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Stable isotopes are powerful tools for elucidating ecological trends in extant vertebrate communities, though their application to Mesozoic ecosystems is complicated by a lack of extant isotope data from comparable environments/ecosystems (e.g. coastal floodplain forest environments, lacking significant C4 plant components). We sampled 20 taxa across a broad phylogenetic, body size, and physiological scope from the Atchafalaya River Basin of Louisiana as an environmental analogue to the Late Cretaceous coastal floodplains of North America. Samples were analysed for stable carbon, oxygen and nitrogen isotope compositions from bioapatite and keratin tissues to test the degree of ecological resolution that can be determined in a system with similar environmental conditions, and using similar constraints, as those in many Mesozoic assemblages. Isotopic results suggest a broad overlap in resource use among taxa and considerable terrestrial-aquatic interchange, highlighting the challenges of ecological interpretation in C3 systems, particularly when lacking observational data for comparison. We also propose a modified oxygen isotope-temperature equation that uses mean endotherm and mean ectotherm isotope data to more precisely predict temperature when compared with measured Atchafalaya River water data. These results provide a critical isotopic baseline for coastal floodplain forests, and act as a framework for future studies of Mesozoic palaeoecology.
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RATIONALE: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A two-step approach for the malnutrition diagnosis was selected, i.e., first screening to identify "at risk" status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSION: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re-considered every 3-5 years.
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Desnutrición/diagnóstico , Adulto , Índice de Masa Corporal , Consenso , Ingestión de Alimentos , Salud Global , Humanos , Fenotipo , Sarcopenia/diagnóstico , Pérdida de PesoRESUMEN
RATIONALE: This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings. METHODS: In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications. RESULTS: A two-step approach for the malnutrition diagnosis was selected, i.e., first screening to identify "at risk" status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (non-volitional weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories. CONCLUSION: A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re-considered every 3-5 years.
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Internacionalidad , Desnutrición/diagnóstico , Evaluación Nutricional , Adulto , Consenso , Humanos , Liderazgo , Estado Nutricional , Sociedades CientíficasRESUMEN
INTRODUCTION: The spleen is one of the most commonly injured abdominal solid organs during blunt trauma. Modern management of splenic trauma has evolved to include non-operative therapies, including observation and angioembolization to preclude splenectomy in most cases of blunt splenic injury. Despite the shift in management strategies, relatively little is known about the hematologic changes associated with these various modalities. The aim of this study was to determine if there are significant differences in hematologic characteristics over time based on the treatment modality employed following splenic trauma. We hypothesized that alterations seen in hematologic parameters would vary between observation (OBS), embolization (EMB), and splenectomy (SPL) in the setting of splenic injury. METHODS: An institutional review board-approved, retrospective study of routine hematologic indices examined data between March 2000 and December 2014 at three academic trauma centers. A convenience sample of patients with splenic trauma and admission lengths of stay >96 h was selected for inclusion, resulting in a representative sample of each sub-group (OBS, EMB, and SPL). Basic demographics and injury severity data (ISS) were abstracted. Platelet count, red blood cell (RBC) count and RBC indices, and white blood cell (WBC) count with differential were analyzed between the time of admission and a maximum of 1080 h (45 days) post-injury. Comparisons between OBS, EMB, and SPL groups were then performed using non-parametric statistical testing, with statistical significance set at p < 0.05. RESULTS: Data from 130 patients (40 SPL, 40 EMB, and 50 OBS) were analyzed. The median age was 40 years, with 67 % males. Median ISS was 21.5 (21 for SPL, 19 for EMB, and 22 for OBS, p = n/s) and median Glasgow Coma Scale (GCS) was 15. Median splenic injury grade varied by interventional modality (grade 4 for SPL, 3 for EMB, and 2 for OBS, p < 0.05). Inter-group comparisons demonstrated no significant differences in RBC counts. However, mean corpuscular volume (MCV) and RBC distribution width (RDW) were elevated in the SPL and EMB groups (p < 0.01). Similarly, EMB and SPL groups had higher platelet counts than the OBS group (p < 0.01). In aggregate, WBC counts were highest following SPL, followed by EMB and OBS (p < 0.01). Similar trends were noted in neutrophil and monocyte counts (p < 0.01), but not in lymphocyte counts (p = n/s). CONCLUSION: This study describes important trends and patterns among fundamental hematologic parameters following traumatic splenic injuries managed with SPL, EMB, or OBS. As expected, observed WBC counts were highest following SPL, then EMB, and finally OBS. No differences were noted in RBC count between the three groups, but RDW was significantly greater following SPL compared to EMB and OBS. We also found that MCV was highest following OBS, when compared to EMB or SPL. Finally, our data indicate that platelet counts are similarly elevated for both SPL and EMB, when compared to the OBS group. These results provide an important foundation for further research in this still relatively unexplored area.
