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BACKGROUND: Although surgery may reduce mortality rates from type II odontoid fractures in the elderly population, post-operative dysphagia resulting from screw fixation remains a serious complication. METHODS: We retrospectively performed a chart review of patients over 65 years of age who underwent odontoid screw placement for type II odontoid fractures (2009-2014) and sustained post-operative dysphagia. The severity of dysphagia was determined based on the requirements for modified diets, PEG tubes, and prolonged length of stay (LOS), while costs were based upon discharge disposition (e.g. home vs. rehabilitation facilities) and total hospital costs. RESULTS: The incidence of postoperative dysphagia was 80%; 33% required feeding tubes, and 35% warranted PEG placement. The mean LOS for patients with dysphagia was 5 days longer and the total hospital costs averaged $50,000 higher. CONCLUSIONS: Age over 65 is a significant predictor of post-operative dysphagia in patients undergoing type II odontoid screw fixation. Notably, with each additional year above 65, the likelihood of post-operative dysphagia increased by 12%. Furthermore, postoperative dysphagia statistically increased the LOS and total costs.
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Nonerosive reflux disease (NERD) is a highly prevalent phenotype of the gastroesophageal reflux disease. In this study, we developed a novel murine model of NERD in mice with microscopic inflammation and impairment in the epithelial esophageal barrier. Female Swiss mice were subjected to the following surgical procedure: the transitional region between the forestomach and the glandular portion of the stomach was ligated, and a nontoxic ring was placed around the duodenum near the pylorus. The control group underwent sham surgery. The animals were euthanized at 1, 3, 7, and 14 days after surgery. Survival and body weight were monitored daily. Esophageal wet weight, macroscopic lesion, histopathological alterations, myeloperoxidase (MPO) activity, cytokine levels, transepithelial electrical resistance (TEER), and mucosal permeability were evaluated. The survival rate was 78% at 14 days, with mild loss in body weight. Surgery did not induce erosive esophagitis but instead induced microscopic inflammation and increased esophageal wet weight, IL-6, keratinocyte-derived cytokine (KC) levels, and MPO activity with maximal peak between 3 and 7 days and resolution at 14 days postsurgery. Epithelial esophageal barrier was evaluated in operated mice at 7 and 14 days postsurgery; a decrease in TEER and increase in the esophageal epithelial permeability were observed compared with the sham-operated group. In addition, the inhibition of acid secretion with omeprazole significantly prevented the esophageal inflammation and impairment of barrier function at 7 days postsurgery. Thus we established a novel experimental model of NERD in mice, which can contribute to understanding the pathophysiological events associated with NERD.NEW & NOTEWORTHY In this study, we standardized an experimental model of nonerosive reflux disease (NERD) in mice. This model involves an acute inflammatory response followed by impaired esophageal mucosal integrity, even in the absence of inflammation. Thus this model can serve for evaluation of pathophysiological aspects of NERD and open new perspectives for therapeutic strategies for patients with this disorder.
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Mucosa Esofágica/patología , Esofagitis Péptica/patología , Reflujo Gastroesofágico/patología , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Duodeno/cirugía , Impedancia Eléctrica , Mucosa Esofágica/efectos de los fármacos , Mucosa Esofágica/metabolismo , Mucosa Esofágica/fisiopatología , Esofagitis Péptica/etiología , Esofagitis Péptica/metabolismo , Esofagitis Péptica/fisiopatología , Femenino , Reflujo Gastroesofágico/etiología , Reflujo Gastroesofágico/metabolismo , Reflujo Gastroesofágico/fisiopatología , Mediadores de Inflamación/metabolismo , Ligadura , Ratones , Tamaño de los Órganos , Permeabilidad , Peroxidasa/metabolismo , Fenotipo , Inhibidores de la Bomba de Protones/farmacología , Estómago/cirugía , Factores de TiempoRESUMEN
A sulfated polysaccharide (SFP) fraction from the marine alga Solieria filiformis was extracted and submitted to microanalysis, molar mass estimation and spectroscopic analysis. We evaluated its gastroprotective potential in vivo in an ethanol-induced gastric damage model and its in vitro antioxidant properties (DPPH, chelating ferrous ability and total antioxidant capacity). Its chemical composition revealed to be essentially an iota-carrageenan with a molar mass of 210.9kDa and high degree of substitution for sulfate groups (1.08). In vivo, SFP significantly (P<0.05) reduced, in a dose dependent manner, the ethanol-induced gastric damage. SFP prevents glutathione consume and increase of malondialdehyde and hemoglobin levels. SFP presented an IC50 of 1.77mg/mL in scavenging DPPH. The chelating ferrous ability was 38.98%, and the total antioxidant capacity was 2.01mg/mL. Thus, SFP prevents the development of ethanol-induced gastric damage by reducing oxidative stress in vivo and possesses relevant antioxidant activity in vitro.
