal implant (Ozurdex, Allergan), while the left control eyes received a sham injection. Eight weeks after DEX intervention, retinal samples were collected and analyzed with tandem mass tag-based mass spectrometry. DEX implant intervention resulted in the upregulation of peptidyl-prolyl cis-trans isomerase FKBP5 (FKBP5) and ubiquilin-4. Immunohistochemistry showed expression of FKBP5 in the nuclei in all cellular layers of the retina. Cell adhesion molecule 3, tumor necrosis factor receptor superfamily member 16, and trans-1,2-dihydrobenzene-1,2-diol dehydrogenase were downregulated following DEX intervention. The upregulation of the corticosteroid-sensitive protein FKBP5 suggests that the implant remained active at the molecular level after eight weeks of treatment. Future studies may investigate if FKBP5 regulates the efficacy and duration of the DEX implant.
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Oclusión de la Vena Retiniana , Animales , Dexametasona/farmacología , Implantes de Medicamentos , Glucocorticoides/farmacología , Oclusión de la Vena Retiniana/tratamiento farmacológico , Oclusión de la Vena Retiniana/metabolismo , Porcinos , Porcinos Enanos , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Agudeza VisualRESUMEN
Aflibercept is a frequently used inhibitor of vascular endothelial growth factor (VEGF) in the treatment of macular edema following central retinal vein occlusion (CRVO). Retinal proteome changes following aflibercept intervention in CRVO remain largely unstudied. Studying proteomic changes of aflibercept intervention may generate a better understanding of mechanisms of action and uncover aspects related to the safety profile. In 10 Danish Landrace pigs, CRVO was induced in both eyes with an argon laser. Right eyes were treated with intravitreal aflibercept while left control eyes received isotonic saline water. Retinal samples were collected 15 days after induced CRVO. Proteomic analysis by tandem mass tag-based mass spectrometry identified a total of 21 proteins that were changed in content following aflibercept intervention. In retinas treated with aflibercept, high levels of aflibercept components were reached, including the VEGF receptor-1 and VEGF receptor-2 domains. Fold changes in the additional proteins ranged between 0.70 and 1.19. Aflibercept intervention resulted in a downregulation of pigment epithelium-derived factor (PEDF) (fold change = 0.84) and endoplasmin (fold change = 0.91). The changes were slight and could thereby not be confirmed with less precise immunohistochemistry and Western blotting. Our data suggest that aflibercept had a narrow mechanism of action in the CRVO model. This may be an important observation in cases when macular edema secondary to CRVO is resistant to aflibercept intervention.
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Edema Macular , Oclusión de la Vena Retiniana , Inhibidores de la Angiogénesis/farmacología , Animales , Inyecciones Intravítreas , Edema Macular/complicaciones , Edema Macular/etiología , Proteoma , Proteómica , Receptores de Factores de Crecimiento Endotelial Vascular , Proteínas Recombinantes de Fusión/farmacología , Oclusión de la Vena Retiniana/complicaciones , Oclusión de la Vena Retiniana/tratamiento farmacológico , Oclusión de la Vena Retiniana/metabolismo , Porcinos , Factor A de Crecimiento Endotelial Vascular , Agudeza VisualRESUMEN
Spinal ependymal tumors form a histologically and molecularly heterogeneous group of tumors with generally good prognosis. However, their treatment can be challenging if infiltration of the spinal cord or dissemination throughout the central nervous system (CNS) occurs and, in these cases, clinical outcome remains poor. Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma. Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization. The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases. Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity. Electron microscopy revealed cilia, complex intercellular junctions and intermediate filaments in a representative sample. Taking these findings into account, we suggest to designate this molecular subgroup spinal ependymoma with MYCN amplification, SP-EPN-MYCN. SP-EPN-MYCN tumors showed distinct growth patterns with intradural, extramedullary localization mostly within the thoracic and cervical spine, diffuse leptomeningeal spread throughout the whole CNS and infiltrative invasion of the spinal cord. Dissemination was observed in 100% of cases. Despite high-intensity treatment, SP-EPN-MYCN showed significantly worse median progression free survival (PFS) (17 months) and median overall survival (OS) (87 months) than all other previously described molecular spinal ependymoma subgroups. OS and PFS were similar to supratentorial ependymoma with RELA-fusion (ST-EPN-RELA) and posterior fossa ependymoma A (PF-EPN-A), further highlighting the aggressiveness of this distinct new subgroup. We, therefore, propose to establish SP-EPN-MYCN as a new molecular subgroup in ependymoma and advocate for testing newly diagnosed spinal ependymal tumors for MYCN amplification.