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Biomarcadores , Traumatismo Múltiple/cirugía , Recuento de Plaquetas , Bazo/lesiones , Heridas no Penetrantes/cirugía , Adulto , Embolización Terapéutica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Traumatismo Múltiple/sangre , Periodo Posoperatorio , Esplenectomía , Heridas no Penetrantes/sangreRESUMEN
INTRODUCTION: Clinical information continues to be limited regarding changes in the temporal risk profile for readmissions during the initial postoperative year in vascular surgery patients. We set out to describe the associations between demographics, clinical outcomes, comorbidity indices, and hospital readmissions in a sample of patients undergoing common extremity revascularization or dialysis access (ERDA) procedures. We hypothesized that factors independently associated with readmission will evolve from "short-term" to "long-term" determinants at 30-, 180-, and 360-day postoperative cutoff points. METHODS: Following IRB approval, medical records of patients who underwent ERDA at two institutions were retrospectively reviewed between 2008 and 2014. Abstracted data included patient demographics, procedural characteristics, the American Society of Anesthesiologists score, Goldman Criteria for perioperative cardiac assessment, the Charlson comorbidity index, morbidity, mortality, and readmission (at 30-, 180-, and 360-days). Univariate analyses were performed for readmissions at each specified time point. Variables reaching statistical significance of P< 0.20 were included in multivariate analyses for factors independently associated with readmission. RESULTS: A total of 450 of 744 patients who underwent ERDA with complete medical records were included. Patients underwent either an extremity revascularization (e.g. bypass or endarterectomy, 406/450) or a noncatheter dialysis access procedure (44/450). Sample characteristics included 262 (58.2%) females, mean age 61.4 ± 12.9 years, 63 (14%) emergent procedures, and median operative time 164 min. Median hospital length of stay (index admission) was 4 days. Cumulative readmission rates at 30-, 180-, and 360-day were 12%, 27%, and 35%, respectively. Corresponding mortality rates were 3%, 7%, and 9%. Key factors independently associated with 30-, 180-, and 360-day readmissions evolved over the study period from comorbidity and morbidity-related issues in the short-term to cardiovascular and graft patency issues in the long-term. Any earlier readmission elevated the risk of subsequent readmission. CONCLUSIONS: We noted important patterns in the temporal behavior of hospital readmission risk in patients undergoing ERDA. Although factors independently associated with readmission were not surprising (e.g. comorbidity profile, cardiovascular status, and graft patency), the knowledge of temporal trends described in this study may help determine clinical risk profiles for individual patients and guide readmission reduction strategies. These considerations will be increasingly important in the evolving paradigm of value-based healthcare.
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Readmisión del Paciente/estadística & datos numéricos , Enfermedad Arterial Periférica/terapia , Complicaciones Posoperatorias/etiología , Medición de Riesgo/métodos , Procedimientos Quirúrgicos Operativos/efectos adversos , Procedimientos Quirúrgicos Vasculares/efectos adversos , Femenino , Humanos , Modelos Logísticos , Extremidad Inferior , Masculino , Análisis Multivariante , Oportunidad Relativa , Enfermedad Arterial Periférica/etnología , Enfermedad Arterial Periférica/cirugía , Complicaciones Posoperatorias/sangre , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/terapia , Periodo Posoperatorio , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Ultrasound is a ubiquitous and versatile diagnostic tool. In the setting of acute injury, ultrasound enhances the basic trauma evaluation, influences bedside decision-making, and helps determine whether or not an unstable patient requires emergent procedural intervention. Consequently, continued education of surgeons and other acute care practitioners in performing focused emergency ultrasound is of great importance. This article provides a synopsis of focused assessment with sonography for trauma (FAST) and the extended FAST (E-FAST) that incorporates basic thoracic injury assessment. The authors also review key pitfalls, limitations, controversies, and advances related to FAST, E-FAST, and ultrasound education.
