RESUMEN
AIMS: This study aimed to describe baseline characteristics and adherence among patients with transthyretin amyloid cardiomyopathy (ATTR-CM) treated with tafamidis (VYNDAQEL®) in Japan using the Japanese Medical Data Vision (MDV) database. METHODS AND RESULTS: This study was a non-interventional, retrospective cohort study of adult (≥18 years old) patients in the Japanese MDV claims database diagnosed with ATTR-CM and with at least two tafamidis prescriptions of dose strength 4 × 20 mg/day between 1 March 2019 and 31 August 2021. The date of the first prescription was defined as the index date, with follow-up time defined as the time between the first and last prescription plus the days' supply from the last refill. Baseline characteristics were assessed during a 12 month pre-index period. Adherence was measured using two metrics: (i) the modified medication possession ratio (mMPR), calculated by taking the sum of days supplied for all fills within the follow-up period, divided by the number of days of follow-up, and reported as a percentage, with patients classified as adherent with an mMPR of ≥80%, and (ii) the proportion of days covered (PDC), calculated by taking the total number of days' supply dispensed during the follow-up period divided by the number of days of follow-up, adjusting for any days' supply overlap. A total of 210 patients were identified; the mean (standard deviation) age of the cohort was 77 (5.9) years, and the majority (89%) were male. The most common baseline cardiovascular comorbidities were heart failure (85%), ischaemic heart disease (66%), hypertensive diseases (49%), and diabetes (35%); 75% of patients received heart failure medications in the 12 months prior to index, with the most common being beta-blockers (49%), diuretics (48%), angiotensin receptor blockers (30%), angiotensin-converting enzyme inhibitors (22%), and sodium-glucose cotransporter-2 inhibitors (8.1%). Over an average 14 month follow-up, mean mMPR was 96% with a median of 100% [inter-quartile range (IQR): 97-101%]; 93% of patients were adherent (defined as an mMPR ≥ 80%). In the same follow-up period, mean PDC was 93.6% with a median of 99% (IQR: 93-100%). Persistence was high with 78% of patients having a 0 day gap between prescription refills. CONCLUSIONS: This study found high adherence rates to tafamidis in this real-world Japanese patient population. Adherence rates in this study were similar to those reported by the tafamidis clinical trial and a previously published US commercial claims adherence analysis. Further studies should be conducted to assess the impact of real-world adherence on real-world outcomes.
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Notch signaling plays a pivotal role in the development and, when dysregulated, it contributes to tumorigenesis. The amplitude and duration of the Notch response depend on the posttranslational modifications (PTMs) of the activated NOTCH receptor - the NOTCH intracellular domain (NICD). In normoxic conditions, the hydroxylase FIH (factor inhibiting HIF) catalyzes the hydroxylation of two asparagine residues of the NICD. Here, we investigate how Notch-dependent gene transcription is regulated by hypoxia in progenitor T cells. We show that the majority of Notch target genes are downregulated upon hypoxia. Using a hydroxyl-specific NOTCH1 antibody we demonstrate that FIH-mediated NICD1 hydroxylation is reduced upon hypoxia or treatment with the hydroxylase inhibitor dimethyloxalylglycine (DMOG). We find that a hydroxylation-resistant NICD1 mutant is functionally impaired and more ubiquitinated. Interestingly, we also observe that the NICD1-deubiquitinating enzyme USP10 is downregulated upon hypoxia. Moreover, the interaction between the hydroxylation-defective NICD1 mutant and USP10 is significantly reduced compared to the NICD1 wild-type counterpart. Together, our data suggest that FIH hydroxylates NICD1 in normoxic conditions, leading to the recruitment of USP10 and subsequent NICD1 deubiquitination and stabilization. In hypoxia, this regulatory loop is disrupted, causing a dampened Notch response.
