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1.
Horm Behav ; 119: 104649, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31821792

RESUMEN

The majority of HIV+ patients present with neuroendocrine dysfunction and ~50% experience co-morbid neurological symptoms including motor, affective, and cognitive dysfunction, collectively termed neuroHIV. In preclinical models, the neurotoxic HIV-1 regulatory protein, trans-activator of transcription (Tat), promotes neuroHIV pathology that can be exacerbated by opioids. We and others find gonadal steroids, estradiol (E2) or progesterone (P4), to rescue Tat-mediated pathology. However, the combined effects of Tat and opioids on neuroendocrine function and the subsequent ameliorative capacity of gonadal steroids are unknown. We found that conditional HIV-1 Tat expression in naturally-cycling transgenic mice dose-dependently potentiated oxycodone-mediated psychomotor behavior. Tat increased depression-like behavior in a tail-suspension test among proestrous mice, but decreased it among diestrous mice (who already demonstrated greater depression-like behavior); oxycodone reversed these effects. Combined Tat and oxycodone produced apparent behavioral disinhibition of anxiety-like responding which was greater on diestrus than on proestrus. These mice made more central entries in an open field, but spent less time there and demonstrated greater circulating corticosterone. Tat increased the E2:P4 ratio of circulating steroids on diestrus and acute oxycodone attenuated this effect, but repeated oxycodone exacerbated it. Corticotropin-releasing factor was increased by Tat expression, acute oxycodone exposure, and was greater on diestrus compared to proestrus. In human neuroblastoma cells, Tat exerted neurotoxicity that was ameliorated by E2 (1 or 10 nM) or P4 (100, but not 10 nM) independent of oxycodone. Oxycodone decreased gene expression of estrogen and κ-opioid receptors. Thus, neuroendocrine function may be an important target for HIV-1 Tat/opioid interactions.


Asunto(s)
Gónadas/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Síndromes de Neurotoxicidad , Oxicodona/efectos adversos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/efectos adversos , Animales , Ansiedad/fisiopatología , Ansiedad/psicología , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Combinación de Medicamentos , Femenino , Hormonas Esteroides Gonadales/fisiología , Gónadas/fisiología , Infecciones por VIH/complicaciones , Infecciones por VIH/fisiopatología , Infecciones por VIH/psicología , VIH-1/fisiología , Humanos , Sistema Hipotálamo-Hipofisario/fisiología , Ratones , Ratones Transgénicos , Trastornos del Humor/inducido químicamente , Trastornos del Humor/patología , Trastornos del Humor/fisiopatología , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/fisiopatología , Síndromes de Neurotoxicidad/psicología , Oxicodona/administración & dosificación , Sistema Hipófiso-Suprarrenal/fisiología , Trastornos Psicomotores/inducido químicamente , Trastornos Psicomotores/patología , Trastornos Psicomotores/fisiopatología , Células Tumorales Cultivadas , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/administración & dosificación , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética
2.
Vet J ; 303: 106063, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38232813

RESUMEN

Equine metabolic syndrome (EMS) is a common welfare problem in horses worldwide. It is characterized by insulin dysregulation (ID), predisposition to laminitis and often obesity. EMS is multifactorial by nature, with both the environment and genetics contributing to the phenotype. Environmental factors, such as feeding and exercise, can be controlled, thus forming the basis for treatment and prevention. Genetic factors, by contrast, are less well-known and not easily controllable. The aim of this study was to identify potential genetic loci influencing ID/EMS in Finnhorses. A single-breed (Finnhorse) case-control genome-wide association study (GWAS) of ID was conducted with controls that included age-appropriate non-ID horses. ID status was determined with an oral sugar test (OST) for fasted horses. Seventy-one Finnhorses participated (n = 34 ID, n = 37 control). DNA samples (hair roots) were genotyped for 65 157 single-nucleotide polymorphisms (SNPs) with the Illumina Equine SNP70 BeadChip, and these data were analysed for association and FST outliers with genomic tools. P-values that exceeded the suggestive threshold (P = 1.00 ×10-5) were found in SNP BIEC2_383954 (P = 3.45 ×10-6) in chromosome 17 and SNP BIEC2_312374 (P = 1.89 ×10-5) in chromosome 15. Hierarchical and Bayesian FST outlier tests also detected these SNPs. Potential candidate genes associated with the ID close to SNP BIEC2_383954, with functions in carbohydrate metabolism, were Arginine and Glutamate Rich 1 (ARGLU1) and Ephrin-B2 (EFNB2).