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Ependimoma/genética , Ependimoma/patología , Proteína Proto-Oncogénica N-Myc/genética , Neoplasias de la Columna Vertebral/genética , Neoplasias de la Columna Vertebral/patología , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Variaciones en el Número de Copia de ADN/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Masculino , Mutación/genéticaRESUMEN
Purpose: To identify retinal protein changes that mediate beneficial effects of intravitreal bevacizumab in experimental branch retinal vein occlusion (BRVO). Methods: In six Danish Landrace pigs, BRVO was induced with argon laser in both eyes. After BRVO was induced, the right eye of each animal was given an intravitreal injection of bevacizumab while the left eye was treated with saline water. The retinas were collected 15 days after BRVO, and differentially expressed proteins were analyzed with tandem mass tags-based mass spectrometry. Validation of statistically significantly changed proteins was performed with immunohistochemistry and western blotting. Results: Fluorescein angiography showed no recanalization of the occluded vessels. A total of 4,013 proteins were successfully identified and quantified. Nine proteins were statistically significantly changed following bevacizumab intervention. In experimental BRVO, bevacizumab treatment resulted in upregulation of transthyretin (TTR) and pantothenate kinase 3. Bevacizumab downregulated protocadherin 7, protein FAM192A, and ATP synthase protein 8. Immunohistochemistry revealed that TTR was highly abundant in the choroid following bevacizumab intervention. Conclusions: Bevacizumab intervention in experimental BRVO resulted in an increased level of TTR. This is the second study in which we showed an increased retinal level of TTR following anti-vascular endothelial growth factor (VEGF) intervention in experimental BRVO. We hypothesize that there is an interaction between TTR and VEGF and that bevacizumab may exert a beneficial effect on the retina by upregulating TTR.
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Inhibidores de la Angiogénesis/farmacología , Bevacizumab/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Prealbúmina/genética , Retina/efectos de los fármacos , Oclusión de la Vena Retiniana/tratamiento farmacológico , Animales , Cadherinas/antagonistas & inhibidores , Cadherinas/genética , Cadherinas/metabolismo , Coroides/irrigación sanguínea , Coroides/diagnóstico por imagen , Coroides/efectos de los fármacos , Coroides/metabolismo , Angiografía con Fluoresceína , Perfilación de la Expresión Génica , Humanos , Cadenas gamma de Inmunoglobulina/genética , Cadenas gamma de Inmunoglobulina/metabolismo , Cadenas kappa de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/metabolismo , Inyecciones Intravítreas , ATPasas de Translocación de Protón Mitocondriales/antagonistas & inhibidores , ATPasas de Translocación de Protón Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Prealbúmina/agonistas , Prealbúmina/metabolismo , Retina/diagnóstico por imagen , Retina/metabolismo , Retina/patología , Oclusión de la Vena Retiniana/diagnóstico por imagen , Oclusión de la Vena Retiniana/genética , Oclusión de la Vena Retiniana/patología , PorcinosRESUMEN
A dexamethasone (DEX) intravitreal implant (OZURDEX) provides an effective treatment of inflammation secondary to branch retinal vein occlusion (BRVO). Retinal proteome changes which mediate the beneficial effects of the implant remain poorly understood. To study retinal proteome changes in BRVO following an intervention with a DEX implant this study combined an experimental model of BRVO with proteomic techniques. In eight Danish Landrace pigs experimental BRVO was induced in both eyes using argon laser. After inducing BRVO a DEX implant was injected into the right eye of each animal while the left control eye was given an identical injection without an implant. Fifteen days after BRVO and DEX implant intervention the retinas were excised and analyzed with tandem mass tag based mass spectrometry. A total of 26 significantly changed proteins were identified. DEX intervention reduced the retinal levels of platelet-derived growth factor receptor-α (PDGFR-α) and vascular endothelial growth factor receptor 2 (VEGFR-2). DEX treatment resulted in increased levels of caveolin-1, peptidyl-prolyl cis-trans isomerase FKBP5 and transgelin. Changes in PDGFR-α and caveolin-1 were confirmed with immunohistochemistry. In BRVO treated with the DEX implant a strong reaction for caveolin-1 was observed in the innermost retinal layers. DEX implant intervention may inhibit PDGF signaling by decreasing the retinal level of PDGFR-α while an increased content of caveolin-1 may help maintain the integrity of the blood-retinal barrier.