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Antioxidantes , Estrés Oxidativo/efectos de los fármacos , Polisacáridos , Rhodophyta/química , Gastropatías/prevención & control , Animales , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Etanol/toxicidad , Ratones , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Polisacáridos/farmacología , Gastropatías/inducido químicamenteRESUMEN
The fluoroacetate-producing bacterium Streptomyces cattleya has evolved a fluoroacetyl-CoA thioesterase (FlK) that exhibits a remarkably high level of discrimination for its cognate substrate compared to the cellularly abundant analogue acetyl-CoA, which differs only by the absence of the fluorine substitution. A major determinant of FlK specificity derives from its ability to take advantage of the unique properties of fluorine to enhance the reaction rate, allowing fluorine discrimination under physiological conditions where both substrates are likely to be present at saturating concentrations. Using a combination of pH-rate profiles, pre-steady-state kinetic experiments, and Taft analysis of wild-type and mutant FlKs with a set of substrate analogues, we explore the role of fluorine in controlling the enzyme acylation and deacylation steps. Further analysis of chiral (R)- and (S)-[(2)H1]fluoroacetyl-CoA substrates demonstrates that a kinetic isotope effect (1.7 ± 0.2) is observed for only the (R)-(2)H1 isomer, indicating that deacylation requires recognition of the prochiral fluoromethyl group to position the α-carbon for proton abstraction. Taken together, the selectivity for the fluoroacetyl-CoA substrate appears to rely not only on the enhanced polarization provided by the electronegative fluorine substitution but also on molecular recognition of fluorine in both formation and breakdown of the acyl-enzyme intermediate to control active site reactivity. These studies provide insights into the basis of fluorine selectivity in a naturally occurring enzyme-substrate pair, with implications for drug design and the development of fluorine-selective biocatalysts.
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Acetilcoenzima A/química , Acetilcoenzima A/metabolismo , Flúor/química , Flúor/metabolismo , Sitios de Unión/fisiología , Dominio Catalítico , Resonancia Magnética Nuclear Biomolecular , Unión Proteica , Streptomyces/enzimología , Especificidad por SustratoRESUMEN
Bone marrow macrophages (BMMs) share common progenitors with osteoclasts and are critical components of bone-tumor microenvironment; however, their function in prostate tumor growth in the skeleton has not been explored. BMMs are the major source of inflammatory factors and proteases, including cysteine protease cathepsin K (CTSK). In this study, utilizing mice deficient in CTSK, we demonstrate the critical involvement of this potent collagenase in tumor progression in bone. We present the evidence that tumor growth and progression in the bone are impaired in the absence of CTSK. Most importantly, we show for the first time that BMM-supplied CTSK may be involved in CCL2- and COX-2-driven pathways that contribute to tumor progression in bone. Together, our data unravel novel roles for CTSK in macrophage-regulated processes, and provide evidence for close interplay between inflammatory, osteolytic and tumor cell-driven events in the bone-tumor microenvironment.