Asunto(s)
Enfermedades de los Caballos , Síndrome Metabólico , Caballos/genética , Animales , Estudio de Asociación del Genoma Completo/veterinaria , Insulina/metabolismo , Teorema de Bayes , Genotipo , Síndrome Metabólico/veterinaria , Sitios Genéticos , Polimorfismo de Nucleótido Simple , Enfermedades de los Caballos/genética , Enfermedades de los Caballos/metabolismo
3.
Mol Ecol ; 22(24): 6060-73, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24118560

RESUMEN

We investigate population genetic structuring in Margaritifera falcata, a freshwater mussel native to western North America, across the majority of its geographical range. We find shallow rangewide genetic structure, strong population-level structuring and very low population diversity in this species, using both mitochondrial sequence and nuclear microsatellite data. We contrast these patterns with previous findings in another freshwater mussel species group (Anodonta californiensis/A. nuttalliana) occupying the same continental region and many of the same watersheds. We conclude that differences are likely caused by contrasting life history attributes between genera, particularly host fish requirements and hermaphroditism. Further, we demonstrate the occurrence of a 'hotspot' for genetic diversity in both groups of mussels, occurring in the vicinity of the lower Columbia River drainage. We suggest that stream hierarchy may be responsible for this pattern and may produce similar patterns in other widespread freshwater species.


Asunto(s)
Anodonta/genética , Variación Genética , Genética de Población/métodos , Unionidae/genética , Animales , Anodonta/clasificación , Anodonta/fisiología , Núcleo Celular/genética , ADN Mitocondrial/genética , Peces , Agua Dulce , Haplotipos , Estadios del Ciclo de Vida , Repeticiones de Microsatélite , Datos de Secuencia Molecular , América del Norte , Reproducción/fisiología , Análisis de Secuencia de ADN , Unionidae/clasificación , Unionidae/fisiología
4.
Arthritis Rheum ; 63(10): 2854-64, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21618201

RESUMEN

OBJECTIVE: To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept. METHODS: In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed. RESULTS: Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients. CONCLUSION: SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.


Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Inmunoconjugados/administración & dosificación , Abatacept , Adulto , Anciano , Antirreumáticos/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Inmunoconjugados/uso terapéutico , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Metotrexato/uso terapéutico , Persona de Mediana Edad , Resultado del Tratamiento
5.
Vet J ; 269: 105610, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33593492

RESUMEN

Alpha-2-adrenoceptor agonists are sedatives that can cause fluctuations in serum insulin and blood glucose (BG) concentrations in horses. The objectives of this study were to investigate the effects of detomidine and vatinoxan on BG, insulin, and glucagon concentrations in horses with and without insulin dysregulation (ID). In a blinded cross-over design, eight horses with ID and eight horses without ID were assigned to each of four treatments: detomidine (0.02 mg/kg; DET), vatinoxan (0.2 mg/kg; VAT), detomidine + vatinoxan (DET + VAT), and saline control (SAL). Blood samples were taken at 0, 1, 2, 4, 6, and 8 h. Change from baseline was used as the response in modelling, and the differences between treatments were evaluated with repeated measures analysis of covariance. P values ≤0.05 were considered significant. Comparing DET vs. SAL and DET vs. DET + VAT, insulin was higher at 2 h in the non-ID group and 2 and 4 h in the ID group. There was no difference in insulin between SAL and DET + VAT or VAT. Comparing DET vs. SAL, BG was higher at 1 and 2 h then was lower at 4 h in both ID and non-ID groups. At 1 h in both groups, BG after DET + VAT was lower than after DET but higher than after SAL. Comparing DET vs. SAL, glucagon was lower at 1 h in the ID group and 1 and 2 h in the non-ID group. Vatinoxan was effective in preventing detomidine-induced hyperglycaemia as well as the subsequent insulin increase in horses with ID.


Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Glucemia/análisis , Glucagón/sangre , Caballos/sangre , Insulina/sangre , Animales , Interacciones Farmacológicas , Femenino , Hipnóticos y Sedantes/farmacología , Imidazoles/farmacología , Resistencia a la Insulina/fisiología , Masculino , Quinolizinas/farmacología
6.
Nat Commun ; 12(1): 3960, 2021 06 25.
Artículo en Inglés | MEDLINE | ID: mdl-34172727

RESUMEN

The Greenland Ice Sheet harbours a wealth of microbial life, yet the total biomass stored or exported from its surface to downstream environments is unconstrained. Here, we quantify microbial abundance and cellular biomass flux within the near-surface weathering crust photic zone of the western sector of the ice sheet. Using groundwater techniques, we demonstrate that interstitial water flow is slow (~10-2 m d-1), while flow cytometry enumeration reveals this pathway delivers 5 × 108 cells m-2 d-1 to supraglacial streams, equivalent to a carbon flux up to 250 g km-2 d-1. We infer that cellular carbon accumulation in the weathering crust exceeds fluvial export, promoting biomass sequestration, enhanced carbon cycling, and biological albedo reduction. We estimate that up to 37 kg km-2 of cellular carbon is flushed from the weathering crust environment of the western Greenland Ice Sheet each summer, providing an appreciable flux to support heterotrophs and methanogenesis at the bed.


Asunto(s)
Biomasa , Cubierta de Hielo/microbiología , Carbono/análisis , Ciclo del Carbono , Recuento de Colonia Microbiana , Groenlandia , Hidrología , Cubierta de Hielo/química , Tiempo (Meteorología)
7.
Ann Rheum Dis ; 68(6): 805-11, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19015206

RESUMEN

BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). Treatment with TNFalpha inhibitors reduces disease activity and improves outcomes for patients with RA. This study evaluated the efficacy and safety of certolizumab pegol 400 mg, a novel, poly-(ethylene glycol) (PEG)ylated, Fc-free TNFalpha inhibitor, as monotherapy in patients with active RA. METHODS: In this 24-week, multicentre, randomised, double-blind, placebo-controlled study, 220 patients previously failing > or =1 disease-modifying antirheumatic drug (DMARD) were randomised 1:1 to receive subcutaneous certolizumab pegol 400 mg (n = 111) or placebo (n = 109) every 4 weeks. The primary endpoint was 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 24. Secondary endpoints included ACR50/70 response, ACR component scores, 28-joint Disease Activity Score Erythrocyte Sedimentation Rate 3 (DAS28(ESR)3), patient-reported outcomes (including physical function, health-related quality of life (HRQoL), pain and fatigue) and safety. RESULTS: At week 24, the ACR20 response rates were 45.5% for certolizumab pegol 400 mg every 4 weeks vs 9.3% for placebo (p<0.001). Differences for certolizumab pegol vs placebo in the ACR20 response were statistically significant as early as week 1 through to week 24 (p<0.001). Significant improvements in ACR50, ACR components, DAS28(ESR)3 and all patient-reported outcomes were also observed early with certolizumab pegol and were sustained throughout the study. Most adverse events were mild or moderate and no deaths or cases of tuberculosis were reported. CONCLUSIONS: Treatment with certolizumab pegol 400 mg monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing > or =1 DMARD compared with placebo, and demonstrated an acceptable safety profile. TRIAL REGISTRATION NUMBER: NCT00548834.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Fragmentos Fab de Inmunoglobulinas/administración & dosificación , Inmunosupresores/administración & dosificación , Polietilenglicoles/administración & dosificación , Adulto , Análisis de Varianza , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Artritis Reumatoide/inmunología , Certolizumab Pegol , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Inmunosupresores/uso terapéutico , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Polietilenglicoles/uso terapéutico , Tamaño de la Muestra , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores
8.
Sci Rep ; 9(1): 5677, 2019 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-30952875

