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BACKGROUND: This case report describes a rare instance of drug-induced aseptic meningitis after an interlaminar lumbar epidural steroid injection. CASE PRESENTATION: A 74 year-old female patient presented to the ED post-procedure day three after an L4-L5 interlaminar lumbar epidural steroid injection with fever, nausea, and vomiting. The patient had previously undergone numerous lumbar epidurals without complications and used identical medications, which included 1% lidocaine, iohexol contrast, methylprednisolone (Depo-medrol), and normal saline. Pertinent labs included a WBC of 15,000 cells/µL. Lumbar MRI revealed L4-S1 aseptic arachnoiditis. Two bone scans with Gallium and T-99 confirmed no infectious process. The patient then had a second admission months later with similar presenting symptoms and hospital course after repeating the lumbar epidural steroid injection. Lumbar MRI and CSF studies confirmed aseptic meningitis. CONCLUSION: This patient's repeated admissions from aseptic meningitis were likely caused by irritation of the meningeal layers from a medication used during the procedure.
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Meningitis Aséptica , Femenino , Humanos , Anciano , Meningitis Aséptica/inducido químicamente , Meningitis Aséptica/diagnóstico , Metilprednisolona , Imagen por Resonancia Magnética , Lidocaína , Inyecciones Epidurales/efectos adversosRESUMEN
OBJECTIVE: To verify the articular branch contributions in the human knee, delineate their anatomical variance, and outline the limitations of currently applied procedure protocols for denervation of the knee joint. DESIGN: A detailed anatomical dissection. SETTING: Cadavers in residence at the Albert Einstein College of Medicine. SUBJECTS: In total, 24 lower extremity specimens from 14 embalmed cadavers. METHODS: Human cadaveric dissections were performed on 24 lower extremities from 14 embalmed cadavers. RESULTS: This cadaveric study has demonstrated that the anterior knee receives sensory innervations from SMGN, SLGN, LRN, NVI, NVL, RFN, and IMGN. The courses of SMGN, SLGN, RFN, and IMGN are similar to recent anatomical studies. However, discrepancies exist in their relative anatomy to bony and radiographic landmarks. CONCLUSIONS: Genicular denervation using classical anatomical landmarks may not be sufficient to treat the anterior knee joint pain. Our findings illustrate more accurate anatomic landmarks for the three-target paradigm and support additional targets for more complete genicular denervation. This cadaveric study provides robust anatomical findings that can provide a foundation for new anatomical landmarks and targets to improve genicular denervation outcomes.
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Articulación de la Rodilla , Rodilla , Puntos Anatómicos de Referencia , Cadáver , Desnervación , Humanos , Rodilla/cirugía , Articulación de la Rodilla/inervación , Articulación de la Rodilla/cirugíaRESUMEN
Histone methyltransferases (HMTases), as chromatin modifiers, regulate the transcriptomic landscape in normal development as well in diseases such as cancer. Here, we molecularly order two HMTases, EZH2 and MMSET, that have established genetic links to oncogenesis. EZH2, which mediates histone H3K27 trimethylation and is associated with gene silencing, was shown to be coordinately expressed and function upstream of MMSET, which mediates H3K36 dimethylation and is associated with active transcription. We found that the EZH2-MMSET HMTase axis is coordinated by a microRNA network and that the oncogenic functions of EZH2 require MMSET activity. Together, these results suggest that the EZH2-MMSET HMTase axis coordinately functions as a master regulator of transcriptional repression, activation, and oncogenesis and may represent an attractive therapeutic target in cancer.
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Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/metabolismo , Complejo Represivo Polycomb 2/metabolismo , Neoplasias de la Próstata/enzimología , Proteínas Represoras/metabolismo , Regiones no Traducidas 3' , Animales , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Embrión de Pollo , Membrana Corioalantoides/patología , Proteína Potenciadora del Homólogo Zeste 2 , Expresión Génica , Técnicas de Silenciamiento del Gen , N-Metiltransferasa de Histona-Lisina/genética , Histonas/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/metabolismo , Invasividad Neoplásica , Trasplante de Neoplasias , Complejo Represivo Polycomb 2/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Interferencia de ARN , Proteínas Represoras/genética , Análisis de Matrices Tisulares , Activación TranscripcionalRESUMEN
Post-herpetic neuralgia is a chronic neuropathic pain disorder that is the sequela of the varicella zoster virus reactivation in the dorsal root ganglion. A variety of treatment modalities have been implemented, but pharmacologic treatments are often limited due to side effects and interventional procedures have yielded mixed results without promising long-term benefits being consistently seen. A dorsal root ganglion stimulator for treatment of post-herpetic neuralgia is a novel treatment option as it is able to specifically target the area affected. We present 3 patients who underwent implantation of permanent dorsal root ganglion stimulators and had a greater than 50% decrease in scoring on numerical rating scale (NRS) up to 18 months post-procedure and significantly reduced analgesic requirements.