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Servicios Médicos de Urgencia/métodos , Ultrasonografía , Heridas y Lesiones , Toma de Decisiones Clínicas , Humanos , Sistemas de Atención de Punto/tendencias , Evaluación de Síntomas/métodos , Ultrasonografía/instrumentación , Ultrasonografía/métodos , Ultrasonografía/tendencias , Heridas y Lesiones/diagnóstico , Heridas y Lesiones/diagnóstico por imagenRESUMEN
Tooth morphology and development can provide valuable insights into the feeding behaviour and evolution of extinct organisms. The teeth of Theropoda, the only clade of predominantly predatory dinosaurs, are characterized by ziphodonty, the presence of serrations (denticles) on their cutting edges. Known today only in varanid lizards, ziphodonty is much more pervasive in the fossil record. Here we present the first model for the development of ziphodont teeth in theropods through histological, SEM, and SR-FTIR analyses, revealing that structures previously hypothesized to prevent tooth breakage instead first evolved to shape and maintain the characteristic denticles through the life of the tooth. We show that this novel complex of dental morphology and tissues characterizes Theropoda, with the exception of species with modified feeding behaviours, suggesting that these characters are important for facilitating the hypercarnivorous diet of most theropods. This adaptation may have played an important role in the initial radiation and subsequent success of theropods as terrestrial apex predators.
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Evolución Biológica , Dinosaurios , Diente/anatomía & histología , Animales , Espectroscopía Infrarroja por Transformada de FourierAsunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Mortalidad Hospitalaria , Hipertensión/tratamiento farmacológico , Trastornos Mentales/tratamiento farmacológico , Polifarmacia , Heridas y Lesiones/complicaciones , Femenino , Humanos , MasculinoAsunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Mortalidad Hospitalaria , Hipertensión/tratamiento farmacológico , Trastornos Mentales/tratamiento farmacológico , Polifarmacia , Heridas y Lesiones/complicaciones , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Recent review of older (≥45-years-old) patients admitted to our trauma center showed that more than one-third were using neuro-psychiatric medications (NPMs) prior to their injury-related admission. Previously published data suggests that use of NPMs may increase patients' risk and severity of injury. We sought to examine the impact of pre-injury NPM use on older trauma patients' morbidity and mortality. MATERIALS AND METHODS: Retrospective record review included medication regimen characteristics and NPM use (antidepressants-AD, antipsychotics-AP, anxiolytics-AA). Hospital morbidity, mortality, and 90-day survival were examined. Comparisons included regimens involving NPMs, further focusing on their interactions with various cardiac medications (beta blocker - BB; angiotensin-converting enzyme inhibitor/angiotensin receptor blocker - ACE/ARB; calcium channel blocker - CCB). RESULTS: 712 patient records were reviewed (399 males, mean age 63.5 years, median ISS 8). 245 patients were taking at least 1 NPM: AD (158), AP (35), or AA (108) before injury. There was no effect of NPM monotherapy on hospital mortality. Patients taking ≥3 NPMs had significantly lower 90-day survival compared to patients taking ≤2 NPMs (81% for 3 or more NPMs, 95% for no NPMs, and 89% 1-2 NPMs, P < 0.01). Several AD-cardiac medication (CM) combinations were associated with increased mortality compared to monotherapy with either agent (BB-AD 14.7% mortality versus 7.0% for AD monotherapy or 4.8% BB monotherapy, P < 0.05). Combinations of ACE/ARB-AA were associated with increased mortality compared to ACE/ARB monotherapy (11.5% vs 4.9, P = 0.04). Finally, ACE/ARB-AD co-administration had higher mortality than ACE/ARB monotherapy (13.5% vs 4.9%, P = 0.01). CONCLUSIONS: Large proportion of older trauma patients was using pre-injury NPMs. Several regimens involving NPMs and CMs were associated with increased in-hospital mortality. Additionally, use of ≥3 NPMs was associated with lower 90-day survival.