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Neoplasias Óseas/secundario , Catepsina K/fisiología , Macrófagos/fisiología , Neoplasias de la Próstata/patología , Animales , Línea Celular Tumoral , Quimiocina CCL2/genética , Ciclooxigenasa 2/genética , Progresión de la Enfermedad , Humanos , Inflamación/prevención & control , Masculino , Ratones , Ratones Noqueados , Invasividad Neoplásica , Osteoclastos/patología , Microambiente TumoralRESUMEN
INTRODUCTION: The use of high-fidelity simulation has been studied in many healthcare education areas. However, the use of this instructional technology in the American Heart Association (AHA) Advanced Cardiovascular Life Support (ACLS) course has not been extensively reported, despite this program being one of the most widely taught standardized medical courses in the United States. METHODS: This study examined high-fidelity versus low-fidelity simulation in the context of an AHA ACLS course to determine subjects' educational outcomes as judged by expert raters reviewing videos of subjects performing a simulated cardiac arrest event immediately after the conclusion of the course. A purposeful sample of 34 subjects was enrolled in one of two ACLS classes. One class used high-fidelity simulation (n = 16), whereas the other used low-fidelity simulation (n = 18). RESULTS: The high-fidelity simulation group had a higher overall mean rank score on expert rater video review (M = 59.55 versus M = 44.34). This difference reached a level of statistical significance (P = 0.010, z = -2.592). On item level analysis of the instrument, 9 of 14 items reached levels of significance (P < 0.05). CONCLUSIONS: Expert raters judged students in a high-fidelity simulation-based AHA ACLS course as more competent than students in a low-fidelity course. On item level analysis, items focused on manual tasks or actions in the first 1 to 2 minutes of the cardiac arrest event were more likely to be nonsignificant. As the scenario grew longer and more complex, expert rater scores of the high-fidelity trained team leaders' confidence, knowledge, and treatment decisions were higher than the low-fidelity team leaders' score at a statistically significant level.
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Apoyo Vital Cardíaco Avanzado/educación , Educación en Enfermería , Enseñanza/métodos , Adulto , Apoyo Vital Cardíaco Avanzado/enfermería , Reanimación Cardiopulmonar/educación , Evaluación Educacional , Femenino , Humanos , Masculino , Maniquíes , Aprendizaje Basado en Problemas , Estados UnidosRESUMEN
OBJECTIVES: To examine the safety and efficacy of bacterial interference in preventing symptomatic urinary tract infection (UTI). METHODS: A prospective, nonrandomized, pilot clinical trial was conducted in patients with spinal cord injury who had neurogenic bladder and had frequent episodes of symptomatic UTI. The bladder of patients was inoculated with a nonpathogenic prototype of Escherichia coli 83972. The rate of symptomatic UTI in successfully colonized patients while colonized with E. coli 83972 was compared with (a) their own baseline prestudy rate and (b) the rate of symptomatic UTI in patients who were not successfully colonized. RESULTS: Of 44 inoculated patients, 30 (68%) became colonized with E. coli 83972 for 1 month or longer. Only two episodes of symptomatic UTI occurred in the group of 30 patients while colonized with E. coli 83972 (a total of 34 patient-years), and none was attributed to E. coli 83972. The group of 30 patients experienced a 63-fold reduction in the rate of symptomatic UTI while colonized with E. coli 83972 versus their baseline prestudy period (mean 0.06 versus 3.77 episodes of symptomatic UTI/patient-year, P <0.001). The rate of symptomatic UTI was also 33-fold lower in this group of 30 patients while colonized with E. coli 83972 than in the well-matched group of 14 patients who were not successfully colonized (mean 0.06 versus 1.80 episodes of symptomatic UTI/patient-year, P <0.001). CONCLUSIONS: The results of this pilot study indicate that bacterial interference using E. coli 83972 may be safe and effective in preventing UTI.