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Neuralgia Posherpética , Neuralgia , Analgésicos , Ganglios Espinales , Humanos , Neuralgia/terapia , Neuralgia Posherpética/terapiaRESUMEN
PURPOSE: Functional MRI contrast has generally been associated with changes in transverse relaxivity caused by blood oxygen concentration, the so-called blood oxygen level dependent contrast. However, this interpretation of fMRI contrast has been called into question by several recent experiments at high spatial resolution. Experiments were conducted to examine contrast dependencies that cannot be explained only by differences in relaxivity in a single-spin population. METHODS: Measurements of functional signal and contrast were obtained in human early visual cortex during a high-contrast visual stimulation over a large range of TEs and for several flip angles. Small voxels (1.5 mm) were used to restrict the measurements to cortical gray matter in early visual areas identified using retinotopic mapping procedures. RESULTS: Measurements were consistent with models that include 2 spin populations. The dominant population has a relatively short transverse lifetime that is strongly modulated by activation. However, functional contrast is also affected by volume changes between this short-lived population and the longer-lived population. CONCLUSION: Some of the previously observed "nonclassical" behaviors of functional contrast can be explained by these interacting dual-spin populations.
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Mapeo Encefálico , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética , Oxígeno/sangre , Retina/patología , Corteza Visual/diagnóstico por imagen , Adulto , Algoritmos , Sangre/metabolismo , Corteza Cerebral/fisiología , Circulación Cerebrovascular , Medios de Contraste , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Estimulación Luminosa , Relación Señal-Ruido , Adulto JovenRESUMEN
AIMS: The role of tumour-associated macrophages (TAMs) in colorectal cancer (CRC) remains elusive. In this study, we aimed to examine the correlation between TAMs, clinicopathological features, tumour-infiltrating lymphocytes (TILs) and prognosis in CRC by the use of image analysis. METHODS AND RESULTS: Immunohistochemical staining for CD68 and CD163 was performed as pan-macrophage and M2-macrophage markers, respectively. Each marker was analysed separately for intra-epithelial and stromal area densities. All four macrophage densities showed a significant correlation with one another (P = 0.001). Intra-epithelial CD68+ macrophage densities showed a correlation with pTNM stage (P = 0.008), microsatellite instability (MSI) (P < 0.001), CpG island methylator phenotype (CIMP) (P < 0.001) and TIL densities (P < 0.001). Intra-epithelial CD163+ macrophage densities were associated with perineural invasion, MSI, CIMP and TIL densities (P < 0.001). Stromal CD68+ and CD163+ macrophage densities had a significant relationship with intra-epithelial and stromal CD3+ (P = 0.001 and P < 0.001, respectively) and CD8+ (P < 0.001) T cells. High intra-epithelial CD68+ macrophage density was associated with worse overall survival (HR = 1.386, 95% CI = 1.043-1.843, P = 0.025) and progression-free survival (HR = 1.522, 95% CI = 1.146-2.020, P = 0.004). Intra-epithelial CD68+ macrophage density was also an independent prognostic factor of the progression-free survival (HR = 1.447, 95% CI = 1.076-1.947, P = 0.015) of CRC patients regardless of pTNM stage, lymphatic, venous, and perineural invasions and TIL densities. CONCLUSION: Our results indicate that the density of intratumoural macrophages is a useful prognostic indicator for further stratifying T cell populations in CRC.
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Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Linfocitos Infiltrantes de Tumor/inmunología , Macrófagos/inmunología , Adulto , Anciano , Neoplasias Colorrectales/mortalidad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND & AIMS: We tested whether non-invasive tests for liver disease severity can stratify hepatocellular carcinoma (HCC) risk in chronic hepatitis B virus (HBV)-infected patients showing low-level viremia (LLV, HBV DNA <2000 IU/mL). METHODS: A retrospective cohort of 1006 chronic hepatitis B patients showing persistently LLV, defined by at least two consecutive assessments in the year before enrolment, was assessed for HCC development. Two non-invasive serum biomarkers, the aspartate aminotransferase to platelet ratio index (APRI) and the Fibrosis-4 (FIB-4), were tested. Cirrhosis was defined with ultrasonography. RESULTS: During a median 5.1 years of follow-up, HCC developed in 36 patients. HCC incidence rate at 5 years was significantly higher for cirrhotic patients (19/139, 13.7%), but was not null for non-cirrhotic patients (17/867, 2.0%, P<.001). APRI at a cut-off of 0.5 was more specific but less sensitive for HCC development, and FIB-4 at a cut-off of 1.45 was more sensitive but less specific. When both APRI and FIB-4 were used to group patients, the 5-year cumulative HCC incidence rate was 13.9%, 1.4% and 1.2% for both high, any high, and both low APRI and FIB-4 score among all patients (n=1006, P<.001), respectively, and was 11.4%, 1.5% and 0.4% in the same respective order among non-cirrhotic patients (n=867, P<.001). CONCLUSIONS: The combined use of two non-invasive serum biomarkers (APRI and FIB-4) could stratify HCC risk for chronic HBV-infected patients with LLV.