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Receptor Notch1 , Hipoxia de la Célula , Humanos , Hidroxilación , Oxigenasas de Función Mixta/metabolismo , Receptor Notch1/metabolismo , Transducción de Señal , Linfocitos T/metabolismo , Ubiquitina Tiolesterasa/metabolismoRESUMEN
Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are instructed by Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (WWTR1/TAZ)-transcriptional enhanced associate domain (TEAD): a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2 and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fuelling nutrient-dependent mTORC1 signalling. By orchestrating the transcription of a repertoire of cell-surface transporters, including the large neutral amino acid transporter SLC7A5, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 activation. Dissociating mTORC1 from these nutrient inputs-elicited by the loss of Rag GTPases-inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. Together, these findings define a pivotal role for YAP/TAZ-TEAD in controlling endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
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Células Endoteliales , Transactivadores , Aciltransferasas/metabolismo , Animales , Células Endoteliales/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Nutrientes , Factores de Transcripción de Dominio TEA/metabolismo , Transactivadores/metabolismo , Proteínas Señalizadoras YAP/metabolismoRESUMEN
Endothelial cells (ECs) adapt their metabolism to enable the growth of new blood vessels, but little is known how ECs regulate metabolism to adopt a quiescent state. Here, we show that the metabolite S-2-hydroxyglutarate (S-2HG) plays a crucial role in the regulation of endothelial quiescence. We find that S-2HG is produced in ECs after activation of the transcription factor forkhead box O1 (FOXO1), where it limits cell cycle progression, metabolic activity and vascular expansion. FOXO1 stimulates S-2HG production by inhibiting the mitochondrial enzyme 2-oxoglutarate dehydrogenase. This inhibition relies on branched-chain amino acid catabolites such as 3-methyl-2-oxovalerate, which increase in ECs with activated FOXO1. Treatment of ECs with 3-methyl-2-oxovalerate elicits S-2HG production and suppresses proliferation, causing vascular rarefaction in mice. Our findings identify a metabolic programme that promotes the acquisition of a quiescent endothelial state and highlight the role of metabolites as signalling molecules in the endothelium.
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Proliferación Celular/genética , Células Endoteliales/metabolismo , Proteína Forkhead Box O1/genética , Neovascularización Fisiológica/genética , Animales , Regulación de la Expresión Génica/genética , Glutaratos/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Metabolismo/genética , Ratones , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal/genética , Valeratos/metabolismoRESUMEN
To form new blood vessels (angiogenesis), endothelial cells (ECs) must be activated and acquire highly migratory and proliferative phenotypes. However, the molecular mechanisms that govern these processes are incompletely understood. Here, we show that Apelin signaling functions to drive ECs into such an angiogenic state. Zebrafish lacking Apelin signaling exhibit defects in endothelial tip cell morphology and sprouting. Using transplantation experiments, we find that in mosaic vessels, wild-type ECs leave the dorsal aorta (DA) and form new vessels while neighboring ECs defective in Apelin signaling remain in the DA. Mechanistically, Apelin signaling enhances glycolytic activity in ECs at least in part by increasing levels of the growth-promoting transcription factor c-Myc. Moreover, APELIN expression is regulated by Notch signaling in human ECs, and its function is required for the hypersprouting phenotype in Delta-like 4 (Dll4) knockdown zebrafish embryos. These data provide new insights into fundamental principles of blood vessel formation and Apelin signaling, enabling a better understanding of vascular growth in health and disease.
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Vasos Sanguíneos/crecimiento & desarrollo , Quimiocinas/genética , Morfogénesis/genética , Transducción de Señal/genética , Proteínas de Pez Cebra/genética , Pez Cebra/genética , Animales , Vasos Sanguíneos/metabolismo , Quimiocinas/metabolismo , Células Endoteliales/metabolismo , Proteínas de Pez Cebra/metabolismoRESUMEN
BACKGROUND: Preoperative evaluation of malignancy in gliomas is important for surgical planning, particularly to determine whether a 1,3-bis-2-chloroethyl-1-nitrosourea wafer should be placed into the tumor cavity. In some cases, the intraoperative pathologic diagnosis of World Health Organization grade differs from the final diagnosis. Supplemental methods in addition to the routine contrast tomography or magnetic resonance imaging sequences may provide a more accurate preoperative diagnosis. Because tumor vascularity has been useful in distinguishing between low- and high-grade gliomas, we evaluated the accuracy of the arterial spin labeling (ASL) method, which could measure the cerebral blood flow (CBF) without using contrast medium, to determine the malignancy of gliomas. METHODS: This study included 102 patients with glioma (grade II, n = 40; grade III, n = 18; grade IV, n = 44). All patients underwent ASL to determine the tumor blood flow (TBF) and CBF in the middle cerebral region. The relative tumor vascular index (tVI), which is calculated as TBF divided by CBF in the contralateral middle cerebral region, was used to avoid dispersion of the absolute TBF value. RESULTS: tVI was significantly greater (1.46 ± 0.751) in high-grade gliomas than in low-grade gliomas (1.05 ± 0.343) (P = 0.003). As for each grade, tVI was statistically higher in grade IV than in grade II (P = 0.03) gliomas. CONCLUSIONS: The noninvasive ASL method provides additional information to distinguish high-grade glioma from low-grade gliomas without using contrast medium.