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Caveolina 1/metabolismo , Dexametasona/administración & dosificación , Modelos Animales de Enfermedad , Glucocorticoides/administración & dosificación , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Oclusión de la Vena Retiniana/tratamiento farmacológico , Animales , Barrera Hematorretinal , Western Blotting , Cromatografía Liquida , Regulación hacia Abajo , Implantes de Medicamentos , Inyecciones Intravítreas , Espectrometría de Masas , Proteínas de Microfilamentos/metabolismo , Proteínas Musculares/metabolismo , Isomerasa de Peptidilprolil/metabolismo , Proteómica , Oclusión de la Vena Retiniana/metabolismo , Porcinos , Proteínas de Unión a Tacrolimus/metabolismo , Regulación hacia Arriba , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Retinal vein occlusion (RVO) is a common retinal vascular disease. RVO may be complicated by pronounced ischemia that often leads to severe loss of visual function. The present work aimed at studying the retinal proteome of RVO complicated by ischemia. In six Danish Landrace pigs RVO was induced with argon laser in the right eye of each animal. As four retinal veins were occluded, the RVO best corresponded to a central retinal vein occlusion (CRVO). Left control eyes received a similar laser treatment without inducing occlusion. RVO and retinal ischemia were verified by angiography. The retinas were collected 15 days after RVO for proteomic analysis. RVO resulted in a downregulation of proteins involved in visual perception, including rhodopsin, transducin alpha chain, and peripherin-2. RVO also caused a downregulation of proteins involved in neurotransmitter transport, including glutamate decarboxylase 1 (GAD1), glutamate decarboxylase 2 (GAD2), and complexins 2â»4. RVO lead to increased contents of proteins involved in inflammation, including interleukin-18 (IL-18), S100A12, and annexin A1 (ANXA1). Immunohistochemistry revealed a general retinal upregulation of IL-18 and ANXA1 while S100A12 was highly abundant in retinal ganglion cells in RVO. IL-18 and S100A12 are likely to be driving forces in the inflammatory response of RVO complicated by ischemia. Our findings also suggest that RVO results in compromised neurotransmission and a downregulation of proteins involved in visual perception.
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Interleucina-18/metabolismo , Oclusión de la Vena Retiniana/metabolismo , Proteína S100A12/metabolismo , Animales , Anexina A1/metabolismo , Western Blotting , Glutamato Descarboxilasa/metabolismo , Espectrometría de Masas , PorcinosRESUMEN
Animal models of experimental branch retinal vein occlusion (BRVO) provide a unique opportunity to study protein changes directly in retinal tissue. Results from these experimental models suggest that experimental BRVO is associated with an upregulation of extracellular matrix remodeling and adhesion signaling processes. To study whether these processes could be blocked by inhibition of VEGF-A, a porcine model of experimental BRVO was combined with proteomic analyses. In six Danish Landrace pigs experimental BRVO was induced with argon laser in both eyes. After 24 h an injection of 0.05 mL ranibizumab was given in the right eyes of the animals while left eyes received an injection of 0.05 mL 9 mg/mL sodium chloride water. Retinas were dissected three days after BRVO and the retinal samples were analyzed with label-free quantification as well as tandem mass tag based proteomics. In retinas treated with ranibizumab five proteins exhibited statistically significant changes in content with both proteomic techniques. These five proteins, which were all decreased in content, included integrin ß-1, peroxisomal 3-ketoacyl-CoA thiolase, OCIA domain-containing protein 1, calnexin and 40S ribosomal protein S5. As anti-integrin therapies are under development for inhibition of angiogenesis in retinal diseases it is interesting that inhibition of VEGF-A in itself resulted in a small decrease in the content of integrin ß-1. The decreased content of integrin ß-1 indicates that extracellular matrix remodeling and adhesion processes associated with BRVO are at least partly reversed through inhibition of VEGF-A.