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Carcinoma Hepatocelular/virología , Hepacivirus/patogenicidad , Hepatitis B Crónica/diagnóstico , Cirrosis Hepática/diagnóstico , Pruebas de Función Hepática , Neoplasias Hepáticas/virología , Viremia/diagnóstico , Adulto , Factores de Edad , Aspartato Aminotransferasas/sangre , Biomarcadores/sangre , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/epidemiología , ADN Viral/sangre , ADN Viral/genética , Progresión de la Enfermedad , Femenino , Hepacivirus/genética , Hepatitis B Crónica/sangre , Hepatitis B Crónica/epidemiología , Hepatitis B Crónica/virología , Humanos , Incidencia , Cirrosis Hepática/sangre , Cirrosis Hepática/epidemiología , Cirrosis Hepática/virología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/epidemiología , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Seúl/epidemiología , Índice de Severidad de la Enfermedad , Factores de Tiempo , Ultrasonografía , Carga Viral , Viremia/virologíaRESUMEN
BACKGROUND: The Ponseti method has been shown to be the most effective treatment for congenital clubfoot. The current challenge is to establish sustainable national clubfoot treatment programs that utilize the Ponseti method and integrate it within a nation's governmental health system. The Brazilian Ponseti Program (Programa Ponseti Brasil) has increased awareness of the utility of the Ponseti method and has trained >500 Brazilian orthopaedic surgeons in it. METHODS: A group of 18 of those surgeons had been able to reproduce the Ponseti clubfoot treatment, and compiled their initial results through structured spreadsheet. RESULTS: The study compiled 1040 patients for a total of 1621 feet. The average follow-up time was 2.3 years with an average correction time of approximately 3 months. Patients required an average of 6.40 casts to achieve correction. CONCLUSIONS: This study demonstrates that good initial correction rates are reproducible after training; from 1040 patients only 1.4% required a posteromedial release. LEVEL OF EVIDENCE: Level IV.
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Moldes Quirúrgicos , Pie Equinovaro/terapia , Manipulación Ortopédica/métodos , Tenotomía , Tendón Calcáneo/cirugía , Preescolar , Países en Desarrollo , Femenino , Accesibilidad a los Servicios de Salud/normas , Humanos , Lactante , Masculino , Evaluación de Programas y Proyectos de Salud , Tenotomía/métodos , Resultado del TratamientoRESUMEN
PURPOSE: The relationship between erectile dysfunction and endothelial dysfunction has been described and is associated with adverse cardiac events. Endothelial dysfunction is believed to precede erectile dysfunction. Our objective was to characterize the prevalence of subjective erectile dysfunction, endothelial dysfunction and commonly related comorbidities in a population of men undergoing wellness screening. MATERIALS AND METHODS: A total of 205 men presented for wellness screening. They underwent testing for endothelial dysfunction via peripheral arterial tonometry and completed a health screening questionnaire. Reactive hyperemia index scores were generated by peripheral arterial tonometry testing. A reactive hyperemia index score of 1.67 or less defined endothelial dysfunction. The Student t-test and Fisher exact test were performed for continuous and categorical variables, respectively. The association of endothelial dysfunction, erectile dysfunction and various comorbidities was calculated using univariate and multivariable analyses. RESULTS: Of 205 men 47 reported subjective erectile dysfunction. Median age was 44 years old. The mean reactive hyperemia index in patients with erectile dysfunction was significantly lower than in patients without erectile dysfunction (1.63 vs 1.87, p = 0.001). Endothelial dysfunction was more common in men with than without erectile dysfunction (55% vs 36%, p = 0.027). Multivariable analysis revealed that men with erectile dysfunction and obesity were twofold more likely to have concomitant endothelial dysfunction (OR 2.45, 95% CI 1.13-4.24, p = 0.02 and OR 2.08, 95% CI 1.16-3.75, p = 0.01, respectively). CONCLUSIONS: Among middle-aged men presenting for wellness screening erectile dysfunction and obesity independently predicted endothelial dysfunction, a known risk factor for long-term adverse cardiac events.
