RESUMEN
A compact, step range filter proton spectrometer has been developed for the measurement of the absolute DD proton spectrum, from which yield and areal density (ρR) are inferred for deuterium-filled thin-shell inertial confinement fusion implosions. This spectrometer, which is based on tantalum step-range filters, is sensitive to protons in the energy range 1-9 MeV and can be used to measure proton spectra at mean energies of â¼1-3 MeV. It has been developed and implemented using a linear accelerator and applied to experiments at the OMEGA laser facility and the National Ignition Facility (NIF). Modeling of the proton slowing in the filters is necessary to construct the spectrum, and the yield and energy uncertainties are ±<10% in yield and ±120 keV, respectively. This spectrometer can be used for in situ calibration of DD-neutron yield diagnostics at the NIF.
RESUMEN
Neutron time-of-flight spectra from inertial confinement fusion experiments with tritium-filled targets have been measured at the National Ignition Facility. These spectra represent a significant improvement in energy resolution and statistics over previous measurements, and afford the first definitive observation of a peak resulting from sequential decay through the ground state of (5)He at low reaction energies E(c.m.) 100 ~ keV. To describe the spectrum, we have developed an R-matrix model that accounts for interferences from fermion symmetry and intermediate states, and show these effects to be non-negligible. We also find the spectrum can be described by sequential decay through â=1 states in (5)He, which differs from previous interpretations.
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To elucidate the role of serotonin in the onset of puberty, the effects of both systemic and in-ovarian bursa administration of serotonin on the neuroendocrine mechanism that modulates the onset of puberty, follicular development and first ovulation were evaluated. Two experiments were carried out. For the first, 25 or 37.5 mg kg⻹ of bodyweight of serotonin creatinine sulfate was administered by a subcutaneous route to 30-day-old female rats. In the second experiment, serotonin creatinine sulfate was administered directly into the ovarian bursa of 34-day-old female rats. Systemic administration of 25 or 37.5 mg kg⻹ of serotonin creatinine sulfate induced a delay in the ages of vaginal opening and first vaginal oestrus, a decrease in the number of ovulating animals, and serum concentrations of FSH, LH, oestradiol and progesterone. An increase in the number of Class 3 (>500 µm) and atretic follicles was observed in the ovaries of these animals. The administration of serotonin creatinine sulfate in the ovarian bursa did not modify the onset of puberty and ovulation, but a reduced serum concentration of oestradiol was observed. Our results suggest that serotonin acts on the components of the hypothalamus-hypophysis-ovary axis by modulating follicular development, ovarian functions and the onset of puberty.
Asunto(s)
Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Oogénesis/efectos de los fármacos , Folículo Ovárico/metabolismo , Ovulación/efectos de los fármacos , Agonistas de Receptores de Serotonina/administración & dosificación , Serotonina/administración & dosificación , Maduración Sexual/efectos de los fármacos , Animales , Creatinina/administración & dosificación , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Estradiol/sangre , Estradiol/metabolismo , Femenino , Hormona Folículo Estimulante/sangre , Hormona Folículo Estimulante/metabolismo , Sistema Hipotálamo-Hipofisario/crecimiento & desarrollo , Sistema Hipotálamo-Hipofisario/metabolismo , Inyecciones Subcutáneas , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Sistemas Neurosecretores/efectos de los fármacos , Folículo Ovárico/citología , Folículo Ovárico/crecimiento & desarrollo , Progesterona/sangre , Progesterona/metabolismo , Ratas , Ratas Endogámicas , Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Vagina/efectos de los fármacos , Vagina/crecimiento & desarrolloRESUMEN
DT neutron yield (Y(n)), ion temperature (T(i)), and down-scatter ratio (dsr) determined from measured neutron spectra are essential metrics for diagnosing the performance of inertial confinement fusion (ICF) implosions at the National Ignition Facility (NIF). A suite of neutron-time-of-flight (nTOF) spectrometers and a magnetic recoil spectrometer (MRS) have been implemented in different locations around the NIF target chamber, providing good implosion coverage and the complementarity required for reliable measurements of Y(n), T(i), and dsr. From the measured dsr value, an areal density (ρR) is determined through the relationship ρR(tot) (g∕cm(2)) = (20.4 ± 0.6) × dsr(10-12 MeV). The proportionality constant is determined considering implosion geometry, neutron attenuation, and energy range used for the dsr measurement. To ensure high accuracy in the measurements, a series of commissioning experiments using exploding pushers have been used for in situ calibration of the as-built spectrometers, which are now performing to the required accuracy. Recent data obtained with the MRS and nTOFs indicate that the implosion performance of cryogenically layered DT implosions, characterized by the experimental ignition threshold factor (ITFx), which is a function of dsr (or fuel ρR) and Y(n), has improved almost two orders of magnitude since the first shot in September, 2010.
