Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system Xc(-) cystine/glutamate exchanger.

The system xc(-) antiporter is a plasma membrane transporter that mediates the exchange of extracellular l-cystine with intracellular l-glutamate. This exchange is significant within the context of the CNS because the import of l-cystine is required for the synthesis of the antioxidant glutathione, while the efflux of l-glutamate has the potential to contribute to either excitatory signaling or excitotoxic pathology. Changes in the activity of the transport system have been linked to the underlying pathological mechanisms of a variety of CNS disorders, one of the most prominent of which is its highly enriched expression in glial brain tumors. In an effort to produce more potent system xc(-) blockers, we have been using amino-3-carboxy-5-methylisoxazole propionic acid (ACPA) as a scaffold for inhibitor development. We previously demonstrated that the addition of lipophilic aryl groups to either the #4 or #5 position on the isoxazole ring markedly increased the inhibitory activity at system xc(-). In the present work a novel series of analogues has been prepared in which aryl groups have been introduced at both the #4 and #5 positions. In contrast to the competitive action of the mono-substituted analogues, kinetic analyses indicate that the di-substituted isoxazoles block system xc(-)-mediated uptake of (3)H-l-glutamate into SNB-19 cells by a noncompetitive mechanism. These new analogues appear to be the first noncompetitive inhibitors identified for this transport system, as well as being among the most potent blockers identified to date. These diaryl-isoxazoles should be of value in assessing the physiological roles and molecular pharmacology of system xc(-).

Estudio clínico-histopatológico e histoquímico del Histiocitoma Fibroso Cutáneo Benigno / Clinical histopathological and histochemical study of Benign Cutaneous Fibrous Histiocytoma

El histiocitoma fibroso cutáneo benignoes un tumor mesenquimatoso frecuente que puede mostrar áreas de diferenciación miofibroblástica. Se lo clasificaba como reactivo o reparativo, pero anomalíascromosómicas en algunos casos, apoyan su naturalezaneoplásica benigna.Objetivo. Analizar la presentación clínico-dermatológica, histopatológica e histoquímica de los histiocitomas fibrosos cutáneos benignos.Diseño. Descriptivo, retrospectivo.Métodos. Se incluyeron 50 casos (N=50) de biopsiasescisionales de piel, con diagnóstico de histiocitoma fibroso, en pacientes de ambos sexos, mayores de 15años, entre el 209 y 2013. Se aplicaron marcacioneshistoquímicas especiales y se valoraron en cruces.Resultados. Los histiocitomas fibrosos se presentarongeneralmente en mujeres (64%), de entre 18 a 87 años.Las lesiones fueron únicas (90%) y se localizaron enextremidades (64%). La variante fibrocolágena fue la másobservada (56%). Las medidas reales del tumor fueronmenores a 0,5 cm (52%). La intensidad de lasmarcaciones citoquímicas para Ácido Periódico de Schif: 24+, Azul de Toluidina: 15 +, Tricrómico de Mason: 19 +.Conclusiones. En este estudio el histiocitoma fibrosocutáneo benigno se presentó como nódulofibrocolágeno, solitario, asintomático, menor a 1 cm.,con predominio de localización en extremidades y mayor frecuencia en el sexo femenino. Destacamos la importancia de los aportes en morfología y componentesintratumorales que otorga el empleo de técnicashistoquímicas para definir el correcto diagnóstico clínico dermatológico.

Background. Cutaneous benign fibrous histiocytoma is afrequent mesenchymal tumor, can also show areas ofmyofibroblastic diferentiation. It was clasifed as reactiveor eparative lesions, but chromosomal abnormalites insome cases, suports its benign neoplastic nature.Objetive. Analyze dermatological, histopathological andhistochemical presentation of cutaneous benign fibroushistiocytomas.Design. Descriptive and retrospective study.Methods. There were 50 cases (N = 50) of excisionaskin biopsy, with fibrous histiocytoma diagnosi, in patientsof both sexes, aged 15 years, betwen 209 and 2013.Special histochemical stains were aplied and evaluatedin croses.Results. The fibrous histiocytoma generaly presents inwomen (64%), beteen 18 to 87 years. The lesions wereunique (90%) and were located in the limbs (64%).Fibrocolagen variant was the most frequent (56%). Realmeasurements of the tumor were les than 0.5 cm (52%).The intensity of the cytochemical stains for Periodic AcidSchif were: 24 +, for Toluidine Blue: 15 +, for Mason'strichrome stain were: 19 + +.Conclusion. In this study cutaneous benign fibroushistiocytoma was presented as a fibrocolagenous solitaryasymptomatic nodule, les than 1 cm., with limbs locationpredominance and more frequently in females. Weemphasize the contributions in morphology andintratumoral components that he use of histochemicaltechniques provides to define the proper dermatologicaldiagnosis.

