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OBJECTIVE: To compare the histological properties and stretch of colorectal mucosal grafts (CMG) and buccal mucosal grafts (BMG) and to evaluate the impact of age, medical comorbidity and tobacco use on these metrics. MATERIALS AND METHODS: Samples of BMGs from patients undergoing augmentation urethroplasty were sent for pathologic review. CMGs were collected from patients undergoing elective colectomy. CMGs were harvested fresh, at full thickness from normal rectum/sigmoid. Patients with inflammatory bowel disease, prior radiation, or chemotherapy were excluded. RESULTS: Seventy two BMGs and 53 CMGs were reviewed. While BMGs and CMGs were both histologically composed of mucosal (epithelium + lamina propria) and submucosal layers, the mucosal layer in CMG had crypts. The outer epithelial layers differed significantly in mean thickness (BMG 573µm vs. CMG 430µm, p=0.0001). Mean lamina propria thickness and submucosal layer thickness also differed significantly (BMG 135µm vs. CMG 400µm, p<0.0001; BMG 1090µm vs. CMG 808µm, p = 0.007, respectively). Mean delta stretch, as to length and width, was greater for CMG (118% x 72%) compared to BMGs (22% x 8%), both p<0.001. CONCLUSION: CMGs and BMGs significantly differ histologically in layer composition, width and architecture, as well as graft stretch. Given its elastic properties, CMG may be useful in covering large surface areas, but its thin epithelium, thick lamina propria and additional muscularis mucosal layer could impact graft take and contracture.
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Neoplasias Colorrectales , Estrechez Uretral , Masculino , Humanos , Estrechez Uretral/cirugía , Estrechez Uretral/patología , Procedimientos Quirúrgicos Urológicos Masculinos , Mucosa Bucal/trasplante , Uretra/cirugía , Uretra/patología , Neoplasias Colorrectales/cirugía , Resultado del TratamientoRESUMEN
PURPOSE: Previous studies have elucidated the unique macroscopic and histological properties of buccal mucosa that make it a viable and durable graft for urethral augmentation. However, no prior literature has directly investigated the impact of preoperative oral health on these features. MATERIALS AND METHODS: We analyzed all consenting patients who underwent buccal mucosal graft (BMG) urethroplasty at our institution from 2018 to 2020. Validated oral health surveys, the Oral Health Impact Profile (OHIP-14) and the Kayser-Jones Brief Oral Health Status Examination (BOHSE) were completed preoperatively. A staff pathologist analyzed BMG histology and quantified oral mucositis using a modified Oral Mucosa Rating Scale. RESULTS: We analyzed 51 patients with a median age of 40 years (IQR 31-58). Mean BOHSE score was 1.1 and OHIP-14 score was 1.4. Median epithelial thickness was 530 µm and lamina propria thickness was 150 µm. On age-adjusted analysis, increasing BOHSE and OHIP-14 were associated with decreasing epithelial thickness (p values <0.05). Higher BOHSE scores also correlated with thinner lamina proprias (p=0.05) and increased graft stretch (p=0.03). The 2 patients with postoperative urine leaks and available graft histology had lamina propria thicknesses well below the cohort median, at 50 µm and 60 µm. CONCLUSIONS: This is the first study to demonstrate that oral health conditions impact graft histology and stretch. Although much remains to be learned, our findings shed light on the potential importance of optimizing oral health prior to BMG urethroplasty, and raise the question of if preoperative mucosal biopsy could help inform surgical decision making and discussions regarding surgical success.