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Proteoma/metabolismo , Proteómica/métodos , Ranibizumab/administración & dosificación , Oclusión de la Vena Retiniana/metabolismo , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Calnexina/metabolismo , Modelos Animales de Enfermedad , Integrina beta1/metabolismo , Inyecciones Intravítreas , Retina/metabolismo , Oclusión de la Vena Retiniana/diagnóstico , Oclusión de la Vena Retiniana/tratamiento farmacológico , Proteínas Ribosómicas/metabolismo , Porcinos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza VisualRESUMEN
INTRODUCTION: The horizontal synchondroses of the infant axis are biomechanical weak regions in trauma. CASE: We report the case of a 6-year-old girl who presented with delayed atlantoaxial dislocation and displaced ossiculum terminale epiphysiolysis after a fall from a tree. TREATMENT: The patient was treated with halo traction for 3 days after which a CT scan showed normal position of the C1/C2 joint, and an acceptable position of the ossiculum terminale whereafter a halo brace was applied. Because of delayed union on CT scans, the treatment was prolonged to a total of 21 weeks. RESULT: At final follow-up 26 months after halo brace removal, the patient demonstrated normal range of movement of the neck on clinical examination and radiographs of the cervical spine including lateral flexion/extension radiographs showed no sign of instability of the atlantoaxial joint. DISCUSSION: Conservative treatment with a halo device versus surgical treatment is discussed.
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Articulación Atlantoaxoidea/lesiones , Epífisis Desprendida/cirugía , Luxaciones Articulares/cirugía , Apófisis Odontoides/lesiones , Soportes Ortodóncicos , Articulación Atlantoaxoidea/patología , Niño , Epífisis Desprendida/complicaciones , Epífisis Desprendida/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Humanos , Luxaciones Articulares/complicaciones , Luxaciones Articulares/diagnóstico por imagen , Imagen por Resonancia Magnética , Apófisis Odontoides/cirugía , Tomografía Computarizada por Rayos XRESUMEN
Branch retinal vein occlusion (BRVO) is a common retinal vascular disease, but global protein changes following the condition remain largely unelucidated. To bring new insights into pathological processes and identify potential therapeutic targets, large-scale retinal protein changes following BRVO were studied by combining a porcine model of experimental BRVO with proteomic analysis by label-free liquid chromatography mass spectrometry. Among a total set of 1974 proteins, 52 significantly upregulated proteins and 10 significantly downregulated proteins were identified in retinas with BRVO after 15 days. Significantly upregulated proteins were involved in signaling pathways of focal adhesion via integrin and blood coagulation. Proteins involved in focal adhesion signaling included collagen α-2 chain, laminin subunit ß-2, laminin subunit γ-1, lipocalin-7, nidogen-2, osteopontin, integrin-ß, α-actinin-1, isoform 2 of α-actinin-1, talin-2 and filamin C. The identified proteins indicate that BRVO was associated with extracellular matrix remodeling processes. The present study identified focal adhesion signaling and ECM remodeling as important biological mechanisms to evaluate in the search for signaling pathways that promote neovascularisation and macular edema following BRVO.