RESUMEN

The modification of river flow regimes poses a significant threat to the world's freshwater ecosystems. Northern Australia's freshwater resources, particularly dry season river flows, are being increasingly modified to support human development, potentially threatening aquatic ecosystems and biodiversity, including fish. More information is urgently needed on the ecology of fishes in this region, including their habitat requirements, to support water policy and management to ensure future sustainable development. This study used electrofishing and habitat survey methods to quantify the dry season habitat use of 20 common freshwater fish taxa in the Daly River in Australia's wet-dry tropics. Of twenty measured habitat variables, water depth and velocity were the two most important factors discriminating fish habitat use for the majority of taxa. Four distinct fish habitat guilds were identified, largely classified according to depth, velocity and structural complexity. Ontogenetic shifts in habitat use were also observed in three species. This study highlights the need to maintain dry season river flows that support a diversity of riverine mesohabitats for freshwater fishes. In particular, shallow fast-flowing areas provided critical nursery and refuge habitats for some species, but are vulnerable to water level reductions due to water extraction. By highlighting the importance of a diversity of habitats for fishes, this study assists water managers in future decision making on the ecological risks of water extractions from tropical rivers, and especially the need to maintain dry season low flows to protect the habitats of native fish.


Asunto(s)
Peces/fisiología , Animales , Australia , Biodiversidad , Conservación de los Recursos Naturales/métodos , Ecología , Ecosistema , Agua Dulce , Ríos , Alimentos Marinos , Estaciones del Año , Agua
9.
J Geophys Res Atmos ; 124(6): 2932-2945, 2019 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-31218150

RESUMEN

Several recent studies from both Greenland and Antarctica have reported significant changes in the water isotopic composition of near-surface snow between precipitation events. These changes have been linked to isotopic exchange with atmospheric water vapor and sublimation-induced fractionation, but the processes are poorly constrained by observations. Understanding and quantifying these processes are crucial to both the interpretation of ice core climate proxies and the formulation of isotope-enabled general circulation models. Here, we present continuous measurements of the water isotopic composition in surface snow and atmospheric vapor together with near-surface atmospheric turbulence and snow-air latent and sensible heat fluxes, obtained at the East Greenland Ice-Core Project drilling site in summer 2016. For two 4-day-long time periods, significant diurnal variations in atmospheric water isotopologues are observed. A model is developed to explore the impact of this variability on the surface snow isotopic composition. Our model suggests that the snow isotopic composition in the upper subcentimeter of the snow exhibits a diurnal variation with amplitudes in δ18O and δD of ~2.5‰ and ~13‰, respectively. As comparison, such changes correspond to 10-20% of the magnitude of seasonal changes in interior Greenland snow pack isotopes and of the change across a glacial-interglacial transition. Importantly, our observation and model results suggest, that sublimation-induced fractionation needs to be included in simulations of exchanges between the vapor and the snow surface on diurnal timescales during summer cloud-free conditions in northeast Greenland.

10.
Structure ; 5(12): 1681-93, 1997 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-9438869

RESUMEN

BACKGROUND: The conversion of prothrombin to thrombin by factor Xa is the penultimate step in the blood clotting cascade. In vivo, where the conversion occurs primarily on activated platelets in association with factor Va and Ca2+ ions, meizothrombin is the major intermediate of the two step reaction. Meizothrombin rapidly loses the fragment 1 domain (F1) by autolysis to become meizothrombin des F1 (mzTBN-F1). The physiological properties of mzTBN-F1 differ dramatically from those of thrombin due to the presence of prothrombin fragment 2 (F2), which remains covalently attached to the activated thrombin domain in mzTBN-F1. RESULTS: The crystal structure of mzTBN-F1 has been determined at 3.1 A resolution by molecular replacement, using only the thrombin domain, and refined to R and Rfree values of 0.205 and 0.242, respectively. The protease active site was inhibited with D-Phe-Pro-Arg-chloromethylketone (PPACK) to reduce autolysis. The mobile linker chain connecting the so-called kringle and thrombin domains and the first two N-acetylglucosamine residues attached to the latter were seen in electron-density maps improved with the program SQUASH. Previously these regions had only been modeled. CONCLUSIONS: The F2 kringle domain in mzTBN-F1 is bound to the electropositive heparin-binding site on thrombin in an orientation that is systematically shifted and has significantly more interdomain contacts compared to a noncovalent complex of free F2 and free thrombin. F2 in mzTBN-F1 forms novel hydrogen bonds to the carbohydrate chain of thrombin and perhaps stabilizes a unique, rigid conformation of the gamma-autolysis loop through non-local effects. The F2 linker chain, which does not interfere with the active site or fibrinogen-recognition site, is arranged so that the two sites cleaved by factor Xa are separated by 36 A. The two mzTBN-F1 molecules in the asymmetric unit share a tight 'dimer' contact in which the active site of one molecule is partially blocked by the F2 kringle domain of its partner. This interaction suggests a new model for prothrombin organization.