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Antibiosis/fisiología , Escherichia coli/fisiología , Vejiga Urinaria/microbiología , Infecciones Urinarias/prevención & control , Adulto , Ciprofloxacina/farmacología , Farmacorresistencia Bacteriana/fisiología , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Femenino , Humanos , Masculino , Proyectos Piloto , Estudios Prospectivos , Resultado del Tratamiento , Infecciones Urinarias/orina , Orina/microbiologíaRESUMEN
During persistent infection, the intracellular bacterial pathogen Chlamydia trachomatis is viable but severely attenuates the production of new, infectious elementary bodies (EBs). To investigate the reasons for this lack of new EB output, we analysed the expression of chlamydial genes encoding products required for DNA replication and cell division, using in vitro models of active versus persistent infection and synovial tissue samples from patients with chronic Chlamydia-associated arthritis. Hep-2 cells were infected with K serovar C. trachomatis and harvested at t = 0-48 h post-infection (p.i; active). Human monocytes were infected similarly and harvested at t = 1-7 days p.i. (persistent). RNA preparations from infected/uninfected cells and patient samples were subjected to reverse transcription-polymerase chain reaction (RT-PCR) targeting polA, dnaA, mutS and parB mRNA, related to chlamydial DNA replication/segregation; these were expressed in infected Hep-2 cells from 11 to 48 h p.i; ftsK and ftsW, related to cell division, were expressed similarly. Real-time PCR analyses demonstrated that significant accumulation of chlamydial chromosome began at about 12 h p.i. in infected Hep-2 cells. In infected human monocytes, polA, dnaA, mutS and parB mRNA were produced from days 1-7 p.i. and were weakly expressed in patient samples. Real-time PCR indicated the continuing accumulation of chlamydial chromosome during the 7 day monocyte infection, although the rate of such accumulation was lower than that occurring during active growth. However, transcripts from ftsK and ftsW were detected only at 1 day p.i. in infected monocytes but not thereafter, and they were absent in all patient samples. Thus, genes whose products are required for chlamydial DNA replication are expressed during persistence, but transcription of genes whose products are required for cytokinesis is severely downregulated. These data explain, at least in part, the observed attenuation of new EB production during chlamydial persistence.
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Proteínas Bacterianas/metabolismo , Chlamydia trachomatis/genética , Replicación del ADN/genética , Genes Bacterianos/genética , Monocitos/microbiología , Proteínas Bacterianas/genética , División Celular/genética , Chlamydia trachomatis/citología , Chlamydia trachomatis/crecimiento & desarrollo , Chlamydia trachomatis/metabolismo , Cromosomas Bacterianos/genética , Cartilla de ADN , Regulación Bacteriana de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Humanos , Modelos Biológicos , ARN Bacteriano/análisis , ARN Bacteriano/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Líquido Sinovial/microbiología , Transcripción Genética , Células Tumorales CultivadasRESUMEN
PURPOSE: Providing charge data to resident physicians has been shown to reduce the amounts spent on diagnostic testing. This pilot study sought to determine the influences of charge data and group decision making on diagnostic test ordering by internal medicine residents. METHOD: In an interactive workshop, 23 internal medicine residents received a hypothetical case. They completed an 18-item questionnaire estimating charges for diagnostic tests and then "ordered" tests. The residents were then randomly divided into groups that either received charge data, received charge data after ordering tests, or received no charge data. The groups ordered tests by consensus. Tests were weighted for appropriateness (+1 to +6) and inappropriateness (-1 to -6). Analyses compared individual and group decisions and effect of availability of charge data. RESULTS: Residents with access to charge data spent less on tests, but also had lower appropriateness scores. The appropriateness of the diagnostic workup was better by groups than by individuals, but cost more. CONCLUSION: Cost-containment interventions targeted towards doctors in training need to address the effect on quality of care and the influence of the group process in clinical decision making. Group diagnostic decisions may be more costly, but more appropriate.