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Neoplasias Encefálicas/diagnóstico por imagen , Circulación Cerebrovascular/fisiología , Glioma/diagnóstico por imagen , Imagen por Resonancia Magnética , Adulto , Anciano , Femenino , Humanos , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Marcadores de Spin , Estadísticas no ParamétricasRESUMEN
BACKGROUND: One of the important aims of surgery for moyamoya disease is to establish indirect revascularization. The purpose of this study was to assess the progress of the middle meningeal artery (MMA) after our novel preservation method and to evaluate the relation between direct and indirect bypass in the chronic stage. METHODS: A total of 24 hemispheric sides of 19 patients with moyamoya disease were included in this study. Craniotomy was performed with preservation of the MMA during the procedure, then direct bypass was carried out. The relationship between anatomic variations of the MMA and success rate of preserving the MMA during craniotomy was noted. The alteration of the MMA and superficial temporal artery (STA) diameters was then evaluated using magnetic resonance imaging, and the correlation between the MMA and the STA in the chronic stage was examined. RESULTS: In total, the MMA was preserved during craniotomy in 20 hemispheric sides (83.3%). During the 3-year follow-up period, the MMA and STA diameters were significantly increased. At 3 years after surgery, the alteration of the MMA diameter was significantly more marked in pediatric cases than in adult cases, and MMA diameter was moderately but significantly negatively correlated with STA diameter. CONCLUSIONS: In moyamoya disease, the MMA could be developed as a pathway for indirect revascularization even after simple preservation, especially in pediatric patients. The progress of the MMA and the STA occurs through their synergistic interaction, and the balance might be decided based on their complementary relations in the chronic stage.
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Velocidad del Flujo Sanguíneo , Revascularización Cerebral/métodos , Circulación Colateral , Arterias Meníngeas/fisiopatología , Enfermedad de Moyamoya/fisiopatología , Enfermedad de Moyamoya/cirugía , Arterias Temporales/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Angiografía por Resonancia Magnética/métodos , Masculino , Arterias Meníngeas/diagnóstico por imagen , Persona de Mediana Edad , Enfermedad de Moyamoya/diagnóstico por imagen , Arterias Temporales/diagnóstico por imagen , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: A 3-dimensional temporal bone model for skull base surgical training was reconstructed via the use of a selective laser sintering technique, which is one of the 3-dimensional printing technologies. METHODS: The temporal bone model was created in 2 pieces to remove powder material in the mastoid air cells and to place dye into the semicircular canal and the Fallopian canal. RESULTS: The powder material was minimal, and the decisive structures were identified in color. CONCLUSIONS: This artificial model will pave the way to a "new era" in surgical training and medical education.