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Endotelio Vascular/fisiopatología , Disfunción Eréctil/etiología , Enfermedades Vasculares/epidemiología , Adulto , Disfunción Eréctil/epidemiología , Promoción de la Salud , Humanos , Hiperemia/fisiopatología , Masculino , Manometría , Tamizaje Masivo/métodos , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Encuestas y Cuestionarios , Enfermedades Vasculares/complicacionesRESUMEN
Calpain, a family of calcium-dependent neutral proteases, plays important roles in neurophysiology and pathology through the proteolytic modification of cytoskeletal proteins, receptors and kinases. Alpha 2 spectrin (αII spectrin) is a major substrate for this protease family, and the presence of the αII spectrin breakdown product (αΙΙ spectrin BDP) in a cell is evidence of calpain activity triggered by enhanced intracytoplasmic Ca(2+) concentrations. Astrocytes, the most dynamic CNS cells, respond to micro-environmental changes or noxious stimuli by elevating intracytoplasmic Ca(2+) concentration to become activated. As one measure of whether calpains are involved with reactive glial transformation, we examined paraffin sections of the human cerebral cortex and white matter by immunohistochemistry with an antibody specific for the calpain-mediated αΙΙ spectrin BDP. We also performed conventional double immunohistochemistry as well as immunofluorescent studies utilizing antibodies against αΙΙ spectrin BDP as well as glial fibrillary acidic protein (GFAP). We found strong immunopositivity in selected protoplasmic and fibrous astrocytes, and in transitional forms that raise the possibility of some of fibrous astrocytes emerging from protoplasmic astrocytes. Immunoreactive astrocytes were numerous in brain sections from cases with severe cardiac and/or respiratory diseases in the current study as opposed to our previous study of cases without significant clinical conditions that failed to reveal such remarkable immunohistochemical alterations. Our study suggests that astrocytes become αΙΙ spectrin BDP immunopositive in various stages of activation, and that spectrin cleavage product persists even in fully reactive astrocytes. Immunohistochemistry for αΙΙ spectrin BDP thus marks reactive astrocytes, and highlights the likelihood that calpains and their proteolytic processing of spectrin participate in the morphologic and physiologic transition from resting protoplasmic astrocytes to reactive fibrous astrocytes.
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Astrocitos/metabolismo , Encéfalo/metabolismo , Calpaína/metabolismo , Citoplasma/metabolismo , Espectrina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana EdadRESUMEN
The neuropathology of traumatic brain injury (TBI) from various causes in humans is not as yet fully understood. The authors review and compare the known neuropathology in humans with severe, moderate, and mild TBI (mTBI) from nonpenetrating closed head injury (CHI) from blunt impacts and explosive blasts, as well as penetrating head injury (PHI). Penetrating head injury and CHI that are moderate to severe are more likely than mTBI to cause gross disruption of the cerebral vasculature. Axonal injury is classically exhibited as diffuse axonal injury (DAI) in severe to moderate CHI. Diffuse axonal injury is also prevalent in PHI. It is less so in mTBI. There may be a unique pattern of periventricular axonal injury in explosive blast mTBI. Neuronal injury is more prevalent in PHI and moderate to severe CHI than mTBI. Astrocyte and microglial activation and proliferation are found in all forms of animal TBI models and in severe to moderate TBI in humans. Their activation in mTBI in the human brain has not yet been studied.
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Traumatismos por Explosión/complicaciones , Lesiones Encefálicas/etiología , Encéfalo/patología , Traumatismos Penetrantes de la Cabeza/complicaciones , HumanosRESUMEN
Carotid body (CB) glomus cells depolarize in response to hypoxia, causing a [Ca(2+)](i) increase, at least in part, through activation of voltage-dependent channels. Recently, Turner et al. (2013) showed that mouse glomus cells with knockout of TASK1/3(-/-) channels have near-normal [Ca(2+)](i) response to hypoxia. Thus, we postulated that TRP channels may provide an alternate calcium influx pathway which may be blocked by the TRP channel antagonist, 2-APB (2-aminoethoxydiphenylborane). We confirmed that 2-APB inhibited the afferent nerve response to hypoxia, as previously reported (Lahiri S, Patel G, Baby S, Roy A (2009) 2-APB mediated effects on hypoxic calcium influx in rat carotid body glomus cells. FASEB 2009, Abstract, LB157; Kumar P, Pearson S, Gu Y (2006) A role for TRP channels in carotid body chemotransduction? FASEB J 20:A12-29). To examine the mechanism for this inhibition, we examined dissociated rat CB glomus cells for [Ca(2+)](i) responses to hypoxia, anoxia (with sodium dithionite), 20 mM K(+), NaSH, NaCN, and FCCP in absence/presence of 2-APB (100 µM). Also the effect of 2-APB on hypoxia and/or anoxia were investigated on NADH and mitochondria (MT) membrane potential. Our findings are as follows: (1) 2-APB significantly blocked the [Ca(2+)](i) increase in response to hypoxia and anoxia, but not the responses to 20 mM K(+). (2) The [Ca(2+)](i) responses NaSH, NaCN, and FCCP were significantly blocked by 2-APB. (3) Hypoxia-induced increases in NADH/NAD(+) and MT membrane depolarization were not effected by 2-APB. Thus TRP channels may provide an important pathway for calcium influx in glomus cells in response to hypoxia.