Asunto(s)
Clorometilcetonas de Aminoácidos/química , Coagulación Sanguínea , Precursores Enzimáticos/química , Trombina/química , Acetilglucosamina/metabolismo , Clorometilcetonas de Aminoácidos/metabolismo , Animales , Antitrombinas/química , Antitrombinas/metabolismo , Bovinos , Cristalización , Cristalografía por Rayos X , Dimerización , Precursores Enzimáticos/antagonistas & inhibidores , Precursores Enzimáticos/metabolismo , Kringles , Modelos Moleculares , Estructura Terciaria de Proteína , Protrombina/química , Relación Estructura-Actividad , Trombina/antagonistas & inhibidores , Trombina/metabolismo
11.
J Am Coll Cardiol ; 36(3): 685-92, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10987585

RESUMEN

OBJECTIVES: The study examined whether antiplatelet treatment with eptifibatide affected the frequency and outcome of shock among patients in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial who had acute coronary syndromes but not persistent ST-segment elevation. BACKGROUND: Preliminary reports suggest a salutary effect of antiplatelet agents when shock complicates acute myocardial infarction. METHODS: We analyzed the impact of antiplatelet treatment with eptifibatide on the frequency and outcome of cardiogenic shock developing after enrollment. PURSUIT was a double-blind, randomized trial that examined the efficacy of eptifibatide (180 microg/kg bolus + continuous infusion of 2.0 microg/kg/min for < or =96 h) versus placebo among patients who had acute coronary syndromes but not persistent ST-segment elevation. RESULTS: Shock developed in 2.5% of the 9,449 patients at a median (25th, 75th interquartiles) of 94.0 (38, 206) h. Death by 30 days occurred in 65.8% of shock patients. Patients who had acute myocardial infarction upon enrollment had a greater incidence of shock (2.9% vs. 2.1%, p = 0.01), developed shock earlier (40.2% <48 h vs. 20.9%, p = 0.001), and had higher 30-day mortality from shock (77.2% vs. 52.7%, p = 0.001). Randomization to eptifibatide did not affect the occurrence of shock (p = 0.71, adjusted odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.72-1.25). However, shock patients treated with eptifibatide had significantly reduced adjusted odds of 30-day death (p = 0.03, adjusted OR = 0.51, 95% CI = 0.28-0.94). CONCLUSIONS: Patients with shock treated with eptifibatide had significantly reduced adjusted odds of death, suggesting a salutary effect of antiplatelet therapy on shock. This finding warrants verification in specifically designed studies.


Asunto(s)
Plaquetas/metabolismo , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/fisiopatología , Electrocardiografía , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Choque/etiología , Anciano , Angiografía Coronaria , Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/terapia , Método Doble Ciego , Femenino , Corazón Auxiliar , Humanos , Masculino , Persona de Mediana Edad , Revascularización Miocárdica , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Síndrome , Factores de Tiempo
12.
Thromb Haemost ; 75(4): 578-84, 1996 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8743182

RESUMEN

Inflammation often is considered a contributing factor to both thrombosis and disseminated intravascular coagulation. The molecular mechanisms that dictate which of these clinical manifestations will result from the inflammatory stimulus remain obscure. Bacterial infection and certain tumors are common initiators of the disseminated intravascular coagulant response. Complement activation resulting from bacterial infection shares with selected tumors the capacity to generate or release membrane particles that lack functional adhesion receptors and hence could circulate to amplify a disseminated intravascular coagulant response. We developed a model of venous thrombosis that resulted in localized thrombus formation without disseminated intravascular coagulation. The model involves infusion of tumor necrosis factor, blockade of protein C and a partial decrease in venous flow caused by ligation of the superficial femoral vein without obstruction of the deep formal vein. Infusion of phospholipid vesicles into this model resulted in amplification of a localized thrombotic response into a consumptive response. Seven different groups of animals were studied. The first three groups established the conditions necessary to produce deep vein thrombosis. The second four groups established the conditions necessary to produce disseminated intravascular coagulation. The infusion of phospholipid vesicles plus tumor necrosis factor and anti-protein C antibody resulted in consumption of fibrinogen, the production of thrombin/antithrombin complexes, a fall in platelet count, and venous thrombosis. Without ligation and catheterization phospholipid vesicles failed to produce the consumptive response. We conclude, therefore, that phospholipid vesicles can amplify a local thrombotic response into a consumptive response, and that vesiculation accompanying inflammation is one means by which localized coagulant activity may be amplified to produce disseminated intravascular coagulation.