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Pruebas Diagnósticas de Rutina/economía , Pruebas Diagnósticas de Rutina/estadística & datos numéricos , Honorarios y Precios , Internado y Residencia/estadística & datos numéricos , Pautas de la Práctica en Medicina/economía , Control de Costos , Toma de Decisiones , Humanos , Medicina Interna/educación , Kentucky , Proyectos PilotoRESUMEN
Despite more than three decades of anti-chlamydial vaccine research and improved vaccine strategies with new technologies, no vaccine candidate has protected against heterologous challenge, nor at more than one site of infection. The majority of experimental anti-chlamydial vaccines to date have targeted the chlamydial major outer membrane protein (MOMP). Many MOMP-directed vaccine candidates have been highly immunogenic, but have failed to protect against infectious challenge. We have extended our previous studies of a different anti-chlamydial vaccine, a monoclonal anti-idiotypic antibody (anti-Id; mAb2) which is a molecular mimic of the chlamydial glycolipid exoantigen (GLXA). The present studies demonstrate that the mAb2 vaccine is protective in a murine genital infection model utilizing a human urogenital strain. After either mucosal (oral or intranasal) or systemic (subcutaneous) immunization with the poly (lactide) encapsulated-mAb2 to GLXA, C3H/HeJ mice were significantly protected against topical vaginal challenge with Chlamydia trachomatis (K serovar; UW-31). Reduced vaginal shedding of organism and genital tract inflammation were associated with GLXA-specific and/or anti-EB neutralizing serum antibody. Our results demonstrate that the anti-Id (mAb2) vaccine is protective against an additional human biovar of C. trachomatis in C3H/HeJ mice, which are allogeneic to the source of mAb2 (BALB/c).
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Anticuerpos Antiidiotipos/administración & dosificación , Infecciones por Chlamydia/inmunología , Infecciones por Chlamydia/prevención & control , Chlamydia trachomatis/inmunología , Enfermedades de los Genitales Femeninos/inmunología , Enfermedades de los Genitales Femeninos/prevención & control , Glucolípidos/inmunología , Polisacáridos Bacterianos/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Anticuerpos Monoclonales/administración & dosificación , Vacunas Bacterianas/administración & dosificación , Infecciones por Chlamydia/patología , Chlamydia trachomatis/genética , Chlamydia trachomatis/aislamiento & purificación , Femenino , Técnica del Anticuerpo Fluorescente Directa , Genes Bacterianos , Enfermedades de los Genitales Femeninos/patología , Humanos , Ratones , Ratones Endogámicos C3H , Pruebas de Neutralización , Reacción en Cadena de la PolimerasaRESUMEN
De novo cardiac myofibril assembly has been difficult to study due to the lack of available cell culture models that clearly and accurately reflect heart muscle development in vivo. However, within precardiac chick embryo explants, premyocardial cells differentiate and commence beating in a temporal pattern that corresponds closely with myocyte differentiation in the embryo. Immunofluorescence staining of explants followed by confocal microscopy revealed that distinct stages of cardiac myofibril assembly, ranging from the earliest detection of sarcomeric proteins to the late appearance of mature myofibrils, were consistently recognized in precardiac cultures. Assembly events involved in the early formation of sarcomeres were clearly visualized and accurately reflected observations described by others during chick heart muscle development. Specifically, the early colocalization of alpha-actinin and titin dots was observed near the cell periphery representing I-Z-I-like complex formation. Myosin-containing thick filaments assembled independently of actin-containing thin filaments and appeared centered within sarcomeres when titin was also linearly aligned at or near cell borders. An N-terminal epitope of titin was detected earlier than a C-terminal epitope; however, both epitopes were observed to alternate near the cell periphery concomitant with the earliest formation of myofibrils. Although vascular actin was detected within cells during early assembly stages, cardiac actin predominated as the major actin isoform in mature thin filaments. Well-aligned thin filaments were also observed in the absence of organized staining for tropomodulin at thin filament pointed ends, suggesting that tropomodulin is not required to define thin filament lengths. Based on these findings, we conclude that the use of the avian precardiac explant system accurately allows for direct investigation of the mechanisms regulating de novo cardiac myofibrillogenesis.