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Mucosa Bucal/trasplante , Salud Bucal/estadística & datos numéricos , Procedimientos de Cirugía Plástica/efectos adversos , Complicaciones Posoperatorias/diagnóstico , Estrechez Uretral/cirugía , Adulto , Autoinjertos/diagnóstico por imagen , Autoinjertos/patología , Autoinjertos/trasplante , Biopsia , Toma de Decisiones Clínicas , Medios de Contraste/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mucosa Bucal/patología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/patología , Complicaciones Posoperatorias/prevención & control , Periodo Preoperatorio , Estudios Prospectivos , Procedimientos de Cirugía Plástica/métodos , Encuestas y Cuestionarios/estadística & datos numéricos , Recolección de Tejidos y Órganos/métodos , Recolección de Tejidos y Órganos/estadística & datos numéricos , Resultado del Tratamiento , Uretra/anomalías , Uretra/diagnóstico por imagen , Uretra/patología , Uretra/cirugía , Urografía/métodosRESUMEN
Infection with the human immunodeficiency virus (HIV) remains a threat to global health. Since its discovery, many efforts have been directed at understanding the mechanisms and consequences of infection. Although there have been substantial advances since the advent of antiretroviral therapy, there are still complications that significantly compromise the health of infected patients, particularly, chronic inflammation and HIV-associated neurocognitive disorders (HAND). In this review, a new perspective is addressed in the field of HIV, where the alpha7 nicotinic acetylcholine receptor (α7-nAChR) is the protagonist. We comprehensively discuss the available evidence implicating α7-nAChRs in the context of HIV and provide possible explanations about its role in HAND and inflammation in both the central nervous system and the periphery.
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Complejo SIDA Demencia/metabolismo , Inflamación/metabolismo , Receptores Nicotínicos/metabolismo , Complejo SIDA Demencia/tratamiento farmacológico , Animales , Terapia Antirretroviral Altamente Activa , Humanos , Modelos Biológicos , Sistema Nervioso/patologíaRESUMEN
Lipid rafts, specialized membrane microdomains in the plasma membrane rich in cholesterol and sphingolipids, are hot spots for a number of important cellular processes. The novel nicotinic acetylcholine receptor (nAChR) mutation αC418W, the first lipid-exposed mutation identified in a patient that causes slow channel congenital myasthenia syndrome was shown to be cholesterol-sensitive and to accumulate in microdomains rich in the membrane raft marker protein caveolin-1. The objective of this study is to gain insight into the mechanism by which lateral segregation into specialized raft membrane microdomains regulates the activable pool of nAChRs. We performed fluorescent recovery after photobleaching (FRAP), quantitative RT-PCR, and whole cell patch clamp recordings of GFP-encoding Mus musculus nAChRs transfected into HEK 293 cells to assess the role of cholesterol and caveolin-1 (CAV-1) in the diffusion, expression, and functionality of the nAChR (WT and αC418W). Our findings support the hypothesis that a cholesterol-sensitive nAChR might reside in specialized membrane microdomains that upon cholesterol depletion become disrupted and release the cholesterol-sensitive nAChRs to the pool of activable receptors. In addition, our results in HEK 293 cells show an interdependence between CAV-1 and αC418W that could confer end plates rich in αC418W nAChRs to a susceptibility to changes in cholesterol levels that could cause adverse drug reactions to cholesterol-lowering drugs such as statins. The current work suggests that the interplay between cholesterol and CAV-1 provides the molecular basis for modulating the function and dynamics of the cholesterol-sensitive αC418W nAChR.