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Cuerpo Carotídeo/fisiología , Canales de Potencial de Receptor Transitorio/fisiología , Animales , Compuestos de Boro/farmacología , Calcio/metabolismo , Cuerpo Carotídeo/citología , Femenino , Masculino , Potencial de la Membrana Mitocondrial , Mitocondrias/fisiología , NAD/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
We have explored the mechanisms of uncatalyzed membrane ion permeation using atomistic simulations and electrophysiological recordings. The solubility-diffusion mechanism of membrane charge transport has prevailed since the 1960s, despite inconsistencies in experimental observations and its lack of consideration for the flexible response of lipid bilayers. We show that direct lipid bilayer translocation of alkali metal cations, Cl(-), and a charged arginine side chain analog occurs via an ion-induced defect mechanism. Contrary to some previous suggestions, the arginine analog experiences a large free-energy barrier, very similar to those for Na(+), K(+), and Cl(-). Our simulations reveal that membrane perturbations, due to the movement of an ion, are central for explaining the permeation process, leading to both free-energy and diffusion-coefficient profiles that show little dependence on ion chemistry and charge, despite wide-ranging hydration energies and the membrane's dipole potential. The results yield membrane permeabilities that are in semiquantitative agreement with experiments in terms of both magnitude and selectivity. We conclude that ion-induced defect-mediated permeation may compete with transient pores as the dominant mechanism of uncatalyzed ion permeation, providing new understanding for the actions of a range of membrane-active peptides and proteins.
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Cloruros/metabolismo , Membrana Dobles de Lípidos/metabolismo , Simulación de Dinámica Molecular , Potasio/metabolismo , Sodio/metabolismo , Transporte Iónico , Membrana Dobles de Lípidos/química , PermeabilidadRESUMEN
BACKGROUND: Environmental factors during perinatal development may influence developmental plasticity and disease susceptibility via alterations to the epigenome. Developmental exposure to the endocrine active compound, bisphenol A (BPA), has previously been associated with altered methylation at candidate gene loci. Here, we undertake the first genome-wide characterization of DNA methylation profiles in the liver of murine offspring exposed perinatally to multiple doses of BPA through the maternal diet. RESULTS: Using a tiered focusing approach, our strategy proceeds from unbiased broad DNA methylation analysis using methylation-based next generation sequencing technology to in-depth quantitative site-specific CpG methylation determination using the Sequenom EpiTYPER MassARRAY platform to profile liver DNA methylation patterns in offspring maternally exposed to BPA during gestation and lactation to doses ranging from 0 BPA/kg (Ctr), 50 µg BPA/kg (UG), or 50 mg BPA/kg (MG) diet (N = 4 per group). Genome-wide analyses indicate non-monotonic effects of DNA methylation patterns following perinatal exposure to BPA, corroborating previous studies using multiple doses of BPA with non-monotonic outcomes. We observed enrichment of regions of altered methylation (RAMs) within CpG island (CGI) shores, but little evidence of RAM enrichment in CGIs. An analysis of promoter regions identified several hundred novel BPA-associated methylation events, and methylation alterations in the Myh7b and Slc22a12 gene promoters were validated. Using the Comparative Toxicogenomics Database, a number of candidate genes that have previously been associated with BPA-related gene expression changes were identified, and gene set enrichment testing identified epigenetically dysregulated pathways involved in metabolism and stimulus response. CONCLUSIONS: In this study, non-monotonic dose dependent alterations in DNA methylation among BPA-exposed mouse liver samples and their relevant pathways were identified and validated. The comprehensive methylome map presented here provides candidate loci underlying the role of early BPA exposure and later in life health and disease status.