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Citoesqueleto de Actina/metabolismo , Corazón/embriología , Proteínas de Microfilamentos , Miocardio/citología , Miofibrillas/metabolismo , Miosinas/metabolismo , Citoesqueleto de Actina/química , Animales , Proteínas Portadoras/metabolismo , Células Cultivadas , Embrión de Pollo , Conectina , Isomerismo , Proteínas Musculares/metabolismo , Miocardio/metabolismo , Proteínas Quinasas/metabolismo , TropomodulinaAsunto(s)
Actitud del Personal de Salud , Curriculum , Educación de Pregrado en Medicina/organización & administración , Competencia Profesional/normas , Desarrollo de Programa/métodos , Estudiantes de Medicina/psicología , Ética Médica , Conocimientos, Actitudes y Práctica en Salud , Humanos , Evaluación de Necesidades , Rol del Médico , Encuestas y CuestionariosAsunto(s)
Prácticas Clínicas/organización & administración , Curriculum , Depresión/diagnóstico , Depresión/terapia , Medicina Interna/educación , Atención Primaria de Salud/organización & administración , Humanos , Desarrollo de Programa , Evaluación de Programas y Proyectos de Salud , Estudiantes de Medicina/psicologíaRESUMEN
Peer and self-evaluation are crucial in the professional development of physicians. However, these skills must be learned, and there are barriers to their acceptance and successful utilization. To overcome these obstacles, it has been suggested that these concepts should be addressed longitudinally throughout medical education. Therefore, first-year medical students were introduced to peer and self-assessment as part of a videotape review during an interviewing course by having students complete written peer and self-assessments of the interviews. Students' self-assessments were compared with the assessments of peers and faculty. Written evaluations showed peers were more lenient than faculty and students were most critical of their own performances. Students could provide balanced assessments of their peers but were predominately negative regarding their own performances. It appears first-year students are capable of evaluating their peers but have difficulty accurately assessing their own performance. Further interventions are needed to foster self-assessment skills in first-year students.
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Educación Médica , Revisión por Pares , Autoevaluación (Psicología) , Humanos , Enseñanza/métodos , Estados UnidosRESUMEN
BACKGROUND: A cataract is any opacity or partial loss of transparency of the lens, whether the absence of transparency is small or complete. Pupil dilation affords a view of a legion of internal variations and abnormalities of the human crystalline lens which often tell us about its events and insults, as well as when in the patient's life these might have occurred. METHODS: In this article, we review the major non-age-related association of cataractogenesis with respect to metabolic, environmental, ocular-specific, infectious, dermatologic, retinal, and toxic etiologies. The data are presented from the clinical perspective of incidence for a given condition and cataract type. RESULTS: Two simplified summary reference sheets are provided: (1) frequency of occurrence vs. etiology and (2) cataract type vs. etiology (color-coded). The busy clinician can refer to both tools chair-side. CONCLUSIONS: The human body has numerous methods of signaling insults and abnormalities. As the crystalline lens is an important gauge of overall health, an argument can be made for routine dilation of all patients. This information is also essential for future neutraceutical and pharmaceutical therapeutic intervention.
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Catarata/etiología , Catarata/inducido químicamente , Catarata/epidemiología , Dermatitis Atópica/complicaciones , Ambiente , Oftalmopatías/complicaciones , Humanos , Incidencia , Infecciones/complicaciones , Enfermedades Metabólicas/complicaciones , Enfermedades de la Retina/complicacionesRESUMEN
Despite numerous studies demonstrating that microsomal triglyceride transfer protein (MTP) activity is critical to apoB secretion, there is still controversy as to whether MTP directly facilitates the translocation of apoB across the membrane of the endoplasmic reticulum (ER) through either the recruitment of lipids and/or chaperone activity. In the present study, a specific inhibitor of MTP (BMS 197636) was utilized in HepG2 cells to investigate whether a direct relationship exists between the translocation of apoB across the ER membrane and the lipid-transferring activity of MTP. Inhibition of MTP (with 10 and 50 nmol/L of the inhibitor) did not significantly affect the translocation of newly synthesized apoB (P = 0.77) or the translocational efficiency of the steady-state apoB mass (P = 0.45), despite a 49% decrease in apoB secretion and increased proteosomal degradation. These results compared well with subcellular fractionation experiments which showed no significant change in the fraction of apoB accumulated in the lumen of isolated microsomes in MTP-treated cells (P = 0.35). In summary, MTP lipid transfer activity does not appear to influence translocational status of apoB, but its inhibition is associated with an increased susceptibility to proteasome-mediated degradation and reduced assembly and secretion of apoB lipoprotein particles.