RESUMEN
The first several campaigns of laser fusion experiments at the National Ignition Facility (NIF) included a family of high-sensitivity scintillator∕photodetector neutron-time-of-flight (nTOF) detectors for measuring deuterium-deuterium (DD) and DT neutron yields. The detectors provided consistent neutron yield (Y(n)) measurements from below 10(9) (DD) to nearly 10(15) (DT). The detectors initially demonstrated detector-to-detector Y(n) precisions better than 5%, but lacked in situ absolute calibrations. Recent experiments at NIF now have provided in situ DT yield calibration data that establish the absolute sensitivity of the 4.5 m differential tissue harmonic imaging (DTHI) detector with an accuracy of ± 10% and precision of ± 1%. The 4.5 m nTOF calibration measurements also have helped to establish improved detector impulse response functions and data analysis methods, which have contributed to improving the accuracy of the Y(n) measurements. These advances have also helped to extend the usefulness of nTOF measurements of ion temperature and downscattered neutron ratio (neutron yield 10-12 MeV divided by yield 13-15 MeV) with other nTOF detectors.
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The National Ignition Facility has been used to compress deuterium-tritium to an average areal density of ~1.0±0.1 g cm(-2), which is 67% of the ignition requirement. These conditions were obtained using 192 laser beams with total energy of 1-1.6 MJ and peak power up to 420 TW to create a hohlraum drive with a shaped power profile, peaking at a soft x-ray radiation temperature of 275-300 eV. This pulse delivered a series of shocks that compressed a capsule containing cryogenic deuterium-tritium to a radius of 25-35 µm. Neutron images of the implosion were used to estimate a fuel density of 500-800 g cm(-3).
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The first 3 of 18 neutron time-of-flight (nTOF) channels have been installed at the National Ignition Facility (NIF). The role of these detectors includes yield, temperature, and bang time measurements. This article focuses on nTOF data analysis and quality of results obtained for the first set of experiments to use all 192 NIF beams. Targets produced up to 2×10(10) 2.45 MeV neutrons for initial testing of the nTOF detectors. Differences in neutron scattering at the OMEGA laser facility where the detectors were calibrated and at NIF result in different response functions at the two facilities. Monte Carlo modeling shows this difference. The nTOF performance on these early experiments indicates that the nTOF system with its full complement of detectors should perform well in future measurements of yield, temperature, and bang time.
RESUMEN
The National Ignition Facility (NIF) successfully completed its first inertial confinement fusion (ICF) campaign in 2009. A neutron time-of-flight (nTOF) system was part of the nuclear diagnostics used in this campaign. The nTOF technique has been used for decades on ICF facilities to infer the ion temperature of hot deuterium (D(2)) and deuterium-tritium (DT) plasmas based on the temporal Doppler broadening of the primary neutron peak. Once calibrated for absolute neutron sensitivity, the nTOF detectors can be used to measure the yield with high accuracy. The NIF nTOF system is designed to measure neutron yield and ion temperature over 11 orders of magnitude (from 10(8) to 10(19)), neutron bang time in DT implosions between 10(12) and 10(16), and to infer areal density for DT yields above 10(12). During the 2009 campaign, the three most sensitive neutron time-of-flight detectors were installed and used to measure the primary neutron yield and ion temperature from 25 high-convergence implosions using D(2) fuel. The OMEGA yield calibration of these detectors was successfully transferred to the NIF.
