RESUMEN
PURPOSE: Many types of lung tumors have a very poor prognosis due to their spread in the whole organ volume. The fact that boron neutron capture therapy (BNCT) would allow for selective targeting of all the nodules regardless of their position, prompted a preclinical feasibility study of ex situ BNCT at the thermal neutron facility of RA-3 reactor in the province of Buenos Aires, Argentina. (l)-4p-dihydroxy-borylphenylalanine fructose complex (BPA-F) biodistribution studies in an adult sheep model and computational dosimetry for a human explanted lung were performed to evaluate the feasibility and the therapeutic potential of ex situ BNCT. METHODS: Two kinds of boron biodistribution studies were carried out in the healthy sheep: a set of pharmacokinetic studies without lung excision, and a set that consisted of evaluation of boron concentration in the explanted and perfused lung. In order to assess the feasibility of the clinical application of ex situ BNCT at RA-3, a case of multiple lung metastases was analyzed. A detailed computational representation of the geometry of the lung was built based on a real collapsed human lung. Dosimetric calculations and dose limiting considerations were based on the experimental results from the adult sheep, and on the most suitable information published in the literature. In addition, a workable treatment plan was considered to assess the clinical application in a realistic scenario. RESULTS: Concentration-time profiles for the normal sheep showed that the boron kinetics in blood, lung, and skin would adequately represent the boron behavior and absolute uptake expected in human tissues. Results strongly suggest that the distribution of the boron compound is spatially homogeneous in the lung. A constant lung-to-blood ratio of 1.3 ± 0.1 was observed from 80 min after the end of BPA-F infusion. The fact that this ratio remains constant during time would allow the blood boron concentration to be used as a surrogate and indirect quantification of the estimated value in the explanted healthy lung. The proposed preclinical animal model allowed for the study of the explanted lung. As expected, the boron concentration values fell as a result of the application of the preservation protocol required to preserve the lung function. The distribution of the boron concentration retention factor was obtained for healthy lung, with a mean value of 0.46 ± 0.14 consistent with that reported for metastatic colon carcinoma model in rat perfused lung. Considering the human lung model and suitable tumor control probability for lung cancer, a promising average fraction of controlled lesions higher than 85% was obtained even for a low tumor-to-normal boron concentration ratio of 2. CONCLUSIONS: This work reports for the first time data supporting the validity of the ovine model as an adequate human surrogate in terms of boron kinetics and uptake in clinically relevant tissues. Collectively, the results and analysis presented would strongly suggest that ex situ whole lung BNCT irradiation is a feasible and highly promising technique that could greatly contribute to the treatment of metastatic lung disease in those patients without extrapulmonary spread, increasing not only the expected overall survival but also the resulting quality of life.
Asunto(s)
Terapia por Captura de Neutrón de Boro/métodos , Neoplasias Pulmonares/radioterapia , Animales , Argentina , Boro/farmacocinética , Boro/uso terapéutico , Compuestos de Boro/farmacocinética , Terapia por Captura de Neutrón de Boro/instrumentación , Estudios de Factibilidad , Fructosa/análogos & derivados , Fructosa/farmacocinética , Humanos , Pulmón/metabolismo , Pulmón/efectos de la radiación , Neoplasias Pulmonares/metabolismo , Modelos Animales , Modelos Biológicos , Fotones , Radiometría/métodos , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Ovinos , Factores de Tiempo , Distribución TisularRESUMEN
Nitric oxide synthase is inhibited by asymmetric NG-methylated derivatives of arginine whose cellular levels are controlled in part by dimethylarginine dimethylaminohydrolase (DDAH, EC 3.5.3.18). Levels of asymmetric NG,NG-dimethylarginine (ADMA) are known to correlate with certain disease states. Here, the first structure of a DDAH shows an unexpected similarity to arginine:glycine amidinotransferase (EC 2.1.4.1) and arginine deiminase (EC 3.5.3.6), thus defining a superfamily of arginine-modifying enzymes. The identification of a Cys-His-Glu catalytic triad and the structures of a Cys to Ser point mutant bound to both substrate and product suggest a reaction mechanism. Comparison of the ADMA-DDAH and arginine-amidinotransferase complexes reveals a dramatic rotation of the substrate that effectively maintains the orientation of the scissile bond of the substrate with respect to the catalytic residues. The DDAH structure will form a basis for the rational design of selective inhibitors, which are of potential use in modulating NO synthase activity in pathological settings.
Asunto(s)
Amidohidrolasas , Inhibidores Enzimáticos/metabolismo , Hidrolasas/química , Hidrolasas/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Secuencia de Aminoácidos , Sustitución de Aminoácidos/genética , Sitios de Unión , Catálisis , Citrulina/metabolismo , Cristalografía por Rayos X , Dimerización , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Hidrolasas/genética , Hidrólisis , Ligandos , Modelos Moleculares , Datos de Secuencia Molecular , Mutación Puntual/genética , Estructura Cuaternaria de Proteína , Estructura Terciaria de Proteína , Rotación , Alineación de Secuencia , Especificidad por SustratoAsunto(s)
Amidohidrolasas , Hidrolasas/genética , Humanos , Hidrolasas/metabolismo , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/genética , Pseudomonas aeruginosa/enzimología , Pseudomonas aeruginosa/genética , Especificidad de la Especie , Streptomyces/enzimología , Streptomyces/genéticaRESUMEN
Methylarginines inhibit nitric oxide synthases (NOS). Cellular concentrations of methylarginines are determined in part by the activity of dimethylarginine dimethylaminohydrolase (DDAH; EC 3.5.3. 18). We have cloned human DDAH and identified and expressed a second novel DDAH isoform (DDAH I and II respectively). DDAH I predominates in tissues that express neuronal NOS. DDAH II predominates in tissues expressing endothelial NOS. These results strengthen the hypothesis that methylarginine concentration is actively regulated and identify molecular targets for the tissue and cell-specific regulation of methylarginine concentration.