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Caveolina 1/genética , Microdominios de Membrana/metabolismo , Mutación , Síndromes Miasténicos Congénitos/genética , Receptores Nicotínicos/genética , Animales , Caveolina 1/metabolismo , Colesterol/deficiencia , Difusión , Endocitosis/efectos de los fármacos , Recuperación de Fluorescencia tras Fotoblanqueo , Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , Humanos , Microdominios de Membrana/química , Microdominios de Membrana/efectos de los fármacos , Ratones , Síndromes Miasténicos Congénitos/metabolismo , Síndromes Miasténicos Congénitos/patología , Ácido Ocadaico/farmacología , Técnicas de Placa-Clamp , Plásmidos/química , Plásmidos/metabolismo , Transporte de Proteínas , Receptores Nicotínicos/metabolismo , TransfecciónRESUMEN
The nicotinic acetylcholine receptor (nAChR), located in the cell membranes of neurons and muscle cells, mediates the transmission of nerve impulses across cholinergic synapses. In addition, the nAChR is also found in the electric organs of electric rays (e.g., the genus Torpedo). Cholesterol, which is a key lipid for maintaining the correct functionality of membrane proteins, has been found to alter the nAChR function. We were thus interested to probe the changes in the functionality of different nAChRs expressed in a model membrane with modified cholesterol to phospholipid ratios (C/P). In this study, we examined the effect of increasing the C/P ratio in Xenopus laevis oocytes expressing the neuronal α7, α4ß2, muscle-type, and Torpedo californica nAChRs in their macroscopic current responses. Using the two-electrode voltage clamp technique, it was found that the neuronal α7 and Torpedo nAChRs are significantly more sensitive to small increases in C/P than the muscle-type nAChR. The peak current versus C/P profiles during enrichment display different behaviors; α7 and Torpedo nAChRs display a hyperbolic decay with two clear components, whereas muscle-type and α4ß2 nAChRs display simple monophasic decays with different slopes. This study clearly illustrates that a physiologically relevant increase in membrane cholesterol concentration produces a remarkable reduction in the macroscopic current responses of the neuronal α7 and Torpedo nAChRs functionality, whereas the muscle nAChR appears to be the most resistant to cholesterol inhibition among all four nAChR subtypes. Overall, the present study demonstrates differential profiles for cholesterol inhibition among the different types of nAChR to physiological cholesterol increments in the plasmatic membrane. This is the first study to report a cross-correlation analysis of cholesterol sensitivity among different nAChR subtypes in a model membrane.
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Colesterol/metabolismo , Activación del Canal Iónico , Receptores Nicotínicos/metabolismo , Animales , Membrana Celular/química , Membrana Celular/metabolismo , Oocitos/metabolismo , Técnicas de Placa-Clamp , Fosfolípidos , Xenopus laevisRESUMEN
Despite the recent advances in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1) remains a global health threat. HIV-1 affects the central nervous system by releasing viral proteins that trigger neuronal death and neuroinflammation, and promotes alterations known as HIV-associated neurocognitive disorders (HAND). This disorder is not fully understood, and no specific treatments are available. Recently, we demonstrated that the HIV-1 envelope protein gp120IIIB induces a functional upregulation of the α7-nicotinic acetylcholine receptor (α7) in neuronal cells. Furthermore, this upregulation promotes cell death that can be abrogated with receptor antagonists, suggesting that α7 may play an important role in the development of HAND. The partial duplication of the gene coding for the α7, known as CHRFAM7A, negatively regulates α7 expression but its role in HIV infection has not been studied. Hence, we studied both CHRNA7 and CHRFAM7A regulation patterns in various gp120IIIB in vitro conditions. In addition, we measured CHRNA7 and CHRFAM7A expression levels in postmortem brain samples from patients suffering from different stages of HAND. Our results demonstrate the induction of CHRNA7 expression accompanied by a significant downregulation of CHRFAM7A in neuronal cells when exposed to pathophysiological concentrations of gp120IIIB. Our results suggest a dysregulation of CHRFAM7A and CHRNA7 expressions in the basal ganglia from postmortem brain samples of HIV+ subjects and expand the current knowledge about the consequences of HIV infection in the brain.
