RESUMEN
BACKGROUND AND PURPOSE: Intra-arterial thrombolytics may be used to treat distal vessel occlusions, which cause incomplete reperfusion following mechanical thrombectomy. Because immediate reperfusion after intra-arterial thrombolytics occurs rarely, the aim of this study was to assess the delayed effect of intra-arterial thrombolytics using follow-up perfusion imaging. MATERIALS AND METHODS: We included patients from a prospective stroke registry (February 2015 to September 2022) who had undergone mechanical thrombectomy and had incomplete reperfusion (expanded TICI 2a-2c) and available 24 hour perfusion imaging. Perfusion imaging was rated as delayed reperfusion if time-sensitive perfusion maps did not show wedge-shaped delays suggestive of persisting occlusions corresponding to the post-mechanical thrombectomy angiographic deficit. Patients treated with intra-arterial thrombolytics were compared with controls using multivariable logistic regression and inverse probability of treatment weighting matching for baseline differences and factors associated with delayed reperfusion. RESULTS: The median age of the final study population (n = 459) was 74 years (interquartile range, 63-81 years), and delayed reperfusion occurred in 61% of cases. Patients treated with additional intra-arterial thrombolytics (n = 40) were younger and had worse expanded TICI scores. After matching was performed, intra-arterial thrombolytics was associated with higher rates of delayed reperfusion (adjusted OR = 2.7; 95% CI, 1.1-6.4) and lower rates of new infarction in the residually hypoperfused territory after mechanical thrombectomy (adjusted OR = 0.3; 95% CI, 0.1-0.7). No difference was found in the rates of functional independence (90-day mRS, 0-2; adjusted OR = 1.4; 95% CI, 0.4-4.1). CONCLUSIONS: Rescue intra-arterial thrombolytics is associated with delayed reperfusion of remaining vessel occlusions following incomplete mechanical thrombectomy. The value of intra-arterial thrombolytics as a potential therapy for incomplete reperfusions after mechanical thrombectomy should be assessed in the setting of randomized controlled trials.
Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Resultado del Tratamiento , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/cirugía , Trombectomía/métodos , Fibrinolíticos/uso terapéutico , Reperfusión/métodos , Terapia Trombolítica , Isquemia Encefálica/terapia , Estudios RetrospectivosRESUMEN
BACKGROUND: Combination of temozolomide (TMZ) with nonpegylated interferon alfa is associated with increased efficacy in terms of response rates compared with monotherapy. A multicenter phase II study was carried out to assess the activity and toxicity of TMZ plus pegylated interferon alfa-2b (peg-IFNalpha-2b), hypothesizing improved efficacy due to modified pharmacokinetic properties of the novel interferon (IFN) formulation. PATIENTS AND METHODS: In all, 124 patients with stage IV melanoma without prior chemotherapy and no cerebral metastases were treated with 100 mug peg-IFNalpha-2b s.c. per week and oral TMZ 200 mg/m(2) (days 1-5, every 28 days). Primary study end point was objective response, and secondary end points were overall and progression-free survival (PFS) and safety. RESULTS: In all, 116 patients were assessable for response: 2 (1.7%) had a complete response and 19 (16.4%) a partial response (overall response rate 18.1%). Of total, 25.0% achieved disease stabilization and 56.9% progressed. Overall survival was 9.4 months; PFS was 2.8 months. Grade 3/4 thrombocytopenia occurred in 20.7% and grade 3/4 leukopenia in 23.3%. CONCLUSIONS: The efficacy of TMZ plus peg-IFNalpha-2b in this large phase II study is moderate and comparable to published results of the combination of TMZ with non-peg-IFN. Likewise, the safety profile of peg-IFNalpha-2b seems to be similar to non-peg-IFN when combined with TMZ.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/secundario , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Adulto , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/análogos & derivados , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Polietilenglicoles , Estudios Prospectivos , Proteínas Recombinantes , Temozolomida , Resultado del TratamientoRESUMEN
Incubation of striatal synaptosomes with the oxygen radical generating enzyme, xanthine oxidase, decreased [3H]dopamine uptake: an effect attributable to a decreased Vmax. Concurrent incubation with the superoxide radical scavenger, superoxide dismutase, abolished the xanthine oxidase-induced decrease. These results indicate that, like methamphetamine administration in vivo, reactive oxygen species diminish dopamine transporter function in vitro. The significance of these findings to mechanisms responsible for effects of methamphetamine is discussed.