Asunto(s)
Fibrinógeno/metabolismo , Fosfolípidos/toxicidad , Proteína C/inmunología , Tromboflebitis/inducido químicamente , Factor de Necrosis Tumoral alfa/toxicidad , Animales , Anticuerpos Monoclonales , Antitrombina III/biosíntesis , Sinergismo Farmacológico , Infusiones Intravenosas , Liposomas , Papio , Péptido Hidrolasas/biosíntesis , Recuento de Plaquetas/efectos de los fármacos
13.
Lung Cancer ; 33(2-3): 115-23, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11551406

RESUMEN

Several studies have suggested that non-small cell lung cancer (NSCLC) patients whose tumors have neuroendocrine (NE) features may be more responsive to chemotherapy. In addition, increased expression of p53 and HER2 may confer relative chemotherapy resistance and shortened survival. The Cancer and Leukemia Group B performed a series of studies involving sequential chemotherapy followed by radiation for patients with unresectable stage III NSCLC. The objectives of this study were to analyze pathological specimens using immunohistochemistry for NE markers, p53 and HER2 to determine if there was a correlation between marker expression and response or survival. Of 160 eligible patients, 28 (18%) were not evaluable because of inadequate material. The percentage of specimens positive for markers was as follows: neuron-specific enolase 38%, Leu-7 2%, chromogranin A 0%, synaptophysin 5%, > or =2+NE markers 3%, p53 61%, and HER2 65%. There was no statistically significant correlation between any individual marker and response to induction chemotherapy or response to combined chemotherapy/radiation except for synaptophysin. Six of 6 (100%) synaptophysin positive tumors responded by the completion of all therapy compared with 69/125 (55%) synaptophysin negative tumors (P=0.04). None of the individual markers had a significant effect on survival in univariate analysis. Neuron-specific enolase was marginally significant in multivariate analysis (P=0.08). In conclusion, this study did not demonstrate that expression of NE markers, p53 and HER2 were predictive of response to chemotherapy, combined chemotherapy/radiation or for survival in this group of patients with stage III NSCLC. Future studies must employ either different markers or be performed on more adequate surgical specimens.


Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Receptor ErbB-2/análisis , Proteína p53 Supresora de Tumor/análisis , Antígeno Carcinoembrionario/análisis , Carcinoma de Pulmón de Células no Pequeñas/química , Carcinoma de Pulmón de Células no Pequeñas/clasificación , Terapia Combinada , Femenino , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/clasificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia
14.
Clin Neurophysiol ; 111(6): 1054-65, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10825713

RESUMEN

OBJECTIVES: The aim of the present study was to elucidate the reasons for apparent inconsistencies in the schizophrenia literature with respect to the mismatch negativity (MMN) waveform of the event-related potential (ERP). While most previous research has shown that MMN is reduced in schizophrenia, there are a small number of studies reporting that frequency MMN is not reduced. METHODS: We recorded ERPs to auditory stimuli with different frequencies and durations from patients with schizophrenia (N = 14) and control subjects (N = 17) of similar age and sex. MMNs to small but discriminable frequency deviants were contrasted with large frequency deviants and duration deviants. RESULTS: Only the MMN to duration deviants was significantly reduced in patients, although there was evidence of a similar trend for large frequency deviants. CONCLUSIONS: The results together with a review of the frequency MMN literature suggest that there are 3 variables which are important in determining whether patients exhibit a reduced MMN to frequency deviants: deviant probability, degree of deviance and interstimulus interval. The results also indicated that patients with schizophrenia may have particular deficits in processing the temporal properties of auditory stimuli. This finding has implications for the pathophysiology of the disorder as time-dependent processing is reliant on the integrity of an extensive network of brain areas consisting of auditory cortex, areas of pre-frontal cortex, the basal ganglia and cerebellum.