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Modelos Anatómicos , Procedimientos Neuroquirúrgicos/educación , Impresión Tridimensional , Base del Cráneo/cirugía , Hueso Temporal/cirugía , HumanosRESUMEN
BACKGROUND: Damage to the motor division of the lower cranial nerves that run into the jugular foramen leads to hoarseness, dysphagia, and the risk of aspiration pneumonia; therefore, its functional preservation during surgical procedures is important. Intraoperative mapping and monitoring of the motor rootlets at the cerebellomedullary cistern using endotracheal tube electrodes is a safe and effective procedure to prevent its injury. OBJECTIVE: To study the location of the somatic and autonomic motor fibers of the lower cranial nerves related to vocal cord movement. METHODS: Twenty-four patients with pathologies at the cerebellopontine lesion were studied. General anesthesia was maintained with fentanyl and propofol. A monopolar stimulator was used at amplitudes of 0.05 to 0.1 mA. Both acoustic and visual signals were displayed as vocalis muscle electromyographic activity using endotracheal tube surface electrodes. RESULTS: The average number of rootlets was 7.4 (range, 5-10); 75% of patients had 7 or 8 rootlets. As many as 6 rootlets (2-4 in most cases) were responsive in each patient. In 23 of the 24 patients, the responding rootlets congregated on the caudal side. The maximum electromyographic response was predominantly in the most caudal or second most caudal rootlet in 79%. CONCLUSION: The majority of motor fibers of the lower cranial nerves run through the caudal part of the rootlets at the cerebellomedullary cistern, and the maximal electromyographic response was elicited at the most caudal or second most caudal rootlet. ABBREVIATION: EMG, electromyographic.
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Raíces Nerviosas Espinales/anatomía & histología , Pliegues Vocales/inervación , Anciano , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio/métodos , Raíces Nerviosas Espinales/diagnóstico por imagen , Raíces Nerviosas Espinales/cirugíaRESUMEN
Here, we report three cases of moyamoya disease with a history of Kawasaki disease. A 33-year-old man was found to have stenotic lesions of the internal carotid arteries(ICAs)on both sides at a nearby hospital where he visited complaining of headache and lisping. He had received immunoglobulin therapy for Kawasaki disease at the ages of 1, 2, and 6 years. MRI showed only a chronic ischemic lesion in the white matter. Angiography showed occlusion at the terminal portion of the ICAs on both sides. He was diagnosed with moyamoya disease, but as he had no symptoms and preserved cerebral blood flow (CBF), he was kept under observation. An 8-year-old boy was diagnosed with moyamoya disease and underwent right encephaloduroarteriosynangiosis at a nearby hospital. He had received immunoglobulin therapy for Kawasaki disease at the age of 1 year. His ischemic symptoms worsened. Although MRI detected no apparent ischemic lesion, angiography revealed severe stenosis at the terminal portions of the ICAs on both sides, and 123I-IMP SPECT showed CBF impairment. Bilateral direct bypass was performed. His father was subsequently also diagnosed with moyamoya disease. A 4-year-old girl with epilepsy was diagnosed with moyamoya disease at a nearby hospital. She had been treated with aspirin for Kawasaki disease at the age of 1 year. MRI detected no remarkable ischemic lesions, but angiography revealed mild stenosis at the terminal portions of the ICAs on both sides. Five months later, her ischemic symptoms were worsening with progressing stenotic lesions, and she underwent bilateral direct bypass.
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Enfermedad de Moyamoya/complicaciones , Síndrome Mucocutáneo Linfonodular/complicaciones , Adulto , Niño , Preescolar , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/patología , Enfermedad de Moyamoya/terapia , Imagen Multimodal , Radiografía , Tomografía Computarizada de Emisión de Fotón Único , Resultado del TratamientoRESUMEN
We report a case of an optic nerve mass lesion associated with IgG4-related disease. A 39-year-old man presented with right blurred vision and proptosis 8 years before admission. Magnetic resonance imaging showed a mass lesion in the center of the right orbit, which was diagnosed as optic nerve sheath meningioma by neuroradiologists and neurosurgeons. Irradiation was selected for treatment of the lesion on the basis of the radiological diagnosis; subsequently, the lesion gradually reduced in size. However, regrowth of an optic nerve mass lesion observed during the previous 2 years caused remarkable exophthalmos, and removal of the orbital mass lesion was performed via a transcranial orbital approach. Pathological examinations resulted in a diagnosis of IgG4-related disease, and hematological tests revealed an elevated level of serum IgG4. Additional radiological examinations showed mass lesions in the left maxillary nerve, bilateral inferior alveolar nerves, paravertebral tissue, and left kidney. Treatment with oral steroids has produced a reduction in the size of these lesions.