Asunto(s)
Cuerpo Estriado/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Dopamina/metabolismo , Metanfetamina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismo , Xantina Oxidasa/metabolismoRESUMEN
Methamphetamine-induced 5-hydroxytryptaminergic neuronal damage purportedly involves transport of newly released dopamine from extracellular spaces into 5-hydroxytryptaminergic terminals. This hypothesis is based primarily on findings that dopamine is required for, whereas 5-hydroxytryptamine (5-HT) uptake inhibitors prevent, methamphetamine-induced deficits in 5-hydroxytryptaminergic neuronal function. This hypothesis is not, however, supported by findings presented in this study that 5-hydroxytryptaminergic neuronal damage, induced by p-chloroamphetamine, does not decrease [3H]dopamine uptake into rat brain synaptosomes prepared from 5-HT-transporter-containing tissue. Moreover, despite having greater affinity for the 5-HT transporter, citalopram has an IC50 for [1H]dopamine transport into these synaptosomal preparations that is considerably greater than that of fluoxetine. These data suggest that 5-HT transporters may not effect dopamine uptake and thereby methamphetamine-induced 5-hydroxytryptaminergic neuronal damage. Other possible mechanisms related to 5-HT uptake inhibitor attenuation of methamphetamine-induced deficits were investigated. Fluoxetine pretreatment prevented the methamphetamine-induced decrease in tryptophan hydroxylase activity: this effect cannot be attributed to altered body temperatures or brain concentrations of methamphetamine which suggests that neither, per se, is sufficient to impair 5-hydroxytryptaminergic neuronal function.
Asunto(s)
Proteínas Portadoras/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Inhibidores de Captación de Dopamina/farmacología , Fluoxetina/farmacología , Glicoproteínas de Membrana/efectos de los fármacos , Proteínas de Transporte de Membrana , Metanfetamina/farmacología , Proteínas del Tejido Nervioso , Triptófano Hidroxilasa/efectos de los fármacos , Animales , Proteínas Portadoras/metabolismo , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Hipocampo/efectos de los fármacos , Masculino , Glicoproteínas de Membrana/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Triptófano Hidroxilasa/metabolismo , Corteza Visual/efectos de los fármacos , Corteza Visual/metabolismoRESUMEN
Microcomputed tomography (microCT) is widely used for nondestructive bone phenotyping in small animals, especially in the mouse. Here, we investigated the reproducibility and resolution dependence of microCT analysis of microstructural parameters in three different compartments in the mouse femur. Reproducibility was assessed with respect to precision error (PE%CV) and intraclass correlation coefficient (ICC). We examined 14 left femurs isolated postmortem from two strains of mice (seven per group). Measurements and analyses were repeated five times on different days. In a second step, analysis was repeated again five times for a single measurement. Resolution dependence was assessed by high-resolution measurements (10 microm) in one strain and subsequent image degrading. Reproducibility was better in full bone compartment and in cortical bone compartment in the diaphysis (PE%CV = 0.06-2.16%) than in trabecular compartment in the distal metaphysis (PE(%CV) = 0.59-5.24%). Nevertheless, ICC (0.92-1.00) showed a very high reliability of the assessed parameters in all regions, indicating very small variances within repeated measurements compared to the population variances. Morphometric indices computed from lower- and higher-resolution images displayed in general only weak dependence and were highly correlated with each other (R2 = 0.91-0.99). The results show that parameters in the full and cortical compartments were very reproducible, whereas precision in the trabecular compartment was somewhat lower. Nevertheless, all compartmental analysis methods were very robust, as shown by the high ICC values, demonstrating high suitability for application in inbred strains, where highest precision is needed due to small population variances.