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Complejo SIDA Demencia/genética , Encéfalo/virología , Proteína gp120 de Envoltorio del VIH/genética , VIH-1/genética , Interacciones Huésped-Patógeno , Receptor Nicotínico de Acetilcolina alfa 7/genética , Complejo SIDA Demencia/metabolismo , Complejo SIDA Demencia/patología , Complejo SIDA Demencia/virología , Adulto , Autopsia , Ganglios Basales/metabolismo , Ganglios Basales/patología , Ganglios Basales/virología , Encéfalo/metabolismo , Encéfalo/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Regulación de la Expresión Génica , Proteína gp120 de Envoltorio del VIH/metabolismo , Proteína gp120 de Envoltorio del VIH/farmacología , VIH-1/metabolismo , VIH-1/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal , Receptor Nicotínico de Acetilcolina alfa 7/metabolismoRESUMEN
BACKGROUND: The collection of autologous peripheral blood (PB) stem cells can be challenging in the subgroup of patients deemed "poor mobilizers" with granulocyte-colony-stimulating factor. Plerixafor, a CXCR-4 antagonist, is an alternative mobilizing agent, but is costly, and the optimal mobilization algorithm has yet to be determined. STUDY DESIGN AND METHODS: To address the question we developed a protocol measuring PB CD34 on Day 4 of mobilization. We examined 26 patients before initiating the protocol versus 24 patients after initiation. RESULTS: Significant differences (p ≤ 0.05) included fewer days of collection (1.25 days vs. 2.42 days), lower total blood volume processed (25.9 L vs. 57.2 L), lower total product volume (324 mL vs. 691 mL), lower RBC content (9 mL vs. 18 mL), and lower granulocyte percentage per collection (35% vs. 11%). There were no significant differences between the two groups in demographics, baseline platelet count, total CD34, or CD34/kg harvested. CONCLUSION: Use of a protocol to assess PB CD34 1 day before collection allows for preemptive administration of plerixafor to augment mobilization. Subsequently, days of collection and processed blood volume are reduced while there is less RBC and granulocyte contamination in the collected stem cell product.
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Algoritmos , Antígenos CD34/sangre , Movilización de Célula Madre Hematopoyética/métodos , Compuestos Heterocíclicos/administración & dosificación , Adulto , Anciano , Bencilaminas , Recuento de Células Sanguíneas/instrumentación , Separación Celular/instrumentación , Separación Celular/métodos , Protocolos Clínicos , Ciclamas , Sinergismo Farmacológico , Eritrocitos , Femenino , Citometría de Flujo/instrumentación , Citometría de Flujo/métodos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/farmacología , Granulocitos , Enfermedades Hematológicas/sangre , Enfermedades Hematológicas/terapia , Compuestos Heterocíclicos/farmacología , Humanos , Masculino , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica , Estudios Retrospectivos , Neoplasias Testiculares/sangre , Neoplasias Testiculares/terapia , Factores de Tiempo , Trasplante Autólogo , Adulto JovenRESUMEN
Elephantiasis nostras verrucosa (ENV) is a rare cutaneous sequela of chronic lymphedema. Treatment of ENV remains poorly elucidated but has historically involved conservative management aimed at relieving the underlying lymphedema, with a few cases managed by surgical intervention. We report a case of a 27-year-old male with primary lymphedema complicated by large painful ENV lesions on his left foot that we excised surgically with good functional and cosmetic results as validated by the patient. To our knowledge, this is the first report of a case of ENV with a pedunculated morphology and the presence of a deep invasive stalk.
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Elefantiasis/cirugía , Pie/cirugía , Linfedema/complicaciones , Adulto , Elefantiasis/etiología , Humanos , MasculinoRESUMEN
This case series provides a diagnosis of myoclonus-dystonia syndrome (MDS) in two patients whose original presentation was thought to be Tourette's syndrome. The first patient presented with dystonia and myoclonus, which progressively worsened with age, and was diagnosed with an epsilon-sarcoglycan gene (SGCE) mutation. The patient's father, who was diagnosed in his childhood with Tourette's syndrome, also received genetic testing, which proved that to be a misdiagnosis and confirmed that he was the carrier of the SGCE mutation. Both patients were subjected to a levodopa trial, which proved to be an effective treatment. To our knowledge, these are the first reported cases of heterozygous pathogenic mutation of SGCE in Puerto Rico.