Estudio clínico-histopatológico e histoquímico del Histiocitoma Fibroso Cutáneo Benigno / Clinical histopathological and histochemical study of Benign Cutaneous Fibrous Histiocytoma

El histiocitoma fibroso cutáneo benignoes un tumor mesenquimatoso frecuente que puede mostrar áreas de diferenciación miofibroblástica. Se lo clasificaba como reactivo o reparativo, pero anomalíascromosómicas en algunos casos, apoyan su naturalezaneoplásica benigna.Objetivo. Analizar la presentación clínico-dermatológica, histopatológica e histoquímica de los histiocitomas fibrosos cutáneos benignos.Diseño. Descriptivo, retrospectivo.Métodos. Se incluyeron 50 casos (N=50) de biopsiasescisionales de piel, con diagnóstico de histiocitoma fibroso, en pacientes de ambos sexos, mayores de 15años, entre el 209 y 2013. Se aplicaron marcacioneshistoquímicas especiales y se valoraron en cruces.Resultados. Los histiocitomas fibrosos se presentarongeneralmente en mujeres (64%), de entre 18 a 87 años.Las lesiones fueron únicas (90%) y se localizaron enextremidades (64%). La variante fibrocolágena fue la másobservada (56%). Las medidas reales del tumor fueronmenores a 0,5 cm (52%). La intensidad de lasmarcaciones citoquímicas para Acido Periódico de Schif: 24+, Azul de Toluidina: 15 +, Tricrómico de Mason: 19 +.Conclusiones. En este estudio el histiocitoma fibrosocutáneo benigno se presentó como nódulofibrocolágeno, solitario, asintomático, menor a 1 cm.,con predominio de localización en extremidades y mayor frecuencia en el sexo femenino. Destacamos la importancia de los aportes en morfología y componentesintratumorales que otorga el empleo de técnicashistoquímicas para definir el correcto diagnóstico clínico dermatológico.(AU)

Background. Cutaneous benign fibrous histiocytoma is afrequent mesenchymal tumor, can also show areas ofmyofibroblastic diferentiation. It was clasifed as reactiveor eparative lesions, but chromosomal abnormalites insome cases, suports its benign neoplastic nature.Objetive. Analyze dermatological, histopathological andhistochemical presentation of cutaneous benign fibroushistiocytomas.Design. Descriptive and retrospective study.Methods. There were 50 cases (N = 50) of excisionaskin biopsy, with fibrous histiocytoma diagnosi, in patientsof both sexes, aged 15 years, betwen 209 and 2013.Special histochemical stains were aplied and evaluatedin croses.Results. The fibrous histiocytoma generaly presents inwomen (64%), beteen 18 to 87 years. The lesions wereunique (90%) and were located in the limbs (64%).Fibrocolagen variant was the most frequent (56%). Realmeasurements of the tumor were les than 0.5 cm (52%).The intensity of the cytochemical stains for Periodic AcidSchif were: 24 +, for Toluidine Blue: 15 +, for Masonstrichrome stain were: 19 + +.Conclusion. In this study cutaneous benign fibroushistiocytoma was presented as a fibrocolagenous solitaryasymptomatic nodule, les than 1 cm., with limbs locationpredominance and more frequently in females. Weemphasize the contributions in morphology andintratumoral components that he use of histochemicaltechniques provides to define the proper dermatologicaldiagnosis.(AU)

Interactions of griseofulvin with cyclodextrins in solid binary systems.