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Antagonistas Adrenérgicos beta/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Mortalidad Hospitalaria , Hipertensión/tratamiento farmacológico , Trastornos Mentales/tratamiento farmacológico , Polifarmacia , Heridas y Lesiones/complicaciones , Antagonistas Adrenérgicos beta/efectos adversos , Anciano , Anciano de 80 o más Años , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Quimioterapia Combinada , Femenino , Humanos , Hipertensión/mortalidad , Puntaje de Gravedad del Traumatismo , Masculino , Trastornos Mentales/mortalidad , Persona de Mediana Edad , Estudios Retrospectivos , Heridas y Lesiones/epidemiologíaRESUMEN
The use of nasoenteric tubes (NETs) is ubiquitous, and clinicians often take their placement, function, and maintenance for granted. NETs are used for gastrointestinal decompression, enteral feeding, medication administration, naso-biliary drainage, and specialized indications such as upper gastrointestinal bleeding. Morbidity associated with NETs is common, but frequently subtle, mandating high index of suspicion, clinical vigilance, and patient safety protocols. Common complications include sinusitis, sore throat and epistaxis. More serious complications include luminal perforation, pulmonary injury, aspiration, and intracranial placement. Frequent monitoring and continual re-review of the indications for continued use of any NET is prudent, including consideration of changing goals of care. This manuscript reviews NET-related complications and associated topics.
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Intubación Gastrointestinal/efectos adversos , Contraindicaciones , Falla de Equipo , Enfermedades del Esófago/etiología , Humanos , Intubación Gastrointestinal/instrumentación , Intubación Gastrointestinal/métodos , Seguridad del Paciente , Enfermedades Respiratorias/etiologíaRESUMEN
Given the increasing complexity of both the modern health care environment and the overall patient population, reduction of medical errors is a high priority task for health policy makers and medical/surgical community alike. The problem of retained surgical foreign bodies (RSFB) has existed ever since the humans first performed surgical procedures. Retained surgical foreign bodies continue to be a significant problem with an incidence between 0.3 and 1.0 per 1,000 abdominal operations. Retained surgical foreign bodies have the potential to cause harm to the patient and carry profound professional and medico-legal consequences to surgical trainees, surgical practitioners, hospitals, and health systems. Currently, there are no known methods of entirely eliminating the occurrence of RSFB. In this manuscript, the authors discuss the available evidence with regards to risk factors associated with RSFB as well as methods of minimizing the incidence of RSFB. Modern technological advances designed to decrease the incidence of RSFB (radio-frequency tagging of surgical sponges) and improved perioperative patient processing (multiple 'checks and balances' and better provider-to-provider communication) are reviewed. The authors also explore the relationship between RSFB and surgical training with emphasis on education in early recognition, prevention, and focus on team-oriented training strategies.
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Cuerpos Extraños/epidemiología , Instrumentos Quirúrgicos , Tapones Quirúrgicos de Gaza , Abdomen , Comunicación , Cuerpos Extraños/prevención & control , Humanos , Responsabilidad Legal , Agujas , Pelvis , Absceso Retrofaríngeo , Instrumentos Quirúrgicos/estadística & datos numéricosRESUMEN
Care for the critically ill patient requires maintenance of adequate tissue perfusion/oxygenation. Continuous hemodynamic monitoring is frequently utilized to achieve these objectives. Pulmonary artery catheters (PAC) allow measurement of hemodynamic variables that cannot be measured reliably or continuously by less invasive means. Inherent to every medical intervention are risks associated with that intervention. This review categorizes complications associated with the PAC into four broad groups--complications of central venous access; complications related to PAC insertion and manipulation; complications associated with short- or long-term presence of the PAC in the cardiovascular system; and errors resulting from incorrect interpretation/use of PAC-derived data. We will discuss each of these four broad categories, followed by in-depth descriptions of the most common and most serious individual complications.