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Apolipoproteínas B/metabolismo , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/metabolismo , Retículo Endoplásmico/metabolismo , Apolipoproteínas B/biosíntesis , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/farmacología , Retículo Endoplásmico/efectos de los fármacos , Humanos , Leupeptinas/farmacología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Complejos Multienzimáticos/antagonistas & inhibidores , Complejos Multienzimáticos/metabolismo , Complejo de la Endopetidasa Proteasomal , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Albúmina Sérica/metabolismo , Especificidad por Sustrato , Termodinámica , Factores de Tiempo , Triglicéridos/metabolismo , Tripsina/metabolismo , Células Tumorales CultivadasRESUMEN
BACKGROUND: Most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1), whose inhibition is associated with gastrointestinal ulceration, and COX-2, whose inhibition is associated with therapeutic benefits. Although agents that do not produce COX-1 activity may have fewer adverse effects, targeted disruption of the COX-2 allele in mice has resulted in severe renal problems, suggesting that COX-2 inhibition may also produce adverse effects. OBJECTIVE: To determine the effect of rofecoxib, a member of the coxib class of drugs and a specific inhibitor of the COX-2 enzyme, on renal function in elderly patients. DESIGN: A randomized, three-period, single-dose crossover study and a randomized, parallel-group, multiple-dose study. SETTING: Clinical research units. PATIENTS: 75 patients 60 to 80 years of age. INTERVENTION: In the first study, single doses of rofecoxib, 250 mg (about 5-fold to 20-fold the recommended dose); indomethacin, 75 mg; and placebo were administered to 15 patients. In the second study, multiple doses of rofecoxib, 12.5 or 25 mg/d; indomethacin, 50 mg three times daily; or placebo were administered to 60 patients. Patients in both studies received a low-sodium diet MEASUREMENTS: Glomerular filtration rate, creatinine clearance, and urinary and serum sodium and potassium values. RESULTS: Compared with placebo, single doses of rofecoxib and indomethacin decreased the glomerular filtration rate by 0.23 m/s (P < 0.001) and 0.18 mL/s (P = 0.003), respectively. In contrast, respective decreases of 0.14, 0.13, and 0.10 mL/s were observed after multiple doses of rofecoxib, 12.5 mg/d (P = 0.019); rofecoxib, 25 mg (P = 0.029), and indomethacin (P = 0.086) were administered. Changes in creatinine clearance and serum and urinary sodium and potassium were less pronounced. CONCLUSIONS: The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs. Thus, COX-2 seems to play an important role in human renal function.
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Inhibidores de la Ciclooxigenasa/farmacología , Dieta Hiposódica , Isoenzimas/antagonistas & inhibidores , Isoenzimas/farmacología , Riñón/efectos de los fármacos , Lactonas/farmacología , Prostaglandina-Endoperóxido Sintasas/farmacología , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Creatinina/metabolismo , Estudios Cruzados , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/administración & dosificación , Método Doble Ciego , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Indometacina/administración & dosificación , Indometacina/farmacología , Lactonas/administración & dosificación , Masculino , Proteínas de la Membrana , Potasio/sangre , Potasio/orina , Método Simple Ciego , Sodio/sangre , Sodio/orina , SulfonasRESUMEN
An estimated 129,400 new cases of colorectal cancer occurred in the United States during 1999. The lifetime risk of developing this cancer is 2.5 to 5 percent in the general population but two to three times higher in persons who have a first-degree relative with colon cancer or an adenomatous polyp. Between 70 and 90 percent of colorectal cancers arise from adenomatous polyps, whereas only 10 to 30 percent arise from sessile adenomas. Tumors or polyps that develop proximal to the splenic flexure carry a poorer prognosis than those that arise more distally, in part because of delayed diagnosis secondary to later development of symptoms. The Dukes system is the classic staging method for colorectal cancer; the TNM staging system is more detailed and therefore more useful for surgical purposes. Although screening guidelines vary, most agree that colorectal cancer screening should begin at 50 years of age in patients without a personal or family history of colorectal cancer.