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Inmunoglobulina G/sangre , Enfermedades del Nervio Óptico/diagnóstico , Enfermedades del Nervio Óptico/etiología , Corticoesteroides/administración & dosificación , Adulto , Biomarcadores/sangre , Diagnóstico Diferencial , Imagen de Difusión por Resonancia Magnética , Humanos , Masculino , Neoplasias Meníngeas , Meningioma , Enfermedades del Nervio Óptico/tratamiento farmacológico , Enfermedades del Nervio Óptico/patología , Neoplasias del Nervio Óptico , Resultado del Tratamiento , Trastornos de la Visión/etiologíaRESUMEN
BACKGROUND: Meningiomas or solitary fibrous tumors arising from the cavernous sinus (CS) are usually treated with radiosurgery to control growth. Surgical removal of cavernous tumors is indicated only for tumors extending outside the CS. However, even after adequate treatment, the tumor may exhibit recurrence or malignant transformation. We report a treatment option for recurrent meningeal tumors of the CS. METHODS: In 4 patients with CS tumors that exhibited regrowth after multiple operations and radiosurgery, radical removal in combination with high-flow bypass was performed, and a vascularized muscle flap was used for reconstruction. One patient had a radiation-induced atypical meningioma, 2 patients had transformed atypical meningiomas, and 1 patient had a frequently recurring solitary fibrous tumor. RESULTS: No local recurrence was observed in any patients during a follow-up period of 13-41 months. In all patients, a Karnofsky performance scale score of >80 on admission was maintained at >70 at the final follow-up evaluation. CONCLUSIONS: Radical removal in combination with high-flow bypass provides favorable results and maintains quality of life in patients with recurrent CS meningeal tumors.
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Seno Cavernoso/cirugía , Neoplasias Meníngeas/cirugía , Meningioma/cirugía , Adulto , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasias Meníngeas/radioterapia , Meningioma/radioterapia , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Procedimientos de Cirugía Plástica , Neoplasias de la Base del Cráneo/cirugía , Colgajos QuirúrgicosRESUMEN
Mitochondrial autophagy eliminates damaged mitochondria and decreases reactive oxygen species (ROS). The autophagy inhibitor chloroquine (CQ) potentiates temozolomide (TMZ) cytotoxicity in glioma cells, but it is not known whether CQ does this by inhibiting mitochondrial autophagy. The effects of CQ and TMZ on MitoSOX Red fluorescence, a mitochondrial ROS indicator, and cell death were examined in rat C6 glioma cells. Mitochondrial autophagy was monitored by the colocalization of MitoTracker Red fluorescence and EGFP-LC3 dots. Mitochondrial content was measured by MitoTracker Green fluorescence and immunoblotting for a mitochondrial protein. Finally, CQ's effects on tumor cells derived from a glioblastoma patient and human U87-MG glioblastoma cells were assessed. TMZ (100-1,000 µM) alone did not affect mitochondrial ROS or cell death in C6 cells, but when administered with CQ (10 µM), it increased mitochondrial ROS and cell death. Antioxidants significantly suppressed the CQ-augmented cell death in TMZ-treated cells, indicating that mitochondrial ROS were involved in this cell death. TMZ treatment reduced MitoTracker Green fluorescence and mitochondrial protein levels, and these effects were inhibited by CQ. TMZ also increased the colocalization of EGFP-LC3 dots with mitochondria, and CQ enhanced this effect. CQ potentiated TMZ-induced cytotoxicity in patient-derived glioblastoma cells as well as human U87-MG glioblastoma cells. These results suggest that CQ increases cellular ROS and augments TMZ cytotoxicity in glioma cells by inhibiting mitochondrial autophagy.