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Purulent bacterial pericarditis is rare and associated with significant short- and long-term morbidity. We report a case of purulent bacterial pericarditis caused by Group A Streptococcus in an immunocompetent young child presenting with a pericardial mass. She was successfully treated with a combined medical and early surgical approach. (Level of Difficulty: Intermediate.).
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SorLA is an established sorting and trafficking protein in neurons with demonstrated relevance to Alzheimer's disease (AD). It shares these roles with the caveolins, markers of membrane rafts microdomains. To further our knowledge on sorLA's expression and traffic, we studied sorLA expression in various cultured glia and its relation to caveolin-1 (cav-1), a caveolar microdomain marker. RT-PCR and immunoblots demonstrated sorLA expression in rat C6 glioma, primary cultures of rat astrocytes (PCRA), and human astrocytoma 1321N1 cells. PCRA were determined to express the highest levels of sorLA's message. Induction of differentiation of C6 cells into an astrocyte-like phenotype led to a significant decrease in sorLA's mRNA and protein expression. A set of complementary experimental approaches establish that sorLA and cav-1 directly or indirectly interact in glia: (1) co-fractionation in light-density membrane raft fractions of rat C6 glioma, PCRA, and human 1321N1 astrocytoma cells; (2) a subcellular co-localization distribution pattern in vesicular perinuclear compartments seen via confocal imaging in C6 and PCRA; (3) additional confocal analysis in C6 cells suggesting that the perinuclear compartments correspond to their co-localization in early endosomes and the trans-Golgi; and; (4) co-immunoprecipitation data strongly supporting their direct or indirect physical interaction. These findings further establish that sorLA is expressed in glia and that it shares its subcellular distribution pattern with cav-1. A direct or indirect cav-1/sorLA interaction could modify the trafficking and sorting functions of sorLA in glia and its proposed neuroprotective role in AD.
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Caveolina 1/metabolismo , Proteínas Relacionadas con Receptor de LDL/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Neuroglía/metabolismo , Animales , Humanos , Neuroglía/química , Transporte de Proteínas/fisiología , Ratas , Fracciones Subcelulares/química , Fracciones Subcelulares/metabolismo , Células Tumorales CultivadasRESUMEN
Over the past three decades, the Torpedo californica nicotinic acetylcholine receptor (nAChR) has been one of the most extensively studied membrane protein systems. However, the effects of detergent solubilization on nAChR stability and function are poorly understood. The use of lipid-analog detergents for nAChR solubilization has been shown to preserve receptor stability and functionality. The present study used lipid-analog detergents from phospholipid-analog and cholesterol-analog detergent families for solubilization and affinity purification of the receptor and probed nAChR ion channel function using planar lipid bilayers (PLBs) and stability using analytical size exclusion chromatography (A-SEC) in the detergent-solubilized state. We also examined receptor mobility on the lipidic cubic phase (LCP) by measuring the nAChR mobile fraction and diffusion coefficient through fluorescence recovery after photobleaching (FRAP) experiments using lipid-analog and non-lipid-analog detergents. Our results show that it is possible to isolate stable and functional nAChRs using lipid-analog detergents, with characteristic ion channel currents in PLBs and minimal aggregation as observed in A-SEC. Furthermore, fractional mobility and diffusion coefficient values observed in FRAP experiments were similar to the values observed for these parameters in the recently LCP-crystallized ß(2)-adrenergic receptor. The overall results show that phospholipid-analog detergents with 16 carbon acyl-chains support nAChR stability, functionality and LCP mobility.