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Modelos Animales de Enfermedad , Proteínas del Ojo/genética , Adhesiones Focales/genética , Regulación de la Expresión Génica/fisiología , Oclusión de la Vena Retiniana/genética , Transducción de Señal/genética , Animales , Cromatografía Liquida , Perfilación de la Expresión Génica , Ontología de Genes , Proteómica/métodos , Porcinos , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: Cardiovascular complications including cardiac arrest and arrhythmias remain a clinical challenge in the management of acute traumatic spinal cord injury (SCI). Still, there is a lack of knowledge regarding the characteristics of arrhythmias in patients with acute traumatic SCI. The aim of this prospective observational study was to investigate the occurrence of cardiac arrhythmias and cardiac arrests in patients with acute traumatic SCI. METHODS: As early as possible after SCI 24-hour Holter monitoring was performed. Additional Holter recordings were performed 1, 2, 3, and 4 weeks after SCI. Furthermore, 12-lead electrocardiograms (ECGs) were obtained shortly after SCI and at 4 weeks. RESULTS: Thirty patients were included. Bradycardia (heart rate (HR) <50 b.p.m.) was present in 17-35% of the patients with cervical (C1-C8) SCI (n = 24) within the first 14 days. In the following 14 days, the occurrence was 22-32%. Bradycardia in the thoracic (Th1-Th12) SCI group (n = 6) was present in 17-33% during the observation period. The differences between the two groups were not statistically significant. The mean minimum HR was significantly lower in the cervical group compared with the thoracic group both on 12-lead ECGs obtained shortly after SCI (P = 0.030) and at 4 weeks (P = 0.041). CONCLUSION: Many patients with cervical SCI experience arrhythmias such as bradycardia, sinus node arrest, supraventricular tachycardia, and more rarely cardiac arrest the first month after SCI. Apart from sinus node arrests and limited bradycardia, no arrhythmias were seen in patients with thoracic SCI. Standard 12-lead ECGs will often miss the high prevalence these arrhythmias have.
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Arritmias Cardíacas/complicaciones , Traumatismos de la Médula Espinal/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Arritmias Cardíacas/diagnóstico , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
We report the case of a 29-year-old woman presenting with severe back pain and S1-radiculopathy. Digital subtraction angiography revealed a spinal cord arteriovenous malformation complicated by acute feeder dissection and pseudoaneurysm (PA) formation causing mass effect. After conservative management with limited angiographic and clinical improvement, selective treatment of the PA by flow diversion (FD) led to occlusion and shrinkage with the resolution of clinical symptoms. FD may be a feasible treatment option for spinal artery aneurysms in selected patients with favorable anatomy. The need for antiplatelet therapy is a limitation of its use with currently available devices.
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Bevacizumab is a frequently used inhibitor of vascular endothelial growth factor (VEGF) in the management of macular edema in central retinal vein occlusion (CRVO). Studying retinal protein changes in bevacizumab intervention may provide insights into mechanisms of action. In nine Danish Landrace pigs, experimental CRVO was induced in both eyes with argon laser. The right eyes received an intravitreal injection of 0.05 mL bevacizumab (n = 9), while the left control eyes received 0.05 mL saline water (NaCl). Retinal samples were collected 15 days after induced CRVO. Label-free quantification nano-liquid chromatography-tandem mass spectrometry identified 59 proteins that were regulated following bevacizumab treatment. Following bevacizumab intervention, altered levels of bevacizumab components, including the Ig gamma-1 chain C region and the Ig kappa chain C region, were observed. Changes in other significantly regulated proteins ranged between 0.58-1.73, including for the NADH-ubiquinone oxidoreductase chain (fold change = 1.73), protein-transport protein Sec24B (fold change = 1.71), glycerol kinase (fold change = 1.61), guanine-nucleotide-binding protein G(T) subunit-gamma-T1 (fold change = 0.67), and prefoldin subunit 6 (fold change = 0.58). A high retinal concentration of bevacizumab was achieved within 15 days. Changes in the additional proteins were limited, suggesting a narrow mechanism of action.