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Compuestos de Bencidrilo/toxicidad , Metilación de ADN/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Fenoles/toxicidad , Animales , Islas de CpG , Bases de Datos Genéticas , Dieta , Femenino , Genoma , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Lactancia , Masculino , Ratones , Cadenas Pesadas de Miosina/genética , Miosina Tipo II/genética , Transportadores de Anión Orgánico/genética , Embarazo , Efectos Tardíos de la Exposición Prenatal , Regiones Promotoras GenéticasRESUMEN
Beginning with precursor lesions, aberrant DNA methylation marks the entire spectrum of prostate cancer progression. We mapped the global DNA methylation patterns in select prostate tissues and cell lines using MethylPlex-next-generation sequencing (M-NGS). Hidden Markov model-based next-generation sequence analysis identified â¼68,000 methylated regions per sample. While global CpG island (CGI) methylation was not differential between benign adjacent and cancer samples, overall promoter CGI methylation significantly increased from ~12.6% in benign samples to 19.3% and 21.8% in localized and metastatic cancer tissues, respectively (P-value < 2 × 10(-16)). We found distinct patterns of promoter methylation around transcription start sites, where methylation occurred not only on the CGIs, but also on flanking regions and CGI sparse promoters. Among the 6691 methylated promoters in prostate tissues, 2481 differentially methylated regions (DMRs) are cancer-specific, including numerous novel DMRs. A novel cancer-specific DMR in the WFDC2 promoter showed frequent methylation in cancer (17/22 tissues, 6/6 cell lines), but not in the benign tissues (0/10) and normal PrEC cells. Integration of LNCaP DNA methylation and H3K4me3 data suggested an epigenetic mechanism for alternate transcription start site utilization, and these modifications segregated into distinct regions when present on the same promoter. Finally, we observed differences in repeat element methylation, particularly LINE-1, between ERG gene fusion-positive and -negative cancers, and we confirmed this observation using pyrosequencing on a tissue panel. This comprehensive methylome map will further our understanding of epigenetic regulation in prostate cancer progression.
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Metilación de ADN , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias de la Próstata/genética , Línea Celular Tumoral , Islas de CpG , ADN de Neoplasias/genética , Epigenómica , Células Epiteliales/metabolismo , Perfilación de la Expresión Génica , Biblioteca de Genes , Humanos , Masculino , Cadenas de Markov , Metástasis de la Neoplasia , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Análisis de Secuencia de ARN , Sitio de Iniciación de la TranscripciónRESUMEN
OBJECTIVE: The short Synacthen test (SST) is widely used as alternative test to the insulin tolerance test (ITT) to investigate central adrenal insufficiency (CAI), but the methodology and cut-off values of the SST are controversial. Our aim was to evaluate the cut-off value of the ITT in normal subjects and to assess the different cut-off values of the high-dose SST (250 µg, HDT) and the low-dose SST (1 µg, LDT) in subjects with suspected CAI. SUBJECTS AND METHODS: We conducted ITTs in 208 normal subjects to establish the cut-off value for the ITT, and 28 of those subjects underwent the HDT and LDT. From 1999 to 2007, 182 patients with suspected CAI were recruited and underwent ITTs, LDTs and HDTs to establish cut-off values and compare the diagnostic accuracy between the LDT and HDT. RESULTS: The 95th percentile of the peak cortisol level during the ITT in the normal control subjects was 14·8 µg/dl. Receiver operator characteristics (ROC) analysis revealed that the optimal cut-off values of peak cortisol in the LDT and HDT in patients with suspected CAI were 15·8 and 17·4 µg/dl, respectively. However, the cut-off values from normative data (mean - 2 SD) were 18·3 µg/dl for the LDT and 20·5 µg/dl for the HDT in normal control. CONCLUSIONS: The optimal cut-off values of SSTs needed to be individualized according to the type of SST and tested patient population.
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Insuficiencia Suprarrenal/diagnóstico , Cosintropina/análisis , Adolescente , Insuficiencia Suprarrenal/metabolismo , Adulto , Anciano , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Adulto JovenRESUMEN
STUDY DESIGN: A biomechanical study. OBJECTIVE: How much of the facet joint and the pars interarticularis (PI) can be removed in microendoscopic lateral decompression (MELD) for lumbar foraminal stenosis (LFS)? SUMMARY OF BACKGROUND DATA: MELD is a surgical modality for patients with LFS. In severe degenerative cases, unilateral facet joint resection or unilateral removal of the lateral part of the PI are sometimes needed to decompress the nerve root adequately. METHODS: Twelve human lumbar motion segments were tested according to the following loading protocol: axial compression, flexion, extension, lateral bending to the right and left, and axial rotation to the right and left. This loading protocol was applied to each motion segment after MELD in 2 experiments: (1) unilateral graded facetectomy was performed in stages of 25%, 50%, 75%, and 100% using 3 segments of L3/L4 and 3 segments of L5/S1; (2) unilateral removal of the lateral part of the PI was performed in stages of 25%, 50%, 75%, and 100% using 3 segments of L3/L4 and 3 segments of L5/S1. The relative stiffness of each motion segments was determined each time. RESULTS: (1) Unilateral facet joint resection of >75% can lead to a significant reduction in stiffness in axial rotation at both L3/L4 and L5/S1. (2) Unilateral removal of 75% of the lateral part of the PI can lead to significant reduction in stiffness in right and left rotation at L3/L4 and in left rotation at L5/S1. (3) Unilateral removal of 100% of the lateral part of the PI can lead to a significant reduction in stiffness in right axial rotation at L5/S1. CONCLUSIONS: It would seem judicious to remove no >50% of the facet joint or the lateral part of the PI in order to prevent postoperative instability when using MELD for LFS.