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Detergentes/química , Fosfolípidos/química , Receptores Nicotínicos/metabolismo , Animales , Membrana Celular/química , Membrana Celular/metabolismo , Colesterol/química , Colesterol/metabolismo , Cromatografía en Gel , Detergentes/metabolismo , Recuperación de Fluorescencia tras Fotoblanqueo , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Potenciales de la Membrana/fisiología , Fosfolípidos/metabolismo , Estabilidad Proteica , Receptores Nicotínicos/aislamiento & purificación , Reproducibilidad de los Resultados , Solubilidad , Torpedo/metabolismoRESUMEN
Despite the fact that they are orphan diseases, congenital myasthenic syndromes (CMS) challenge those who suffer from it by causing fatigable muscle weakness, in the most benign cases, to a progressive wasting of muscles that may sentence patients to a wheelchair or even death. Compared to other more common neurological diseases, CMS are rare. Nevertheless, extensive research in CMS is performed in laboratories such as ours. Among the diverse neuromuscular disorders of CMS, we are focusing in the slow-channel congenital myasthenic syndrome (SCS), which is caused by mutations in genes encoding acetylcholine receptor subunits. The study of SCS has evolved from clinical electrophysiological studies to in vitro expression systems and transgenic mice models. The present review evaluates the methodological approaches that are most commonly employed to assess synaptic impairment in SCS and also provides perspectives for new approaches. Electrophysiological methodologies typically employed by physicians to diagnose patients include electromyography, whereas patient muscle samples are used for intracellular recordings, single-channel recordings and toxin binding experiments. In vitro expression systems allow the study of a particular mutation without the need of patient intervention. Indeed, in vitro expression systems have usually been implicated in the development of therapeutic strategies such as quinidine- and fluoxetine-based treatments and, more recently, RNA interference. A breakthrough in the study of SCS has been the development of transgenic mice bearing the mutations that cause SCS. These transgenic mice models have actually been key in the elucidation of the pathogenesis of the SCS mutations by linking IP-3 receptors to calcium overloading, as well as caspases and calpains to the hallmark of SCS, namely endplate myopathy. Finally, we summarize our experiences with suspected SCS patients from a local perspective and comment on one aspect of the contribution of our group in the study of SCS.
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Modelos Animales de Enfermedad , Síndromes Miasténicos Congénitos/etiología , Animales , Electromiografía , Expresión Génica , Ratones , Síndromes Miasténicos Congénitos/genética , Síndromes Miasténicos Congénitos/fisiopatologíaRESUMEN
OBJECTIVES: To determine concordance/discordance between morphology and molecular testing (MT) among synchronous pulmonary carcinomas using targeted next generation sequencing (NGS), with and without comprehensive molecular review (CMR), vs analyses of multiple singe genes (non-NGS). METHODS: Results of morphologic and MT assessment were classified as concordant, discordant, or indeterminate. For discordant cases, comprehensive histologic assessment (CHA) was performed. RESULTS: Forty-seven cases with 108 synchronous tumors were identified and underwent MT (NGS, nâ =â 23 and non-NGS, nâ =â 24). Histology and MT were concordant, discordant, and indeterminate in 53% (25/47), 21% (10/47), and 26% (12/47) of cases, respectively. CHA of the 10 discordant cases revised results of three cases. CONCLUSIONS: There is discordance between histology and MT in a subset of cases and MT provides an objective surrogate for staging synchronous tumors. A limited gene panel is sufficient for objectively assessing a relationship if the driver mutations are distinct. Relatedness of mutations require CMR with a larger NGS panel (eg, 50 genes).
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Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Metástasis de la Neoplasia/genética , Neoplasias Primarias Múltiples/genética , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/patología , Anciano , Anciano de 80 o más Años , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/patología , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/patologíaRESUMEN
Although Fourier transform (FT) and tryptophan-scanning mutagenesis (TrpScanM) have been extremely useful for predicting secondary structures of membrane proteins, they are deemed to be low-resolution techniques. Herein, we describe the combined use of FT and TrpScanM (FT-TrpScanM) as a more reliable approach for the prediction of secondary structure. Five TrpScanM studies of the acetylcholine receptor lipid-exposed transmembrane domains (LETMDs) were revisited and analyzed by FT-TrpScanM. FT analysis of the raw data from the aforementioned TrpScanM studies supports and validates the conclusions derived from their tryptophan-periodicity profiles. Furthermore, by FT-TrpScanM, we were able to determine the minimum number of consecutive tryptophan substitutions necessary for more robust prediction of alpha-helical secondary structures and evaluate the quality of structure predictions by alpha-helical character curves. Finally, this study encourages future utilization of FT-TrpScanM to more reliably predict secondary structures of the membrane protein LETMDs.