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Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Cloroquina/farmacología , Dacarbazina/análogos & derivados , Sinergismo Farmacológico , Glioma/patología , Mitocondrias/efectos de los fármacos , Animales , Antimaláricos/farmacología , Antineoplásicos Alquilantes/farmacología , Dacarbazina/farmacología , Glioma/tratamiento farmacológico , Glioma/metabolismo , Humanos , Mitocondrias/metabolismo , Mitocondrias/patología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Temozolomida , Células Tumorales CultivadasRESUMEN
Maximum tumor extirpation with preservation of the facial and cochlear nerve function is the goal of surgery for vestibular schwannoma. To preserve cochlear nerve function, the surgeon must employ a detailed knowledge of microanatomy, precise microsurgical techniques, and persistence. This paper describes the "pearls" of surgical techniques based on the anatomical study inside the mastoid from the view of the retrosigmoid transmeatal approach. A total of 592 consecutive patients underwent surgical removal of unilateral vestibular schwannoma (VS) between January 1994 and December 2009. The hearing preservation rate was 53.7 % for large vestibular schwannomas (>20 mm in diameter) and 74.1 % for tumors of all sizes. The key procedures for hearing preservation surgery are as follows: bloodless microdissection, sufficient coring-debulking, capsular elevation to locate the facial and cochlear nerves both electrophysiologically and by visual observation, sharp dissection of the facial and cochlear nerves, and avoidance of heat and mechanical injury to the nerves, the internal auditory artery, and the brain stem. Besides these techniques, appropriate instruments are essential to preserve hearing. The function of the facial and cochlear nerves should be the foremost concern. Meticulous techniques and the knowledge of microsurgical anatomy lead to hearing preservation with maximum tumor removal.
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Neoplasias Encefálicas/cirugía , Tronco Encefálico/cirugía , Nervio Coclear/cirugía , Audición/fisiología , Microcirugia , Neurilemoma/cirugía , Nervio Facial/cirugía , Humanos , Microcirugia/instrumentación , Microcirugia/métodos , Monitoreo Intraoperatorio/métodosRESUMEN
Melanoma is highly metastatic, but the mechanism of melanoma cell migration is still unclear. We found that melanoma cells expressed the nicotinamide adenine dinucleotide-dependent protein deacetylase SIRT1 in the cytoplasm. Cell membrane extension and migration of melanoma cells were inhibited by SIRT1 inhibitors or SIRT1 knockdown, whereas SIRT1 activators enhanced elongation of protrusion and cellular motility. In B16F1 cells, growth factor stimulation induced lamellipodium extension, a characteristic feature at the leading edge of migrating cells, and SIRT1 was found in the lamellipodium. SIRT1 inhibitor nicotinamide (NAM) or SIRT1 small interfering RNAs suppressed the lamellipodium extension by serum or platelet-derived growth factor (PDGF). The lamellipodium formation by dominant-active Rac1 was also inhibited by NAM, a SIRT1 inhibitor. NAM inhibited the accumulation of phosphorylated Akt at the submembrane by serum or PDGF. Using fluorescence resonance energy transfer, we found that NAM impaired PDGF-dependent increase in the phosphatidylinositol-3,4,5-trisphosphate level at the leading edge. NAM inhibited the abdominal metastasis of transplanted B16F1 melanoma cells in C57BL6/J mice and improved survival. Finally, SIRT1-knockdown B16F1 cells showed significantly reduced metastasis in transplanted mice compared with that in control B16F1 cells. These results indicate that SIRT1 inhibition is a strategy to suppress metastasis of melanoma cells.