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Descompresión Quirúrgica/métodos , Vértebras Lumbares/fisiología , Vértebras Lumbares/cirugía , Microcirugia/métodos , Estenosis Espinal/cirugía , Anciano , Anciano de 80 o más Años , Fenómenos Biomecánicos/fisiología , Cadáver , Fuerza Compresiva/fisiología , Endoscopía/métodos , Femenino , Humanos , Masculino , Radiografía , Rango del Movimiento Articular/fisiología , Rotación , Índice de Severidad de la Enfermedad , Estenosis Espinal/diagnóstico por imagen , Articulación Cigapofisaria/fisiología , Articulación Cigapofisaria/cirugíaRESUMEN
Although the presence of MLH1 methylation in microsatellite-unstable colorectal cancer generally indicates involvement of the CpG island methylator phenotype (CIMP) in the development of the tumor, these two conditions do not always correlate. A minority of microsatellite-unstable colorectal cancers exhibit discordance between CIMP and MLH1 methylation statuses. However, the clinicopathological features of such microsatellite-unstable colorectal cancers with discrepant MLH1 methylation and CIMP statuses remain poorly studied. Microsatellite-unstable colorectal cancers (n=220) were analyzed for CIMP and MLH1 methylation statuses using the MethyLight assay. Based on the combinatorial CIMP and MLH1 methylation statuses, the microsatellite-unstable colorectal cancers were grouped into four subtypes (CIMP-high (CIMP-H) MLH1 methylation-positive (MLH1m+), CIMP-H MLH1 methylation-negative, CIMP-low/0 (CIMP-L/0) MLH1m+, and CIMP-L/0 MLH1 methylation-negative), which were compared in terms of their associations with clinicopathological and molecular features. The CIMP-L/0 MLH1 methylation-negative and CIMP-H MLH1m+ subtypes were predominant, comprising 63.6 and 24.1% of total microsatellite-unstable colorectal cancers, respectively. The discordant subtypes, CIMP-H MLH1 methylation-negative and CIMP-L/0 MLH1m+, were found in 5 and 7% of microsatellite-unstable colorectal cancers, respectively. The CIMP-H MLH1 methylation-negative subtype exhibited elevated incidence rates in male patients and was associated with larger tumor size, more frequent loss of MSH2 expression, increased frequency of KRAS mutation, and advanced cancer stage. The CIMP-L/0 MLH1m+ subtype was associated with onset at an earlier age, a predominance of MLH1 loss, and earlier cancer stage. None of the CIMP-L/0 MLH1m+ subtype patients succumbed to death during the follow-up. Our findings suggest that the discordant subtypes of colorectal cancers exhibit distinct clinicopathological and molecular features, although the proportion of discordant subtypes is low. The microsatellite-unstable colorectal cancers of the same CIMP status tended to exhibit different clinicopathological features depending on MLH1 methylation status.