Asunto(s)
Encéfalo/fisiopatología , Electroencefalografía , Potenciales Evocados Auditivos/fisiología , Esquizofrenia/fisiopatología , Estimulación Acústica , Adulto , Corteza Auditiva/fisiopatología , Ganglios Basales/fisiopatología , Encéfalo/fisiología , Cerebelo/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Corteza Prefrontal/fisiopatología , Valores de Referencia
15.
J Clin Densitom ; 2(2): 143-52, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10499973

RESUMEN

Mechanical response tissue analysis (MRTA) is a noninvasive measure of ulnar bending stiffness in vivo. It is unique in that the mechanical response to the lower range of vibrational frequencies is used to determine the average cross-sectional bending stiffness. The objective of this study was to compare ulnar bending stiffness among normal, osteopenic, and osteoporotic Caucasian women. World Health Organization criteria were used to define cohorts. Ulnar bending stiffness was expressed as the product of Young's modulus of elasticity (E) and the cross-sectional moment of inertia (I) in units of square Newton meters using MRTA. There was no difference in the mean body weight between cohorts but mean age was significantly different (p < 0.0001, analysis of variance): normal women, 34 +/- 12 yr (n = 55); women with age-related/idiopathic osteopenia, 52 +/- l l yr (n = 36(; and women with osteoporosis, 65 +/- 10 yr (n = 24). The mean EI of osteoporotic Caucasian women (25 Nm(2)) was 25% lower than normal subjects (33.1 Nm(2)) (p < 0.0001). However, there was no significant difference between EI of normal women and osteopenic women (30.l Nm(2)). EI was significantly but weakly correlated (i.e., the greatest r(2) value was 37%) to all dual X-ray absorptiometry variables, ulnar width, age, and body weight. In summary, results with MRTA were consistent with previous studies using classical ex vivo biomechanical techniques and in vivo vibrational techniques, showing decreased strength (i.e., bending stiffness) in osteoporotic bone compared with normal bone and a generalized decrease in bending stiffness with increasing age.


Asunto(s)
Osteoporosis/fisiopatología , Cúbito/fisiopatología , Adulto , Factores de Edad , Análisis de Varianza , Densidad Ósea/fisiología , Femenino , Humanos , Persona de Mediana Edad , Osteoporosis/etnología , Docilidad , Población Blanca , Organización Mundial de la Salud
16.
Am Surg ; 66(5): 495-501, 2000 May.
Artículo en Inglés | MEDLINE | ID: mdl-10824753

RESUMEN

Cystic lesions of the pancreas are encountered frequently in clinical practice. Cystic neoplasms of the pancreas are much less common. In order to diagnose and most effectively treat these lesions, the surgeon must understand their clinical presentation in order to plan appropriate preoperative evaluation and therapeutic intervention. The following is a descriptive outline of the most common types of cystic neoplasms of the pancreas and a discussion of their preoperative, intraoperative, and postoperative management. The goal of the paper is to provide a functional understanding of cystic neoplasms of the pancreas so that they may be recognized and appropriately treated.


Asunto(s)
Quiste Pancreático , Neoplasias Pancreáticas , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/terapia , Cistadenoma Seroso/diagnóstico , Cistadenoma Seroso/terapia , Dilatación Patológica , Humanos , Quiste Pancreático/diagnóstico , Quiste Pancreático/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia
17.
Am Surg ; 63(4): 314-6, 1997 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-9124748

RESUMEN

Pheochromocytomas are functioning paragangliomas often presenting with paroxysmal hypertension due to catecholamine secretion. The preferential diagnostic workup includes urine and serum catecholamine measurements. Therapeutic management consists of pharmacologic cardiovascular manipulation and volume expansion with subsequent surgical resection. We have encountered a symptomatic pheochromocytoma in a chronic renal insufficiency patient on hemodialysis. The diagnostic dilemma arose due to the patient's anuric status and the inherent increase in serum catecholamine levels noted in anuric patients. The therapeutic dilemma arose in the proper pharmacologic management and volume expansion in this patient on hemodialysis. The patient underwent successful resection of the pheochromocytoma and has done well. An analysis of our diagnostic and therapeutic processes as well as a review of the literature are presented to assist in the management of this difficult clinical situation.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/diagnóstico , Fallo Renal Crónico/complicaciones , Feocromocitoma/diagnóstico , Diálisis Renal , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/rehabilitación , Humanos , Hipertensión/etiología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Feocromocitoma/complicaciones , Feocromocitoma/rehabilitación
18.
Am Surg ; 63(8): 741-3, 1997 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-9247445

RESUMEN

Eosinophilic gastroenteritis is a quite uncommon clinical entity usually involving the stomach or small bowel. Occasionally, the colon is involved. We have encountered a case of eosinophilic colitis leading to a left-sided colocolonic intussusception and subsequent large bowel obstruction. This is a unique presentation that, to our knowledge, has not been previously reported. We present our case in detail as well as a review of the literature to better understand this rare clinical entity.