Asunto(s)
Fémur/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Animales , Densidad Ósea/fisiología , Femenino , Fémur/metabolismo , Procesamiento de Imagen Asistido por Computador , Imagenología Tridimensional , Ratones , Ratones Endogámicos , Reproducibilidad de los Resultados , Especificidad de la Especie , Tomografía Computarizada por Rayos X/instrumentaciónRESUMEN
Cutaneous T-cell lymphoma represent a heterogeneous group of diseases characterized by skin invasion of monoclonal T-lymphocytes. These cutaneous T-cell lymphomas are divided into 3 groups based on clinical, histological and immunohistological characteristics: Indolent with a survival time of over 10 years, aggressive with a survival time less than 10 years and provisional (EORTC classification). Standard treatments such as PUVA, total skin electron beam, methotrexate, polychemotherapy regimens, retinoids and photopheresis have been used for years. Bexarotene is a newly registered drug. To achieve better response rates, several new drugs are being evaluated in clinical trails, including imiquimod, denileukon-diftitox, liposomal doxorubicin, adeno-interferon-gamma and various combination approaches.
Asunto(s)
Linfoma de Células T/terapia , Neoplasias Cutáneas/terapia , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Aminoquinolinas/uso terapéutico , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/uso terapéutico , Anticarcinógenos/administración & dosificación , Anticarcinógenos/uso terapéutico , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bexaroteno , Clorambucilo/administración & dosificación , Clorambucilo/uso terapéutico , Ensayos Clínicos como Asunto , Ciclofosfamida/uso terapéutico , Doxorrubicina/administración & dosificación , Doxorrubicina/uso terapéutico , Humanos , Imiquimod , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/uso terapéutico , Linfoma de Células T/clasificación , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/mortalidad , Linfoma de Células T/radioterapia , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Terapia PUVA , Fotoféresis , Prednisona/uso terapéutico , Teleterapia por Radioisótopo , Dosificación Radioterapéutica , Radioterapia de Alta Energía , Proteínas Recombinantes , Retinoides/administración & dosificación , Retinoides/uso terapéutico , Neoplasias Cutáneas/clasificación , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/radioterapia , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/uso terapéutico , Vincristina/uso terapéuticoRESUMEN
Cutaneous lymphomas are uncommon. They must be distinguished from secondary skin manifestations of primary nodal lymphomas. Primary cutaneous lymphomas are divided into B-cell- and T-cell cutaneous lymphoma and commonly have good prognosis. Therapy is based on the stage of the disease. Since cure is not possible, the aim of treatment is to control the disease and reduce symptoms. A variety of new and promising therapeutic modalities have been introduced in recent years.
Asunto(s)
Linfoma de Células B/diagnóstico , Linfoma Cutáneo de Células T/diagnóstico , Neoplasias Cutáneas/diagnóstico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biopsia , Terapia Combinada , Diagnóstico Diferencial , Humanos , Linfoma de Células B/clasificación , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Linfoma Cutáneo de Células T/clasificación , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Estadificación de Neoplasias , Pronóstico , Piel/patología , Neoplasias Cutáneas/clasificación , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
The skin is the organ most commonly affected by malignancies. Various cancers of the skin show a dramatic increase in incidence over the last decades. Epithelial skin tumors are most frequently, e.g., basal cell carcinoma and the squamous cell carcinoma with its precursors, the actinic keratoses. Melanoma, which is extremely difficult to treat in advanced tumor stages, is dreaded. Besides that, there are other epithelial malignant diseases, e.g. Morbus Bowen and adnexal tumors originating from the skin appendices. Mesenchymal malignant neoplasias such as Morbus Kaposi, angiosarcomas and other dermal sarcomas, are rare. Since the majority of malignant neoplasms is removable and curable by a simple surgical intervention, the knowledge of the different skin tumors is essential for non-dermatologist.