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Numerical modeling of the neutron imaging system for the National Ignition Facility (NIF), forward from calculated target neutron emission to a camera image, will guide both the reduction of data and the future development of the system. Located 28 m from target chamber center, the system can produce two images at different neutron energies by gating on neutron arrival time. The brighter image, using neutrons near 14 MeV, reflects the size and symmetry of the implosion "hot spot." A second image in scattered neutrons, 10-12 MeV, reflects the size and symmetry of colder, denser fuel, but with only â¼1%-7% of the neutrons. A misalignment of the pinhole assembly up to ±175 µm is covered by a set of 37 subapertures with different pointings. The model includes the variability of the pinhole point spread function across the field of view. Omega experiments provided absolute calibration, scintillator spatial broadening, and the level of residual light in the down-scattered image from the primary neutrons. Application of the model to light decay measurements of EJ399, BC422, BCF99-55, Xylene, DPAC-30, and Liquid A suggests that DPAC-30 and Liquid A would be preferred over the BCF99-55 scintillator chosen for the first NIF system, if they could be fabricated into detectors with sufficient resolution.
Asunto(s)
Dolor Abdominal/etiología , Fiebre/etiología , Policitemia Vera/complicaciones , Infarto del Bazo/diagnóstico , Anciano , Humanos , Laparotomía , Masculino , Radiografía Abdominal , Recurrencia , Esplenectomía , Infarto del Bazo/complicaciones , Infarto del Bazo/etiología , Infarto del Bazo/cirugía , Esplenomegalia/diagnóstico por imagen , Esplenomegalia/etiología , Tomografía Computarizada por Rayos XRESUMEN
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Humanos , Masculino , Anciano de 80 o más Años , Linfoma no Hodgkin/patología , Neoplasias Mandibulares/patología , Linfoma Anaplásico de Células Grandes/patología , Metástasis Linfática/patologíaRESUMEN
Objetivo. El objetivo de este trabajo es analizar los cuadros de poliuria precoz encontrados en un alto porcentaje de nuestros pacientes sometidos a procedimientos de cirugía ortognática. Material y método. Hemos realizado un estudio descriptivo retrospectivo, a partir de la revisión de las historias clínicas de los 172 pacientes sometidos a cirugía ortognática entre los años 1997 y 2002, con el fin de recoger datos analíticos y de diuresis referentes tanto a la cirugía como al período de estancia en Reanimación. Resultados. Un 55% de los pacientes que ingresaron en la unidad de reanimación postoperatoria presentaron poliurias precoces autolimitadas. Todas fueron tratadas con éxito con un correcto manejo hidroelectrolítico, salvo un caso que necesitó desmopresina intranasal. Dos pacientes presentaron alteraciones iónicas: un caso de hipopotasemia y otro de hiponatremia. Ambos respondieron adecuadamente a la reposición hidroelectrolítica. Discusión y conclusiones. Casi el 50% de los pacientes tratados de deformidades dentofaciales mediante cirugía ortognática desarrolla poliuria en el postoperatorio inmediato. Las tres hipótesis etiológicas que barajamos fueron: una intoxicación hídrica producida en el quirófano, una inhibición de la producción hipofisaria de hormona antidiurética tras las osteotomías faciales y un síndrome de gasto de sal relacionado con excreción inadecuada del péptido atrial natriurético. En nuestros casos lo más probable es que se trate de una intoxicación hídrica producida durante la cirugía, que haga replantearse el manejo de líquidos en el período perioperatorio
Introduction. The aim of this article is to analize the early polyuria cases that we found among our patients that have undergone a orthognatic procedure. Materials and methods. We reviewed data from 172 patients that have undergone an orthognatic surgycal procedures between 1997 and 2002. We collected data during the intraoperatory period, and the first 24 postoperatory hours. Results. 55% of the patients that staid for more than 24 hours in Reanimation showed early autolimited polyuria. All of them were successfully treated with a proper hidroelectrolitic treatment. One needed intranasal desmopresin. However hypopotasemy in one case and hyponatremy in another were resolved with hidroelectrolitic treatment. Disscusion and conclusions. Almost 50% of patients surgically treated of dentofacial deformities present polyuria in the early postoperatory period. There are three main etiologic hypotesis: hydric intoxication during surgery, inhibition of ADH liberation due to facial osteotomies, and salt wasting syndrome. The most probable in our serie is an hydric intoxication during surgery