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OBJECTIVE: To investigate the incidence of cardiac arrhythmias at six months following traumatic spinal cord injury (SCI) and to compare the prevalence of arrhythmias between participants with cervical and thoracic SCI. DESIGN: A prospective observational study using continuous twenty-four-hour Holter monitoring. SETTING: Inpatient rehabilitation unit of a university research hospital and patient home setting. PARTICIPANTS: Fifty-five participants with acute traumatic SCI were prospectively included. For each participant, the SCI was characterized according to the International Standards for Neurological Classification of SCI by the neurological level and severity according to the American Spinal Injury Association Impairment Scale. OUTCOME MEASURES: Comparisons between demographic characteristics and arrhythmogenic occurrences as early as possible after SCI (4 ± 2 days) followed by 1, 2, 3, 4 weeks and 6 month time points of Holter monitoring. RESULTS: Bradycardia (heart rate [HR] <50 bpm) was present in 29% and 33% of the participants with cervical (C1-C8) and thoracic (T1-T12) SCI six months after SCI, respectively. The differences in episodes of bradycardia between the two groups were not significant (P < 0.54). The mean maximum HR increased significantly from 4 weeks to 6 months post-SCI (P < 0.001), however mean minimum and maximum HR were not significantly different between the groups at the six-month time point. There were no differences in many arrhythmias between recording periods or between groups at six months. CONCLUSIONS: At the six-month timepoint following traumatic SCI, there were no significant differences in occurrences of arrhythmias between participants with cervical and thoracic SCI compared to the findings observed in the first month following SCI.
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Traumatismos de la Médula Espinal , Traumatismos Vertebrales , Arritmias Cardíacas/epidemiología , Arritmias Cardíacas/etiología , Bradicardia , Humanos , Estudios Prospectivos , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/epidemiologíaRESUMEN
Aflibercept is an inhibitor of vascular endothelial growth factor (VEGF) used to treat macular edema following branch retinal vein occlusion (BRVO). Despite well-documented efficacy, there is limited knowledge about proteome changes following aflibercept intervention in BRVO. Proteome changes may provide insights into mechanisms of action as well as aspects related to safety profile. In seven Danish Landrace pigs, BRVO was induced with a well-established experimental model of argon laser-induced BRVO. BRVO was induced in both eyes. Three days after the induced BRVO, aflibercept was injected intravitreally in the right eyes, while the left eyes received intravitreal isotonic saline water. Retinas were collected 15 days after the induced BRVO and analyzed with label-free quantification liquid chromatography tandem mass spectrometry (LFQ LC-MS/MS). Fourteen proteins were changed in expression following aflibercept intervention in the BRVO model. LFQ LC-MS/MS identified an upregulation of DnaJ homolog subfamily C member 17 (DNAJC17) (fold change = 6.19) and a modest downregulation of isoform 2 of the protein encoded by N-myc downstream regulated gene 2 (NDRG2) (fold change = 0.40). NDRG2 was unchanged by Western blotting. In the additional significantly regulated proteins, only discrete changes were observed (fold changes 0.52-1.59). Our study is the first to report an association between aflibercept intervention and the heat shock protein DNAJC17. Our results indicate that the role of heat shock proteins in the treatment of BRVO should be further explored.