Asunto(s)
Amidohidrolasas , Hidrolasas/metabolismo , Isoenzimas/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , ADN Complementario , Humanos , Hidrolasas/química , Hidrolasas/genética , Isoenzimas/química , Isoenzimas/genética , Datos de Secuencia Molecular , Ratas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Homología de Secuencia de AminoácidoRESUMEN
The presence of antibody to hepatitis C virus was determined in 316 HBsAg-negative patients with non-alcoholic chronic hepatitis who did not receive any blood transfusion once the diagnosis was made. A titre of antinuclear antibodies of 1/40 or lower was found in 18 patients. Persistent chronic hepatitis was present in 21 patients, active chronic hepatitis in 145, hepatic cirrhosis in 128, and hepatocarcinoma in 22 patients. One hundred and three patients had previously received blood transfusion, 76 had undergone previous surgery without transfusion, a clinical episode of hepatitis could be traced in 14, 13 patients were drug addicts (all of them HIV negative), 1 patient had received multiples injections, another had been treated with acupuncture, and 108 patients were free of any of the above. Anti-HCV was present in 76.6% of patients; a significantly higher proportion (87.4%) was found among patients who had received blood transfusion than in patients with previous surgery (72.4%) (p = 0.012), clinical hepatitis (57.1%), or without previous hepatic disease (70.3%) (p = 0.003). The incidence of anti-HCV was lower among cirrhotics (70.3%) than in patients with active chronic hepatitis (84.1%) (p = 0.006); in contrast, previous blood transfusion was significantly higher (p = 0.001) among the latter (40.7%) than in cirrhotics (21.9%). The incidence of anti-HCV was similar among patients with (78.6%) and without (75.8%) type B infection. Our results suggest that infection with virus C may account for a high proportion of non-alcoholic non-B chronic hepatitis.
Asunto(s)
Hepacivirus/inmunología , Anticuerpos Antihepatitis/sangre , Hepatopatías/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We report a complicated case of hydatid cyst mimicking a renal tumor, diagnosed by fine needle aspiration cytology. The cytological features are described and the diagnostic value of fine needle aspiration biopsy is underscored.
Asunto(s)
Equinococosis/complicaciones , Equinococosis/patología , Neoplasias Renales/diagnóstico , Anciano , Biopsia con Aguja , Diagnóstico Diferencial , Equinococosis/diagnóstico , Humanos , MasculinoRESUMEN
A patient is reported who had urolithiasis and pyonephrosis of the right kidney. In the terminal phase of his disease he developed chronic diarrhea and hematochezia. Sigmoidoscopy showed changes in the colo-rectal mucosa compatible with ulcerative colitis with moderate activity. Histology demonstrated large amyloid deposits of the AA type in the lamina propia around the vessels and with atrophy and ulceration if the epithelium.
Asunto(s)
Amiloidosis/diagnóstico , Enfermedades del Colon/diagnóstico , Colitis Ulcerosa/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , SigmoidoscopíaRESUMEN
Enfoca la problemática de la contaminación del agua en las comunidades rurales y la necesidad de contar con este recurso en condiciones sanitarias aceptables. Detalla el plan nacional de agua potable rural como solución al problema, señalando su origen, participación comunitaria, estructura del organismo rector, mecanismos que regirán la ejecución del plan nacional y su financiamiento. Muestra algunos resultados obtenidos a la fecha y la inversión total del programa
Asunto(s)
Argentina , Participación de la Comunidad , Contaminación del Agua , Agua PotableRESUMEN
Enfoca la problemática de la contaminación del agua en las comunidades rurales y la necesidad de contar con este recurso en condiciones sanitarias aceptables. Detalla el plan nacional de agua potable rural como solución al problema, señalando su origen, participación comunitaria, estructura del organismo rector, mecanismos que regirán la ejecución del plan nacional y su financiamiento. Muestra algunos resultados obtenidos a la fecha y la inversión total del programa
Asunto(s)
Argentina , Agua Potable , Participación de la Comunidad , Contaminación del AguaRESUMEN
The functional sequelae of 131 patients with urogenital tuberculosis were examined. At the time of diagnosis, more than half of the patients already suffered from global renal failure which was moderate in 42.7 per cent and severe in 15.5 per cent. We believe that the primary functional damage occurs at the medullary level with tubular and interstitial involvement. Indeed, the red phenol test for postglomerular blood flow was altered in a higher proportion than was the creatinine clearance (67.9 per cent). The maximum concentrating ability was altered even more frequently (84 per cent). When we compared various glomerular filtration levels with the grade of alteration of the maximum ability concentration test, we also saw clearly that the alteration of the tubular interstitial medullar function dominated the alteration of the glomerular global function. This proves at a functional level the predominantly medullary localization of the lesion in renal tuberculosis.