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Receptores Colinérgicos/química , Receptores Colinérgicos/genética , Animales , Femenino , Análisis de Fourier , Técnicas In Vitro , Lípidos de la Membrana/química , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Ratones , Mutagénesis Insercional , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Torpedo , Triptófano/química , Xenopus laevisRESUMEN
BACKGROUND AND AIM OF THE STUDY: The aortic mechanical prosthesis (AMP) generates shear stress and causes erythrocyte fragmentation with ADP release that leads to platelet activation, the cause of thromboembolism. Thromboprophylaxis with the antiplatelet agents clopidogrel and aspirin (Clop-ASA) should reduce thromboembolic events in patients receiving an AMP. METHODS: Over an eight-year period at the authors' institutions, a total of 135 patients underwent aortic valve replacement (AVR), with or without concomitant thoracic aortic procedures, and received Clop-ASA as thromboprophylaxis. Platelet reactivity was measured using the Verify Now system. Thromboelastography was commenced in August 2006, and patients were followed at six-month intervals, with echocardiography and assessment of platelet reactivity. RESULTS: The total follow up was 4,776 months (equivalent to 398 patient-years (pt-yr)); the average follow up was 35.4 +/- 25 months. During follow up, 18 patients (13.3%) died, eight from coronary artery disease and three from valve-related causes. Five patients (3.7%; 1.2%/pt-yr) had bleeding complications, but none experienced valve thrombosis. Two patients (1.5%; 0.5%/pt-yr) had a transient ischemic attack (TIA); one of these occurred in a patient who discontinued Clop-ASA, and the other in a responder to Clop-ASA. Seven patients (5.2%; 1.7%/pt-yr) had strokes, one of which occurred at 48.5 months after AVR. Of the remaining six patients who had a stroke, one was a non-responder to clopidogrel and five had stopped taking Clop-ASA. The incidence of strokes before using the Accumetrics and TEG devices was 2.5% per pt-yr, but only 1.0% per pt-yr thereafter. CONCLUSION: Thromboprophylaxis in patients with AMP receiving Clop-ASA seems to be effective. Patients had a low incidence of bleeding, TIA and ischemic stroke, and no valve thrombosis. The use of assays to determine platelet reactivity helped to identify those patients who were resistant to clopidogrel, hyporesponders, and poorly compliant patients. Notably, the incidence of strokes after implementing assays to monitor platelet reactivity was reduced. Deaths were due primarily to myocardial infarction, and none of the deaths was anticoagulant-related. Patients receiving Clop-ASA should undergo routine testing of platelet reactivity, and also continue antiplatelet therapy so as to reduce the risk of ischemic stroke.