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Masculino , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Humanos , Desequilibrio Hidroelectrolítico/epidemiología , Poliuria/epidemiología , Desequilibrio Hidroelectrolítico/fisiopatología , Epidemiología Descriptiva , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Anomalías Dentarias/complicaciones , Anomalías Dentarias/cirugía , Anomalías de la Boca/complicaciones , Anomalías de la Boca/cirugía , Cuidados Posoperatorios/métodosRESUMEN
Dendritic arbor development of subventricular zone-derived interneurons is a critical step in their integration into functional circuits of the postnatal olfactory bulb. However, the mechanism and molecular control of this process remain unknown. In this study, we have developed a culture model where dendritic development of purified subventricular zone cells proceeds under serum-free conditions in the absence of added growth factors and non-neural cells. We demonstrate that the large majority of these cells in culture express GABA and elaborate dendritic arbors with spine-like protrusions but they do not possess axons. These neurons expressed receptors for neurotrophins including p75, TrkB and TrkC but not TrkA. Application of exogenous neurotrophins, including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and nerve growth factor (NGF), to cultures stimulated dendritic growth and led to more complex dendritic arbors during the initial 3 days in culture. Our results suggest that these effects are independent of Trk receptors and mediated by the p75/ceramide signaling pathway. We also show that brain-derived neurotrophic factor is the only neurotrophin that is able to influence late-phase dendritic development via TrkB receptor activation. These results suggest that dendritic arbor development of subventricular zone-derived cells may be regulated by neurotrophins through the activation of p75 and the TrkB receptor signaling pathways in a sequentially defined temporal pattern.
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Ventrículos Cerebrales/citología , Dendritas/fisiología , Neuronas/fisiología , Receptor trkB/metabolismo , Receptores de Factor de Crecimiento Nervioso/metabolismo , Células Madre/fisiología , Actinas/metabolismo , Animales , Animales Recién Nacidos , Factor Neurotrófico Derivado del Encéfalo/farmacología , Muerte Celular , Células Cultivadas , ADN Complementario/biosíntesis , Dendritas/efectos de los fármacos , Diagnóstico por Imagen/métodos , Proteína GAP-43/metabolismo , Inmunohistoquímica/métodos , Etiquetado Corte-Fin in Situ/métodos , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Factor de Crecimiento Nervioso/farmacología , Proteínas del Tejido Nervioso/metabolismo , Nestina , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Neuronas/efectos de los fármacos , Neurotrofina 3/farmacología , Reacción en Cadena de la Polimerasa/métodos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Factor de Crecimiento Nervioso , Receptor trkA/metabolismo , Ácidos Siálicos/metabolismo , Factores de Tiempo , Tubulina (Proteína)/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The use of the activated carbon produced from rice hulls to control NOx emissions for future deep space missions has been demonstrated. The optimal carbonization temperature range was found to be between 600 and 750 degrees C. A burnoff of 61.8% was found at 700 degrees C in pyrolysis and 750 degrees C in activation. The BET surface area of the activated carbon from rice hulls was determined to be 172 m2/g when prepared at 700 degrees C. The presence of oxygen in flue gas is essential for effective adsorption of NO by activated carbon. On the contrary, water vapor inhibits the adsorption efficiency of NO. Consequently, water vapor in flue gas should be removed by drying agents before adsorption to ensure high NO adsorption efficiency. All of the NO in the flue gas was removed for more than 1.5 h when 10% oxygen was present and the ratio of the carbon weight to the flue gas flow rate (W/F) was 15.4 g min/L. Reduction of the adsorbed NO to form N2 could be effectively accomplished under anaerobic conditions at 550 degrees C. The adsorption capacity of NO on the activated carbon was found to be 5.02 mg of NO/g of carbon. The loss of carbon mass was determined to be about 0.16% of the activated carbon per cycle of regeneration if the regeneration occurred when the NO in the flue gas after the carbon bed reached 4.8 ppm, the space maximum allowable concentration. The reduction of the adsorbed NO also regenerated the activated carbon, and the regenerated activated carbon exhibited an improved NO adsorption efficiency.