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Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Melanoma/metabolismo , Seudópodos/metabolismo , Sirtuina 1/metabolismo , Neoplasias Cutáneas/metabolismo , Animales , Femenino , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Metástasis de la Neoplasia , Niacinamida/química , Factor de Crecimiento Derivado de Plaquetas/metabolismo , ARN Interferente Pequeño/metabolismoRESUMEN
BACKGROUND: Various modalities have been used to confirm the blood flow through parent arteries or surrounding perforating arteries during surgical aneurysm clipping, including motor-evoked potentials (MEPs), Doppler ultrasound, and indocyanine green videoangiography. Nonetheless, contralateral hemiparesis due to arterial blood flow insufficiency may arise because of false-positive or false-negative errors. By performing controlled intraoperative awakening during aneurysm clipping, we compared patients' voluntary movements with simultaneous MEP. METHODS: Four patients with anterior choroidal artery aneurysms and one patient with a dorsal internal carotid artery aneurysm were included in this study. MEP and intraoperative voluntary movements under awake craniotomy were assessed simultaneously during and after the clipping procedure. RESULTS: Aneurysms were safely and successfully clipped in all patients, with no evidence of postoperative neurological deficits. Voluntary movements and MEP findings did not differ from the control state in three patients. In the other two patients, we observed a discrepancy between MEP amplitudes and voluntary movements. In one patient, deterioration and subsequent improvement in voluntary movements were preceded by MEP amplitude reduction during clipping. In the other patient, MEP amplitude did not change although voluntary movement deteriorated during temporary occlusion of the internal carotid artery. CONCLUSIONS: Intraoperative neurological assessment during aneurysmal clipping under awake craniotomy is feasible and safe, and should be valuable for the assessment of ischemia, especially in the anterior choroidal artery. From a neurophysiologic viewpoint, MEP may be insufficiently sensitive for evaluating voluntary movement under ischemia.
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Potenciales Evocados Motores/fisiología , Aneurisma Intracraneal/cirugía , Monitoreo Intraoperatorio/métodos , Movimiento/fisiología , Procedimientos Neuroquirúrgicos/métodos , Adulto , Anciano , Anestesia , Neoplasias Encefálicas/cirugía , Monitores de Conciencia , Craneotomía , Estimulación Eléctrica , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Arterial spin labeling (ASL) magnetic resonance imaging (MRI) is a technique for depicting cerebral perfusion without contrast medium. The purpose of this study was to determine whether ASL can be used to detect hyperperfusion after revascularization for moyamoya disease as effectively as N-isopropyl-[123I]ß-iodoamphetamine ((123)I-IMP) single-photon emission computed tomography (SPECT). Fifteen consecutive patients with moyamoya disease were included in the study. All patients underwent surgical revascularization. Postoperatively, regional cerebral blood flow (rCBF) was measured by flow-sensitive alternating inversion recovery (FAIR) ASL and (123)I-IMP SPECT during the acute stage, and rCBF of the operative side was compared with the other side. The asymmetry ratio (AR) was then calculated from the rCBF as measured using each modality. The postoperative AR of ASL was moderately correlated with that of (123)I-IMP SPECT (y = 0.180x + 0.819; R = 0.80; P = .0003). In this series, 2 patients (13.3%) suffered symptomatic hyperperfusion after revascularization and accordingly exhibited increased AR of ASL. Our data indicate that early increases in rCBF in patients with hyperperfusion could be detected using FAIR ASL supplemental to (123)I-IMP SPECT after revascularization. Our data indicate that FAIR ASL is a convenient method for evaluating hyperperfusion that can be performed repeatedly without the use of contrast medium or radioisotopes.
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Arterias Cerebrales/cirugía , Revascularización Cerebral , Circulación Cerebrovascular , Imagen por Resonancia Magnética , Enfermedad de Moyamoya/cirugía , Imagen de Perfusión Miocárdica/métodos , Marcadores de Spin , Adolescente , Adulto , Presión Sanguínea , Edema Encefálico/diagnóstico , Edema Encefálico/fisiopatología , Arterias Cerebrales/diagnóstico por imagen , Arterias Cerebrales/fisiopatología , Revascularización Cerebral/efectos adversos , Niño , Preescolar , Femenino , Humanos , Yofetamina , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Enfermedad de Moyamoya/diagnóstico , Enfermedad de Moyamoya/fisiopatología , Valor Predictivo de las Pruebas , Radiografía , Radiofármacos , Factores de Tiempo , Tomografía Computarizada de Emisión de Fotón Único , Resultado del Tratamiento , Adulto JovenRESUMEN
Primary central nervous system lymphoma (PCNSL) is usually diffuse large B-cell lymphoma. Anaplastic large-cell lymphoma (ALCL) rarely occurs in the central nervous system. PCNSL always presents as single or multiple nodular contrast-enhancing mass lesions within T2-hyperintense areas on magnetic resonance imaging (MRI). Infrequently, diffuse infiltrating change with little contrast enhancement called lymphomatosis cerebri can be seen in PCNSL. In this report, we describe a 75-year-old immunocompetent man who had progressive dementia. On MRI, diffuse white matter lesions with little contrast enhancement were observed to gradually progress, which was clinically consistent with his worsening condition. A biopsy specimen revealed non-destructive, diffusely infiltrating, anaplastic large CD30-positive lymphoma, indicating a diagnosis of ALCL. After the biopsy, he was treated by whole brain irradiation (total 46 Gy) and focal boost irradiation (total 14 Gy). However, his performance status worsened and there was no symptom improvement. The patient died 8 months after symptom onset. The clinical course, diagnostic workup, pathologic correlates, and treatment outcomes are described herein.