Griseofulvin/cyclodextrin interactions were investigated in aqueous environment and in solid state. Two cyclodextrin derivatives (beta-cyclodextrin and 2-hydroxypropyl beta-cyclodextrin) were used to prepare different physical mixtures and kneaded systems, and the drug/cyclodextrin ratios were 1:1 and 1:2 mol/mol. Scanning electron microscopy (SEM), hot-stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetry (TG), and X-ray powder diffractometry were employed to characterize pure substances and their kneaded counterparts and all of the binary systems. The solubility of griseofulvin was increased in accord with the quantity of cyclodextrin added. HSM examination revealed that 2-hydroxypropyl-beta-cyclodextrin was dissolved in the droplets of melted griseofulvin, but did not show any interactions between melted griseofulvin and beta-cyclodextrin particles. The presence of griseofulvin endothermic peak in the DSC curves of all binary systems suggests the absence of any griseofulvin/cylcodextrin inclusion compound in the solid state. In TG, data of weight loss owing to the dehydration of cyclodextrins was similar for both kneaded systems and physical mixtures. X-ray diffraction patterns exhibited the amorphous nature of 2-hydroxypropyl-beta-cyclodextrin and the crystalline nature of griseofulvin and binary systems. Griseofulvin dissolution profiles from all binary systems showed an improvement in drug dissolution, which indicates that an "in situ" drug/cyclodextrin inclusion compound was formed in the aqueous dissolution medium.

Dorsal midbrain syndrome due to mesencephalic hemorrhage. Case report with serial imaging.

Spontaneous, nontraumatic, nonhypertensive, midbrain hemorrhage is an uncommon cause of the dorsal midbrain syndrome. We describe a patient with this syndrome in whom the initial neuroimaging studies failed to clearly identify the lesion. Subsequent magnetic resonance imaging studies disclosed a dorsal midbrain hemorrhage. The patient experienced gradual spontaneous resolution of her dorsal midbrain signs and symptoms over several months. The evolution on serial neuroimaging studies of the dorsal midbrain hemorrhage in this patient is described.

MR susceptometry: an external-phantom method for measuring bulk susceptibility from field-echo phase reconstruction maps.

A novel method for estimating the susceptibility of an object by using the magnetic resonance (MR) imaging field distortions in an external-reference water bath next to the object is described. The field measurement was obtained with a phase reconstruction from a gradient-echo acquisition. A field model of an arbitrary object in a static magnetic field was discretely calculated from geometry determined from the magnitude reconstruction. Least-squares estimation yields the susceptibility of the object. Required (and proven) assumptions include validity of superposition, object homogeneity, negligible higher-order field terms, field-model accuracy, geometric-model accuracy, and correlation of gradient-echo phase to field distortion. MR susceptometry estimation of phantoms yielded susceptibility estimates that correlated well with known values (r > .9975). This MR susceptometry method is a first step toward quantitation of iron levels through MR imaging phase information in patients with iron overload.

MR of ballistic materials: imaging artifacts and potential hazards.

The most common ballistic materials available in the urban setting were studied for their MR effects on deflection force, rotation, heating, and imaging artifacts at 1.5 T to determine the potential efficacy and safety for imaging patients with ballistic injuries. The 28 missiles tested covered the range of bullet types and materials suggested by the Cleveland Police Department. The deflection force was measured by the New method. Rotation was evaluated 30 min after bullets had been placed in a 10% (weight per weight) ballistic gelatin designed to simulate brain tissue, with the long axis of the bullet placed parallel and perpendicular to the Z axis of the magnet. Heating was measured with alcohol thermometers by imaging for 1 hr alternatively with gradient-echo and spin-echo sequences (RF absorption = 0.033 and 0.326 w/kg respectively). Image artifacts on routine sequences were evaluated. All the steel-containing bullets except for the Winchester armor-piercing 38 caliber exhibited deflection. A nonsteel 7.38-mm Mauser also deflected. Deflection range was 514 to 15,504 dynes. Rotation occurred when the bullets were not parallel to the Z axis. Temperature changes were not significant. Deflecting projectiles resulted in obliteration of the image. The artifacts from other projectiles were small but varied by content. The artifact of the Winchester armor-piercing 38-caliber bullet was similar to those without steel. Bullets that contain steel or ferromagnetic contaminates such as nickel can be rotated within the MR unit.(ABSTRACT TRUNCATED AT 250 WORDS)

Intercalated discs as a cause for discontinuous propagation in cardiac muscle: a theoretical simulation.

A theoretical model of a cardiac muscle fiber (strand) based on core conductor principles and which includes a periodic intercalated disc structure has been developed. The model allows for examination of the mechanism of electrical propagation in cardiac muscle on a microscopic cell-to-cell level. The results of the model simulations demonstrate the discontinuous nature of electrical propagation in cardiac muscle and the inability of classical continuous cable theory to adequately describe propagation phenomena in cardiac muscle.