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Válvula Aórtica , Aspirina/uso terapéutico , Prótesis Valvulares Cardíacas/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Tromboembolia/prevención & control , Ticlopidina/análogos & derivados , Anciano , Aspirina/farmacología , Plaquetas/efectos de los fármacos , Clopidogrel , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Cardiopatías/mortalidad , Cardiopatías/cirugía , Implantación de Prótesis de Válvulas Cardíacas , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/farmacología , Puerto Rico/epidemiología , Tromboembolia/etiología , Ticlopidina/farmacología , Ticlopidina/uso terapéutico , Estados Unidos/epidemiologíaRESUMEN
Assessment of ALK gene rearrangements is strongly recommended by the Molecular Testing Guideline for Selection of Lung Cancer Patients proposed by IASLC, AMP, and CAP at the time of diagnosis for patients with advanced stage disease. Non-small-cell lung cancer (NSCLC) with ALK gene rearrangements or the resulting fusion proteins have been, for the most part, successfully targeted with ALK tyrosine kinase inhibitors (TKIs). The most frequent rearrangement, the EML4-ALK oncogenic fusion, has more than 10 distinct variants, each with a discrete breakpoint in EML4 Recent studies have suggested that EML4-ALK variants may have differential responses to TKIs. Additionally, non-EML4-ALK fusions that result from ALK rearrangements with diverse 5' partners could possibly have varied biologic and clinical implications in their therapeutic responses and outcomes of patients with NSCLC. Existing literature documents at least 20 non-EML4 fusion partners for ALK, and the clinical responsiveness to crizotinib ranges from increased sensitivity to resistance. This underscores the importance of identifying the precise 5' fusion partner to ALK before initiation of therapy. Herein we report the identification of a novel SLMAP-ALK fusion in a patient with NSCLC.
Asunto(s)
Adenocarcinoma del Pulmón/genética , Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Crizotinib/uso terapéutico , Neoplasias Pulmonares/genética , Proteínas de la Membrana/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma del Pulmón/diagnóstico por imagen , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Anciano , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Fusión Génica , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , MasculinoRESUMEN
ABSTRACT Objective: To compare the histological properties and stretch of colorectal mucosal grafts (CMG) and buccal mucosal grafts (BMG) and to evaluate the impact of age, medical comorbidity and tobacco use on these metrics. Materials and Methods: Samples of BMGs from patients undergoing augmentation urethroplasty were sent for pathologic review. CMGs were collected from patients undergoing elective colectomy. CMGs were harvested fresh, at full thickness from normal rectum/sigmoid. Patients with inflammatory bowel disease, prior radiation, or chemotherapy were excluded. Results: Seventy two BMGs and 53 CMGs were reviewed. While BMGs and CMGs were both histologically composed of mucosal (epithelium + lamina propria) and submucosal layers, the mucosal layer in CMG had crypts. The outer epithelial layers differed significantly in mean thickness (BMG 573μm vs. CMG 430μm, p=0.0001). Mean lamina propria thickness and submucosal layer thickness also differed significantly (BMG 135μm vs. CMG 400μm, p<0.0001; BMG 1090μm vs. CMG 808μm, p = 0.007, respectively). Mean delta stretch, as to length and width, was greater for CMG (118% x 72%) compared to BMGs (22% x 8%), both p<0.001. Conclusion: CMGs and BMGs significantly differ histologically in layer composition, width and architecture, as well as graft stretch. Given its elastic properties, CMG may be useful in covering large surface areas, but its thin epithelium, thick lamina propria and additional muscularis mucosal layer could impact graft take and contracture.
RESUMEN
Currently, there are no specific therapies to treat HIV-1 associated neurocognitive disorders (HAND). The HIV-1 envelope, gp120, induces neuropathological changes similar to those in HAND patients; furthermore, it triggers an upregulation of the α7-nicotinic acetylcholine receptor (α7-nAChR), facilitating intracellular calcium overload and neuronal cell death. Using a gp120IIIB-transgenic mouse (gp120-tgm) model, we demonstrate that α7-nAChRs are upregulated on striatal neurons. Activation of α7-nAChRs leads to an increase in both intracellular calcium and percentage of apoptotic cells, which can be abrogated by antagonizing the receptor, suggesting a role for α7-nAChRs in gp120-induced neurotoxicity. Moreover, we demonstrate for the first time that gp120-tgm have learning deficiencies on a striatum-dependent behavioral task. They also show locomotor deficiencies, which improved with α7-nAChR antagonists, further supporting a role for this receptor in gp120-induced neurotoxicity. Together, these results uncover a new mechanism through which gp120-induced modulation of α7-nAChRs in the striatum can contribute to HAND development.