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Cateterismo de Swan-Ganz/efectos adversos , Cateterismo Venoso Central/efectos adversos , Falla de Equipo , Humanos , Errores Médicos/efectos adversos , Factores de Riesgo , Factores de TiempoRESUMEN
Bullet embolism is a rare complication of penetrating vascular trauma that requires a high index of suspicion for timely diagnosis and management. Delays in identification may result in poor early management and subsequent loss of limb or life [1]. There are two types of bullet embolism: arterial and venous. In this report, we discuss a rare case of venous bullet embolus to the right ventricle from the right femoral vein.
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Embolia/diagnóstico por imagen , Migración de Cuerpo Extraño/diagnóstico por imagen , Lesiones Cardíacas/diagnóstico por imagen , Heridas por Arma de Fuego/diagnóstico por imagen , Adulto , Embolia/etiología , Vena Femoral/diagnóstico por imagen , Migración de Cuerpo Extraño/complicaciones , Lesiones Cardíacas/etiología , Ventrículos Cardíacos/lesiones , Humanos , Masculino , Tomografía Computarizada por Rayos X , Heridas por Arma de Fuego/complicacionesRESUMEN
A 58-year-old Caucasian male with end-stage renal disease and peripheral arterial disease was referred to us for management of his complex vascular access. His vascular access history included a left wrist primary fistula, a left upper arm access graft, a left leg loop graft, and multiple PermCaths in his jugular veins with recurrent infections. Magnetic resonance venography (MRV) of his chest revealed extensive bilateral venous occlusions due to numerous past hemodialysis access catheters. The patient was scheduled for right lower extremity arteriovenous graft placement, but intraoperatively was found to have severe peripheral arterial disease and a thromboendarterectomy was performed instead. Lower body venous imaging demonstrated patent iliac veins. Based on these anatomic considerations a right axillary artery to right common iliac vein polytetrafluoroethylene (PTFE) graft was placed. The graft required revision twice--once for graft ultrafiltration at the arterial end of the graft and once for needle stick infection--but continues to serve as sufficient access after 15 months. Grafts based off the axillary artery have become increasingly popular in recent years and several venous outflow options have been considered, each with distinct advantages. The common iliac vein offers a central location with high flow rate and low probability of infection. Axillary artery to iliac vein arteriovenous grafting may have a place in the vascular surgeon's armamentarium for complex vascular access cases.
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1. The in vitro cooperativity exhibited by cytochrome P450 (CYP) 3A4 is influenced by the nature of the recombinant system in which the phenomenon is studied. Diclofenac, piroxicam and R-warfarin were used as model substrates, and quinidine was the effector. 2. The 5-, 5'- and 10-hydroxylation of diclofenac, piroxicam and R-warfarin, respectively, were enhanced five- to sevenfold by quinidine in human liver microsomal incubations. Whereas these cooperative drug interactions were apparent in incubations with CYP3A4 expressed in human lymphoblast cells, similar phenomena were not observed with the enzyme expressed in insect cells. 3. Insect cell microsomes were treated with a detergent and CYP3A4 was solubilized into a buffer medium. In incubations with CYP3A4 'freed' from its host membrane, the 5-hydroxylation of diclofenac increased with increasing quinidine concentrations, reaching a maximal eightfold elevation relative to controls. The metabolism of piroxicam and warfarin was similarly enhanced by quinidine. 4. Kinetically, enhancement by quinidine of the 5-hydroxylation of diclofenac in incubations with solubilized CYP3A4 was characterized by increases in the rate of metabolism with little change in the substrate-binding affinity. Conversely, the 3-hydroxylation of quinidine was not affected by diclofenac. 5. The data suggest that certain properties of CYP3A4 are masked by expression of the protein in insect cells and reinforce the concept that the enzyme possesses multiple binding domains. The absence of cooperative drug interactions with quinidine when CYP3A4 was expressed in insect cells might be due to an absence of enzyme conformation changes on quinidine binding, or the inability of quinidine to gain access to a putative effector-binding domain. 6. Caution should be exercised when comparing models for CYP3A4 cooperativity derived from different recombinant preparations of the enzyme.