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Proteínas Adaptadoras Transductoras de Señales/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Islas de CpG/genética , Metilación de ADN , Inestabilidad de Microsatélites , Proteínas Nucleares/genética , Anciano , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , FenotipoRESUMEN
OBJECTIVE: The number of endovascular procedures performed is increasing exponentially as technology improves. A serious complication of endovascular therapy is loss of a foreign body in the vasculature. We reviewed our experience and evaluated the cause, management, and outcomes of intravascular foreign body (IVFB) misplacement. METHODS: We completed a retrospective review of patients who underwent endovascular retrieval of IVFBs between 2005 and 2010. Patients were identified by current procedural terminology code or by our hospital's risk management team. Patients undergoing routine endovascular retrieval of temporary vena cava filters were excluded. RESULTS: Twenty-seven IVFBs were identified in 26 patients. Twenty patients were asymptomatic (76.9%). Six patients were symptomatic (22.2%) with either pain (n = 4) or abnormal physical findings (n = 2). There were 13 (48.1%) catheter fragments, six (22.2%) guidewires, five (18.5%) inferior vena cava (IVC) filter (embolisms), two (7.4%) stents, and one (3.7%) sheath fragment. There were five (15.6%) embolizations of an IVFB into the right heart, three (9.4%) into a pulmonary artery, eight (25%) into the vena cava, eight (25%) into peripheral veins, five (15.6%) into peripheral arteries, one (3.1%) into a coronary artery, one (3.1%) into a hepatic vein, and one (3.1%) into adjacent soft tissue. The mechanism of endovascular loss was device fracture in 16 (59.3%) cases, loss of control in six cases (22.2%), migration in four (14.8%) cases, and incorrect device deployment in one case (3.7%). The probable cause of foreign body loss was technical error in eight (29.6%) cases. In three cases, IVFB retrieval was not attempted. The misplacement and retrieval were completed during the same procedure in 13 (48%) cases. Twenty-four endovascular retrievals were performed. Fifteen (62.5%) procedures used a snare to remove the IVFB and two (8.2%) used balloon catheters. Three IVFBs could not be removed and two cases were converted to open procedures. Technical success was achieved in 19/24 cases (79.2%). There were no immediate complications related to the retrieval of the IVFB; however, there was a single late complication of pulmonary embolism after failed endovascular retrieval (1/24, 4.2%). Thirty-day survival was 100%. CONCLUSIONS: Intravascular foreign bodies are a serious complication of endovascular therapy that can be minimized with proper device selection and deployment. When an intravascular foreign body is identified, endovascular retrieval should be attempted due to its high success rate and minimal morbidity.
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Vasos Sanguíneos , Remoción de Dispositivos/métodos , Procedimientos Endovasculares/instrumentación , Cuerpos Extraños/terapia , Corazón , Errores Médicos , Stents , Dispositivos de Acceso Vascular , Filtros de Vena Cava , Procedimientos Endovasculares/efectos adversos , Falla de Equipo , Cuerpos Extraños/diagnóstico , Migración de Cuerpo Extraño/terapia , Humanos , Falla de Prótesis , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Endovascular adjuncts, like atherectomy, were developed to improve outcomes of endovascular arterial interventions. The true impact of atherectomy on endovascular outcomes remains to be determined, and little data exist on the influence of atherectomy on tibial interventions. Our study compares early and late outcomes of tibial intervention with angioplasty vs atherectomy-assisted interventions. METHODS: We completed a retrospective review of all tibial interventions between 2008 and 2010. Outcomes were analyzed using single and multivariate analysis, Cox regression, and Kaplan-Meier curves. Primary outcomes were primary, primary assisted, and secondary patency rates, as well as limb salvage and survival rates. RESULTS: Over a 2-year period, 480 tibial interventions were completed for 421 patients. Eighty-seven percent (n = 418) of interventions were performed for critical limb ischemia (CLI) and 13% (n = 62) for claudication. The CLI cohort of 418 interventions was analyzed. These patients had a mean age of 71 years with a mean follow-up time of 16 ± 15 months (range, 0-59 months). Of the 418 interventions, 339 underwent percutaneous transluminal angioplasty (PTA): 333 PTA alone, six PTA + stent. The remaining 79 interventions received atherectomy: 33 laser, 13 directional, and 33 orbital either alone or in conjunction with PTA (11 atherectomy only, 68 atherectomy + PTA). The groups did not differ significantly in terms of demographics, risk factors, or technical success. The atherectomy group had more TASC B lesions (54% vs 38%; P = .013), while the PTA-alone group had more TASC D lesions (25% vs 13%; P = .004). TASC A and C lesions did not differ significantly between the groups. No significant differences existed with respect to the early (30-day) outcomes of loss of patency (11% vs 13%; P = .699), complications (8% vs 13%; P = .292), or major amputation (17% vs 13%; P = .344) in the PTA-alone group vs the atherectomy-assisted group. Kaplan-Meier analysis revealed no difference for all primary outcomes of PTA alone vs the atherectomy-assisted group at 12 and 36 months: primary patency (69%, 55% vs 61%, 46%; P = .158), primary assisted patency (83%, 71% vs 85%, 67%; P = .801), secondary patency (94%, 89% vs 95%, 89%; P = .892), limb salvage (79%, 70% vs 81%, 77%; P = .485), or survival (77%, 56% vs 80%, 50%; P = .944). CONCLUSIONS: The adjunctive use of atherectomy offered no improvement in primary outcomes over PTA alone in either early or late outcomes in CLI patients who underwent endovascular tibial interventions. Considering the additional cost and increased procedural time, these findings put into question the routine use of adjunctive atherectomy.