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Carbón Orgánico/química , Sistemas Ecológicos Cerrados , Sistemas de Manutención de la Vida/instrumentación , Óxido Nítrico/química , Oryza/química , Vuelo Espacial/instrumentación , Adsorción , Aire Acondicionado/métodos , Contaminantes Atmosféricos/química , Contaminantes Atmosféricos/normas , Contaminación del Aire Interior/prevención & control , Biomasa , Dióxido de Carbono/química , Carbón Orgánico/síntesis química , Estudios de Evaluación como Asunto , Incineración , Óxido Nítrico/normas , Nitrógeno/química , Oxígeno/química , Vuelo Espacial/normas , TemperaturaRESUMEN
La tasa de éxito total de los injertos libres microvascularizados se sitúa actualmente por encima del 95 por ciento en la mayoría de los Servicios. Los intentos de rescate en distintas series son exitosos en un 28-87,5 por ciento de los casos. La insuficiencia venosa es responsable de la mayor parte de los fracasos iniciales. Presentamos un caso clínico en el que se detectó trombosis venosa del injerto que finalmente fue rescatado con el empleo coadyuvante de sanguijuelas. (AU)
Asunto(s)
Humanos , Sanguijuelas , Trasplantes/efectos adversos , Trombosis de la Vena/etiología , Muslo , EspañaRESUMEN
BACKGROUND: Porphyria cutanea tarda (PCT) is sometimes associated with hepatitis C virus chronic infection. The aim of this study was to describe the effect of interferon alfa (IFN-alpha) in the treatment of patients with chronic hepatitis C and PCT. METHODS: We treated a total of 66 patients with chronic hepatitis C with IFN-alpha 2b (5 MU t.i.w.) for 12 months. Twenty-two of these patients suffered from PCT as well. These patients differed from patients without PCT in that they were men, past history of alcohol abuse and HFE gene mutations were more common and the source of infection was almost always unknown. RESULTS: Sustained virologic response was obtained in 19.7% of the 66 treated patients, 27.3% in the non-PCT group and 4.5% in the PCT group (P < 0.05). This difference could not be ascribed to the difference in sex of patients, history of alcohol abuse, HCV genotype or iron status. CONCLUSION: Multivariate logistic regression analysis revealed that PCT is independently and significantly associated with non-sustained response to IFNalpha therapy. In conclusion, patients with chronic hepatitis C and PCT rarely responded to IFNalpha treatment.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón Tipo I/uso terapéutico , Porfiria Cutánea Tardía/tratamiento farmacológico , Adulto , Alanina Transaminasa/sangre , Alanina Transaminasa/efectos de los fármacos , Antivirales/administración & dosificación , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral/genética , Farmacorresistencia Viral/fisiología , Femenino , Estudios de Seguimiento , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Humanos , Interferón Tipo I/administración & dosificación , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Porfiria Cutánea Tardía/genética , Porfiria Cutánea Tardía/virología , Valor Predictivo de las Pruebas , ARN Viral/sangre , ARN Viral/efectos de los fármacos , ARN Viral/genética , Proteínas Recombinantes , Estudios Retrospectivos , España , Resultado del Tratamiento , Carga ViralRESUMEN
Injury to the nervous system results in reactive astrogliosis that is a critical determinant of neuronal regeneration. To analyze glial responses to mechanical injury and the role of the polysialic neural cell adhesion molecule (PSA-NCAM) in this process, we established primary glia cultures from newborn rat cerebral cortex. Scratching a confluent monolayer of primary glial cells resulted in two major events: rapid migration of oligodendrocyte progenitor-like (O-2A) cells into the wounded area and development of polarized morphology of type 1 astrocytes at the wound edge. Migrating O-2A progenitors had a bipolar morphology and exhibited A2B5 and O4 immunolabeling. Once these cells were established inside the wounded area, they lost A2B5 immunoreactivity and differentiated into glial fibrillary acidic protein-positive astrocytes. Migrating O-2A cells expressed PSA-NCAM, but type 1 astrocytes at the wound edge did not. Treatment of wounded cultures with Endo-N, which specifically removes PSA from the surface of cells, resulted in a significant decrease in O-2A cell migration into the wounded area and completely blocked the wound closure. Video time-lapse analysis showed that, in the presence of Endo-N, O-2A cells remained motile and migrated short distances but did not move away from the monolayer. These results demonstrate that O-2A progenitors contribute to reactive astrogliosis in culture and that PSA-NCAM is involved in this process by regulating cell migration.