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Sistema Enzimático del Citocromo P-450/metabolismo , Animales , Línea Celular , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/genética , Diclofenaco/metabolismo , Interacciones Farmacológicas , Humanos , Hidroxilación , Técnicas In Vitro , Cinética , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Biológicos , Piroxicam/metabolismo , Quinidina/farmacología , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Warfarina/metabolismoRESUMEN
Muscarinic acetylcholine receptors (M(1)-M(5)) regulate many key functions in the central and peripheral nervous system. Due to the lack of receptor subtype-selective ligands, however, the physiological roles of individual muscarinic receptor subtypes remain to be determined. In this study, we examined the effects of the muscarinic M(2)/M(4) receptor-preferring agonist [5R-(exo)]-6-[4-butylthio-1,2,5-thiadiazol-3-yl]-1-azabicyclo-[3.2.1]-octane (BuTAC) on serum corticosterone levels in M(2) and M(4) receptor single knockout (KO) and M(2,4) receptor double KO mice. Responses were compared with those obtained with the corresponding wild-type (WT) mice. BuTAC (0.03-0.3 mg/kg s.c.) dose dependently and significantly increased serum corticosterone concentrations in WT mice to 5-fold or greater levels compared with vehicle controls. In muscarinic M(2) and M(2,4) KO mice, however, BuTAC had no significant effect on corticosterone concentrations at doses of 0.1, 0.3, and 1 mg/kg s.c. In both WT and muscarinic M(4) KO mice increases in serum corticosterone concentrations induced by BuTAC (0.1 and 0.3 mg/kg) were not significantly different and were blocked by scopolamine. In summary, the muscarinic M(2,4)-preferring agonist BuTAC had no effect on corticosterone levels in mice lacking functional muscarinic M(2) receptors. These data suggest that the muscarinic M(2) receptor subtype mediates muscarinic agonist-induced activation of the hypothalamic-pituitary-adrenocortical axis in mice.
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Corticosterona/sangre , Agonistas Muscarínicos/farmacología , Receptores Muscarínicos/fisiología , Tropanos/farmacología , Animales , Cinética , Ratones , Ratones Endogámicos , Ratones Noqueados , Pergolida/farmacología , Receptor Muscarínico M2 , Receptor Muscarínico M4 , Receptores Muscarínicos/deficiencia , Receptores Muscarínicos/genética , Escopolamina/farmacologíaRESUMEN
The metabolism of diclofenac has been reported to produce reactive benzoquinone imine intermediates. We describe the identification of mercapturic acid derivatives of diclofenac in rats and humans. Three male Sprague-Dawley rats were administered diclofenac in aqueous solution (pH 7) at 50 mg/kg by intraperitoneal injection, and urine was collected for 24 h. Human urine specimens were obtained, and samples were pooled from 50 individuals. Urine samples were analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Two metabolites with MH(+) ions at m/z 473 were detected in rat urine and identified tentatively as N-acetylcysteine conjugates of monohydroxydiclofenac. Based upon collision-induced fragmentation of the MH(+) ions, accurate mass measurements of product ions, and comparison of LC/MS/MS properties of the metabolites with those of synthetic reference compounds, one metabolite was assigned as 5-hydroxy-4-(N-acetylcystein-S-yl)diclofenac and the other as 4'-hydroxy-3'-(N-acetylcystein-S-yl)diclofenac. The former conjugate also was detected in the pooled human urine sample by multiple reaction-monitoring LC/MS/MS analysis. It is likely that these mercapturic acid derivatives represent degradation products of the corresponding glutathione adducts derived from diclofenac-2,5-quinone imine and 1',4'-quinone imine, respectively. Our data are consistent with previous findings, which suggest that oxidative bioactivation of diclofenac in humans proceeds via benzoquinone imine intermediates.