Asunto(s)
Carcinoma Basocelular , Carcinoma de Células Escamosas , Melanoma , Neoplasias Cutáneas , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/uso terapéutico , Aminoquinolinas/administración & dosificación , Aminoquinolinas/uso terapéutico , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Biopsia , Enfermedad de Bowen/diagnóstico , Enfermedad de Bowen/tratamiento farmacológico , Enfermedad de Bowen/radioterapia , Enfermedad de Bowen/cirugía , Carcinoma Basocelular/diagnóstico , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/radioterapia , Carcinoma Basocelular/cirugía , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/cirugía , Carcinoma de Células de Merkel/terapia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirugía , Ensayos Clínicos como Asunto , Terapia Combinada , Crioterapia , Diagnóstico Diferencial , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Infecciones por VIH/complicaciones , Hemangiosarcoma/diagnóstico , Humanos , Imiquimod , Inmunoterapia , Queratosis/diagnóstico , Queratosis/tratamiento farmacológico , Queratosis/cirugía , Escisión del Ganglio Linfático , Metástasis Linfática , Linfoma/clasificación , Linfoma/diagnóstico , Linfoma/tratamiento farmacológico , Linfoma/radioterapia , Linfoma/cirugía , Masculino , Melanoma/diagnóstico , Melanoma/tratamiento farmacológicoRESUMEN
Salicylate is a precursor of pyochelin in Pseudomonas aeruginosa and both compounds display siderophore activity. To elucidate the salicylate biosynthetic pathway, we have cloned and sequenced a chromosomal region of P. aeruginosa PAO1 containing two adjacent genes, designated pchB and pchA, which are necessary for salicylate formation. The pchA gene encodes a protein of 52 kDa with extensive similarity to the chorismate-utilizing enzymes isochorismate synthase, anthranilate synthase (component I) and p-aminobenzoate synthase (component I), whereas the 11 kDa protein encoded by pchB does not show significant similarity with other proteins. The pchB stop codon overlaps the presumed pchA start codon. Expression of the pchA gene in P. aeruginosa appears to depend on the transcription and translation of the upstream pchB gene. The pchBA genes are the first salicylate biosynthetic genes to be reported. Salicylate formation was demonstrated in an Escherichia coli entC mutant lacking isochorismate synthase when this strain expressed both the pchBA genes, but not when it expressed pchB alone. By contrast, an entB mutant of E. coli blocked in the conversion of isochorismate to 2,3-dihydro-2,3-dihydroxybenzoate formed salicylate when transformed with a pchB expression construct. Salicylate formation could also be demonstrated in vitro when chorismate was incubated with a crude extract of P. aeruginosa containing overproduced PchA and PchB proteins; salicylate and pyruvate were formed in equimolar amounts. Furthermore, salicylate-forming activity could be detected in extracts from a P. aeruginosa pyoverdin-negative mutant when grown under iron limitation, but not with iron excess. Our results are consistent with a pathway leading from chorismate to isochorismate and then to salicylate plus pyruvate, catalyzed consecutively by the iron-repressible PchA and PchB proteins in P. aeruginosa.
Asunto(s)
Proteínas Bacterianas/genética , Ácido Corísmico/metabolismo , Genes Bacterianos , Transferasas Intramoleculares , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/metabolismo , Salicilatos/metabolismo , Secuencia de Aminoácidos , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Secuencia de Bases , Clonación Molecular , Cinética , Datos de Secuencia Molecular , Mutagénesis , Mutagénesis Insercional , Piruvatos/metabolismo , Proteínas Recombinantes/metabolismo , Mapeo Restrictivo , Homología de Secuencia de AminoácidoRESUMEN
Mesenchymal tumors are a heterogeneous group of tumors often arising in the skin and soft tissue. The tumors have been reclassified by the WHO in 2002. Benign mesenchymal tumors are about a hundred times more frequent than malignant mesenchymal tumors. Clinically, mesenchymal tumors often present as skin-colored nodes. Overall, elderly persons are more affected than younger individuals. The etiology is often unknown, sometimes there is an association with insults such as radiation, scars, or lymphedematous or venous stasis. Whereas some years ago a wide excision with a margin of 3-5 cm was performed for malignant variants, today micrographic surgery is preferred, as it can avoid mutilating procedures. Early detection and removal is critical since mesenchymal skin tumors often cannot be cured by radiation or chemotherapy.