Asunto(s)
Colitis/diagnóstico , Eosinofilia/diagnóstico , Obstrucción Intestinal/diagnóstico , Intususcepción/diagnóstico , Enfermedades del Sigmoide/diagnóstico , Adulto , Colitis/complicaciones , Colitis/patología , Diagnóstico Diferencial , Eosinofilia/complicaciones , Eosinofilia/patología , Femenino , Hemorragia/patología , Humanos , Mucosa Intestinal/patología , Obstrucción Intestinal/etiología , Intususcepción/etiología , Músculo Liso/patología , Necrosis , Enfermedades del Sigmoide/etiología
19.
Am Surg ; 62(4): 280-6, 1996 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-8600848

RESUMEN

We have undertaken a review of the small bowel carcinoids treated at Georgia Baptist Medical Center during the last 27 years in order to evaluate the clinical behavior, diagnostic approaches, treatment options, and prognosis of these neoplasms. A retrospective analysis of the tumor registry at Georgia Baptist Medical Center was undertaken. A total of 148 cases of carcinoid tumors were identified. Of these, 34 were located in the small bowel. Twenty-eight of these cases were diagnosed at our institution. The others were referred for oncology care. The patient records were reviewed for sex, race, age at presentation, location, 5-HIAA status, coexistent neoplasms, multifocality, size, metastatic status, clinical presentation, diagnostic intervention, extension, adjuvant therapy, treatment intervention, and survival. A review of the available literature was undertaken to analyze the historical results in the aforementioned categories. In retrospect, many of these tumors had been clinically active for some time. The authors outline a more aggressive workup in order to avoid acute, in extremis, and late stage presentation. We present an analysis of traditional views on survival and prognosis as related to the size and spread of small bowel carcinoid. We expect that this information will assist in the development of definitive treatment, effective adjuvant therapy, and symptomatic relief for this often frustrating neoplasm.


Asunto(s)
Tumor Carcinoide/diagnóstico , Neoplasias Duodenales/diagnóstico , Neoplasias del Íleon/diagnóstico , Neoplasias del Yeyuno/diagnóstico , Adulto , Anciano , Tumor Carcinoide/terapia , Neoplasias Duodenales/terapia , Femenino , Humanos , Neoplasias del Íleon/terapia , Neoplasias del Yeyuno/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
20.
Am Surg ; 61(3): 271-6, 1995 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-7887545

RESUMEN

The adult rhabdomyoma (ARM) is an unusual and extremely uncommon tumor. Only 96 cases have been reported. Adult rhabdomyomas are found most often in the region of the base of the tongue, floor of the mouth, larynx, and pharynx. Uncommon locations include the soft palate, uvula, lip and cheek, orbit, and stomach. One prior case of extension of an ARM from the supraclavicular region into the mediastinum has been described as an incidental finding at autopsy. It is important to be aware of and correctly identify this tumor because total excision may be curative. Follow-up must be long-term, as recurrence can occur after 35 years. The authors present a case of an ARM diagnosed during the evaluation and treatment of a symptomatic mediastinal mass. This ARM was found to involve the esophagus and trachea from the inferior constrictors in the neck to the azygous vein in the mediastinum. This case represents a previously undescribed presentation of an ARM. We present a review of ARM and outline our diagnostic, therapeutic, and follow-up plans.


Asunto(s)
Neoplasias de Cabeza y Cuello , Neoplasias del Mediastino , Rabdomioma , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Neoplasias del Mediastino/diagnóstico por imagen , Neoplasias del Mediastino/patología , Persona de Mediana Edad , Rabdomioma/diagnóstico por imagen , Rabdomioma/patología , Tomografía Computarizada por Rayos X
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