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Acetilcisteína/orina , Benzoquinonas/metabolismo , Diclofenaco/farmacocinética , Animales , Biotransformación , Cromatografía Líquida de Alta Presión , Humanos , Iminas/metabolismo , Masculino , Espectrometría de Masas , Ratas , Ratas Sprague-DawleyRESUMEN
1. The metabolism of 2,5-bis(trifluoromethyl)-7-benzyloxy-4-trifluoromethylcoumarin (BFBFC) to 7-hydroxy-4-trifluoromethylcoumarin (HFC) was studied in human liver microsomes and in cDNA-expressed human liver CYP isoforms. For purposes of comparison, some limited studies were also performed with 7-benzyloxyquinoline (7BQ). 2. Initial interactive docking studies with a homology model of human CYP3A4 indicated that BFBFC was likely to be a selective substrate for CYP3A4 with a relatively high binding affinity, due to the presence of several key hydrogen bonds with active site amino acid residues. 3. Kinetic analysis of NADPH-dependent BFBFC metabolism to HFC in three preparations of pooled human liver microsomes revealed mean (+/- TSEM) Km and Vmax = 4.6 +/- 0.3 microM and 20.0 +/- 3.8 pmol/min/mg protein, respectively. 4. The metabolism of BFBFC to HFC was determined in a characterized bank of 24 individual human liver microsomal preparations employing a BFBFC substrate concentration of lO microM (i.e. around twice Km). Good correlations (r2 = 0.736-0.904) were observed between BFBFC metabolism and markers of CYP3A isoforms. 5. While 10O microM BFBFC was metabolized to HFC by cDNA-expressed CYP3A4, little or no metabolism was observed with cDNA-expressed CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. 6. The metabolism of 10 microM BFBFC in human liver microsomes was markedly inhibited by 5-50 microM troleandomycin and 0.2-5 microM ketoconazole, but stimulated by 0.2-10 microM alpha-naphthoflavone. The metabolism of 10 microM BFBFC in human liver microsomes was also markedly inhibited by an antibody to CYP3A4. 7. Kinetic analysis of NADPH-dependent 7BQ metabolism to 7-hydroxyquinoline (7HQ) in human liver microsomes revealed Km and Vmax = 70 microM and 3.39 nmol/min/mg protein, respectively. 8. While 80 microM 7BQ was metabolized to 7HQ by cDNA-expressed CYP3A4, only low rates of metabolism were observed with cDNA-expressed CYPIA2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. 9. In summary, by correlation analysis, the use of cDNA-expressed CYP isoforms, chemical inhibition and inhibitory antibodies, BFBFC metabolism in human liver microsomes appears to be primarily catalysed by CYP3A4. BFBFC may be a useful fluorescent probe substrate for human hepatic CYP3A4, but compared with 7BQ has only a low rate of metabolism in human liver microsomes.
Asunto(s)
Cumarinas/química , Cumarinas/metabolismo , Sistema Enzimático del Citocromo P-450/química , Sistema Enzimático del Citocromo P-450/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Oxigenasas de Función Mixta/metabolismo , Cumarinas/farmacocinética , Citocromo P-450 CYP3A , ADN Complementario/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Cinética , Hígado/metabolismo , Microsomas Hepáticos/enzimología , Microsomas Hepáticos/metabolismo , Modelos Químicos , Modelos Moleculares , Fenotipo , Unión Proteica , Isoformas de Proteínas , Quinolinas/metabolismo , Quinolinas/farmacología , Especificidad por Sustrato , Factores de TiempoRESUMEN
BACKGROUND: A long-term review of metal prosthetic radial head replacement in patients with radial head fractures associated with gross instability of the elbow has been performed. METHOD: Twenty patients were reviewed using a modified Mayo Clinic functional rating index system. The mean follow-up was 12.1 years, with a range from 6 to 29 years. RESULTS: Results were excellent in 12 patients, good in 4 patients, fair in 2 patients, and poor in 2 patients. A metal radial head replacement restored elbow stability when fracture of the radial head occurred in combination with dislocation of the elbow, rupture of the medial collateral ligament, fracture of the proximal ulna, and/or fracture of the coronoid process. CONCLUSION: We conclude that a metal radial head prosthesis has select indications. We advocate its use when the radial head cannot be reconstructed in the setting of a clinically unstable elbow. Results suggest that it functions well on a long-term basis.