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Complete resection is the treatment of choice for most pediatric brain tumors, but early postoperative MRI for detection of residual tumor may be misleading because of MRI signal changes caused by the operation. PET imaging with amino acid tracers in adults increases the diagnostic accuracy for brain tumors, but the literature in pediatric neurooncology is limited. A hybrid PET/MRI system is highly beneficial in children, reducing the number of scanning procedures, and this is to our knowledge the first larger study using PET/MRI in pediatric neurooncology. We evaluated if additional postoperative 18F-fluoro-ethyl-tyrosine (18F-FET) PET in children and adolescents would improve diagnostic accuracy for the detection of residual tumor as compared with MRI alone and would assist clinical management. Methods: Twenty-two patients (7 male; mean age, 9.5 y; range, 0-19 y) were included prospectively and consecutively in the study and had 27 early postoperative 18F-FET PET exams performed preferentially in a hybrid PET/MRI system (NCT03402425). Results: Using follow-up (93%) or reoperation (7%) as the reference standard, PET combined with MRI discriminated tumor from treatment effects with a lesion-based sensitivity/specificity/accuracy (95% confidence intervals) of 0.73 (0.50-1.00)/1.00 (0.74-1.00)/0.87 (0.73-1.00) compared with MRI alone: 0.80 (0.57-1.00)/0.75 (0.53-0.94)/0.77 (0.65-0.90); that is, the specificity for PET/MRI was 1.00 as compared with 0.75 for MRI alone (P = 0.13). In 11 of 27 cases (41%), results from the 18F-FET PET scans added relevant clinical information, including one scan that directly influenced clinical management because an additional residual tumor site was identified. 18F-FET uptake in reactive changes was frequent (52%), but correct interpretation was possible in all cases. Conclusion: The high specificity for detecting residual tumor suggests that supplementary 18F-FET PET is relevant in cases where reoperation for residual tumor is considered.
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Neoplasias Encefálicas/diagnóstico por imagen , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Neoplasias de la Médula Espinal/diagnóstico por imagen , Adolescente , Astrocitoma/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Niño , Preescolar , Femenino , Fluorodesoxiglucosa F18 , Estudios de Seguimiento , Glioma/diagnóstico por imagen , Humanos , Lactante , Recién Nacido , Masculino , Imagen Multimodal , Neoplasia Residual/diagnóstico por imagen , Pediatría , Periodo Posoperatorio , Estudios Prospectivos , Reoperación , Reproducibilidad de los Resultados , Tumor Rabdoide/diagnóstico por imagen , Sensibilidad y Especificidad , Neoplasias de la Médula Espinal/cirugía , Teratoma/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
INTRODUCTION: Superficial CNS siderosis was previously almost unknown but is now diagnosed with increasing frequency owing to magnetic resonance imaging. Patients may present with sensory deafness, gait ataxia, various sensorimotor signs and, eventually, cognitive decline. They typically have a history of traumatic brain or spinal cord injury or previous neurosurgery, or may harbour congenital malformations. However, knowledge about treatment outcomes remains scarce. METHODS: We present a series of nine consecutive patients from a large tertiary neuroscience centre in order to highlight the challenges related to the diagnosis and treatment of superficial siderosis. RESULTS: A potential bleeding aetiology was identified in all patients, but removal of the offending bleeding source was achieved only in three (33%). Symptom progression was halted in just one patient (11%), which suggests that neurodegeneration due to haemosiderin-associated iron toxicity becomes irreversible with time. CONCLUSION: Surgical therapy in superficial CNS siderosis is rarely achieved. We suggest that prospective, large-scale multicentre studies are needed to search for non-surgical therapies that reverse (or prevent) ongoing neurotoxicity due to accumulating iron toxicity. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.
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Enfermedades del Sistema Nervioso Central/terapia , Hemosiderosis/terapia , Siderosis/diagnóstico , Siderosis/terapia , Adulto , Anciano , Enfermedades del Sistema Nervioso Central/complicaciones , Enfermedades del Sistema Nervioso Central/diagnóstico , Femenino , Hemosiderina/toxicidad , Hemosiderosis/complicaciones , Hemosiderosis/diagnóstico , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Síndromes de Neurotoxicidad , Siderosis/complicaciones , Hemorragia Subaracnoidea/etiología , Hemorragia Subaracnoidea/cirugía , Resultado del TratamientoRESUMEN
A 74-year-old man presented with sensory deficits and lower limb weakness four years after a renal transplant. MRI showed an intramedullary mass at the T5 level. Following surgical excision the diagnosis post-transplant lymphoproliferative disorder (PTLD) was made. Although the frequency of PTLD is low in kidney transplant recipients (≤ 1%), it is an important differential diagnosis in a patient with new-onset neurological deficits following solid-organ transplantation.