Asunto(s)
Neoplasias Mesoteliales/clasificación , Sarcoma/clasificación , Neoplasias Cutáneas/clasificación , Neoplasias de los Tejidos Blandos/clasificación , Organización Mundial de la Salud , Humanos , Cirugía de Mohs , Neoplasias Mesoteliales/diagnóstico , Neoplasias Mesoteliales/cirugía , Sarcoma/diagnóstico , Sarcoma/cirugía , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/cirugía , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/cirugíaRESUMEN
The high-affinity siderophore salicylate is an intermediate in the biosynthetic pathway of pyochelin, another siderophore and chelator of transition metal ions, in Pseudomonas aeruginosa. The 2.5-kb region upstream of the salicylate biosynthetic genes pchBA was sequenced and found to contain two additional, contiguous genes, pchD and pchC, having the same orientation. The deduced amino acid sequence of the 60-kDa PchD protein was similar to those of the EntE protein (2,3-dihydroxybenzoate-AMP ligase) of Escherichia coli and other adenylate-forming enzymes, suggesting that salicylate might be adenylated at the carboxyl group by PchD. The 28-kDa PchC protein showed similarities to thioesterases of prokaryotic and eukaryotic origin and might participate in the release of the product(s) formed from activated salicylate. One potential product, dihydroaeruginoate (Dha), was identified in culture supernatants of iron-limited P. aeruginosa cells. The antifungal antibiotic Dha is thought to arise from the reaction of salicylate with cysteine, followed by cyclization of cysteine. Inactivation of the chromosomal pchD gene by insertion of the transcription and translation stop element omega Sm/Sp abolished the production of Dha and pyochelin, implying that PchD-mediated activation of salicylate may be a common first step in the synthesis of both metabolites. Furthermore, the pchD::omega Sm/Sp mutation had a strong polar effect on the expression of the pchBA genes, i.e., on salicylate synthesis, indicating that the pchDCBA genes constitute a transcriptional unit. A full-length pchDCBA transcript of ca. 4.4 kb could be detected in iron-deprived, growing cells of P. aeruginosa. Transcription of pchD started at tandemly arranged promoters, which overlapped with two Fur boxes (binding sites for the ferric uptake regulator) and the promoter of the divergently transcribed pchR gene encoding an activator of pyochelin biosynthesis. This promoter arrangement allows tight iron-mediated repression of the pchDCBA operon.
Asunto(s)
Hierro/fisiología , Operón/genética , Fenoles/metabolismo , Pseudomonas aeruginosa/genética , Tiazoles/metabolismo , Secuencia de Aminoácidos , Proteínas Bacterianas/genética , Composición de Base , Secuencia de Bases , Genes Bacterianos/genética , Hierro/farmacología , Modelos Químicos , Datos de Secuencia Molecular , Pseudomonas aeruginosa/metabolismo , ARN Bacteriano/análisis , ARN Mensajero/análisis , Mapeo Restrictivo , Salicilatos/metabolismo , Ácido Salicílico , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Sideróforos/metabolismo , Transcripción Genética/efectos de los fármacos , Transcripción Genética/genéticaRESUMEN
The global activator GacA, a highly conserved response regulator in Gram-negative bacteria, is required for the production of exoenzymes and secondary metabolites in Pseudomonas spp. The gacA gene of Pseudomonas aeruginosa PAO1 was isolated and its role in cell-density-dependent gene expression was characterized. Mutational inactivation of gacA resulted in delayed and reduced formation of the cell-density signal N-butyryl-L-homoserine lactone (BHL), of the cognate transcriptional activator RhIR (VsmR), and of the transcriptional activator LasR, which is known to positively regulate RhIR expression. Amplification of gacA on a multicopy plasmid caused precocious and enhanced production of BHL, RhIR and LasR. In parallel, the gacA gene dosage markedly influenced the BHL/RhIR-dependent formation of the cytotoxic compounds pyocyanin and cyanide and the exoenzyme lipase. However, the concentrations of another known cell-density signal of P. aeruginosa, N-oxododecanoyl-L-homoserine lactone, did not always match BHL concentrations. A model accounting for these observations places GacA function upstream of LasR and RhIR in the complex, cell-density-dependent signal-transduction pathway regulating several exoproducts and virulence factors of P. aeruginosa via BHL.