Asunto(s)
Neoplasias Encefálicas/patología , Encéfalo/patología , Linfoma de Células B Grandes Difuso/patología , Linfoma Anaplásico de Células Grandes/patología , Anciano , Diagnóstico Diferencial , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
The recent introduction of multidetector row computed tomography (MDCT) scanners has enabled high-resolution 3-dimensional reconstruction. The purpose of this study was to establish a method to evaluate moyamoya disease using computed tomography angiography (CTA), specifically MDCT. Twenty-four patients (48 sides total) with moyamoya disease diagnosed by magnetic resonance angiography (MRA) were evaluated by means of CTA using MDCT by 3 independent observers, and the resulting 144 sides were analyzed. CTA and MRA were compared in terms of the steno-occlusive changes exhibited in each vessel. CTA and MRA scores were assigned on the basis of the severity of occlusive changes in the internal carotid artery, middle cerebral artery, anterior cerebral artery, and posterior cerebral artery. CTA scores were significantly correlated with MRA scores (P < .0001), and the 2 scores were in complete agreement in 57 sides (39.6%). The mean CTA score was significantly lower than the mean MRA score (P < .0001). Compared with CTA, MRA overestimated occlusion in 115 of the 576 vessels assessed. The mean MRA score was significantly higher in the overestimation group than in the good correlation group (P < .0001). CTA had a significantly higher rate of detection of moyamoya-affected vessels (P = .0001). Our data indicate that CTA using MDCT is a more reliable technique than MRA for diagnosing moyamoya disease. The ability to perform CTA quickly is a significant benefit for patients with moyamoya disease, particularly in pediatric and emergency cases.
Asunto(s)
Arteria Carótida Interna/diagnóstico por imagen , Angiografía Cerebral/métodos , Arterias Cerebrales/diagnóstico por imagen , Enfermedad de Moyamoya/diagnóstico por imagen , Tomografía Computarizada Multidetector , Adolescente , Adulto , Distribución de Chi-Cuadrado , Niño , Preescolar , Femenino , Humanos , Angiografía por Resonancia Magnética , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
In patients with vascular compression syndromes, the preoperative recognition of the cranial nerves and compressed vessels will contribute to improved surgical results. The aim of this study was to clarify the pathophysiology of hemifacial spasm (HFS) associated with the vertebral artery (VA) and to assess the value of preoperative imaging. Fifty-three consecutive patients with HFS underwent microvascular decompression (MVD). Of these, 18 cases of HFS were associated with the VA; this case series was compared with the remaining non-VA-associated HFS. For preoperative assessment, magnetic resonance imaging (MRI) was performed. Since January 2006, fusion imaging has been performed by combining MRI and computed tomography angiography. Of the 18 cases of VA-associated HFS, 17 (94.4 %) were on the left side; this was significantly higher than in the non-VA-associated HFS cases (p < 0.0001). The VA was attached to the root exit zone (REZ) directly in three cases. In the other 15 cases, the VA was compressing the REZ indirectly as a result of other intervening vessels. In all cases, preoperative imaging fully simulated the status of the REZ. The symptom disappeared in 17 cases (94.4 %) after MVD, and there was no significant difference in the surgical results between the VA-associated group and the non-VA-associated group (p = 0.9925). HFS associated with VA is not a rare condition. Preoperative recognition is thus important to the improvement of surgical results. Fusion imaging is useful to determine the status of the REZ, especially in indirect VA-associated HFS.