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Movimiento Celular/fisiología , Molécula L1 de Adhesión de Célula Nerviosa/biosíntesis , Neuroglía/metabolismo , Oligodendroglía/citología , Oligodendroglía/metabolismo , Ácidos Siálicos/biosíntesis , Células Madre/citología , Células Madre/metabolismo , Animales , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Gliosis/metabolismo , Neuroglía/citología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Porphyria cutanea tarda (PCT) is sometimes associated with hepatitis C virus chronic infection. The aim of this study was to describe the effect of interferon alfa (IFN-a) in the treatment of patients with chronic hepatitis C and PCT. METHODS: We treated a total of 66 patients with chronic hepatitis C with IFN-a 2b (5 MU t.i.w.) for 12 months. Twenty-two of these patients suffered from PCT as well. These patients differed from patients without PCT in that they were men, past history of alcohol abuse and HFE gene mutations were more common and the source of infection was almost always unknown. RESULTS: Sustained virologie response was obtained in 19.7% of the 66 treated patients, 27.3% in the non-PCT group and 4.5% in the PCT group (P < 0.05). This difference could not be ascribed to the difference in sex of patients, history of alcohol abuse, HCV genotype or iron status. CONCLUSION: Multivariate logistic regression analysis revealed that PCT is independently and significantly associated with non-sustained response to IFNa therapy. In conclusion, patients with chronic hepatitis C and PCT rarely responded to IFNa treatment.
RESUMEN
Previous studies have shown a high prevalence of hepatitis C virus (HCV) infection in patients with porphyria cutanea tarda (PCT). The aim of this study was to assess hepatic porphyrin concentrations (HPC) and hepatic uroporphyrinogen decarboxylase (UROD) activity in HCV-infected patients free of PCT. Thirty-two HCV-infected patients (20 M, 12 F, mean age 51 years) and seven control patients (4 M, 3 F, mean age 59 years) free of liver disease, were studied. Knodell's score was determined on liver biopsy by two independent anatomopathologists. Measurement of HPC and hepatic UROD activity levels were carried out on liver biopsy. Relative to controls, HCV-infected patients had high HPC levels (mean +/- SD: 47 +/- 20 vs. 17 +/- 6 pmol/mg protein, P < 0.001) and low hepatic UROD activity levels (514 +/- 95 vs. 619 +/- 125 pmol Copro/h/mg protein, P < 0.05). HPC was not correlated with hepatic UROD activity and the increase was due to coproporphyrin accumulation. No correlation was observed between HPC or hepatic UROD activity values and HCV-RNA concentrations, Knodell's score, hepatic fibrosis, periportal necrosis, periportal inflammation or hepatic iron content in HCV-infected patients. Hepatocellular necrosis was significantly correlated with HPC value (P < 0.005). Hence, in HCV-infected patients, HPC is significantly increased and hepatic UROD activity is very slightly decreased as compared to controls. HPC values and UROD activity are not correlated with HCV-RNA concentrations, hepatic iron content and hepatic fibrosis. The small increase in HPC values in hepatitis C infection is linked with hepatic injury and not with a direct effect on hepatic UROD enzyme.