RESUMEN
A preterm baby boy was born in good condition at 31+5 weeks gestation with a birth weight of 1956 g, following a precipitous labour with no prolonged rupture of membranes and no opportunity for administration of antenatal steroids to mother. Following admission to the neonatal unit, he developed respiratory distress and was commenced on nasal continuous positive airway pressure (CPAP) of 6 cm of water. At 24 hours of age, he developed a left-sided tension pneumothorax (figure 1), requiring endotracheal intubation and insertion of a chest drain. He received two doses of surfactant and was extubated onto CPAP on day 3. There was reaccumulation of the pneumothorax on day 4, which was subsequently drained. He remained self-ventilating in air in the second week of life. From day 15 to day 30, he required humidified high flow nasal cannula oxygen (fractional inspired oxygen up to 0.4), in view of marked subcostal and intercostal recession, intolerance to handling and a compensated respiratory acidosis on capillary blood gases. Figure 2 is the chest radiograph undertaken in the third week of life.
Asunto(s)
Neumotórax , Síndrome de Dificultad Respiratoria del Recién Nacido , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Masculino , Neumotórax/diagnóstico , Neumotórax/terapia , Embarazo , Enfisema Pulmonar , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Síndrome de Dificultad Respiratoria del Recién Nacido/etiología , Síndrome de Dificultad Respiratoria del Recién Nacido/terapiaRESUMEN
The current study sought to evaluate the validity and reliability of a brief measure of overall functioning for adolescents. Clinicians were asked to complete the Overall Functioning Scale (OFS) for 72 adolescents consecutively admitted to the adolescent psychiatric inpatient service of a community safety net medical center. The results revealed that this new measure is related to the patients' length of stay, clinician-rated measures of social cognition and object relations, Global Assessment of Functioning (GAF) score at admission, as well as global rating of engagement in individual psychotherapy. The results also showed that the OFS was related to the patients' history of nonsuicidal self-harm as well as treatment outcome as assessed by measures of psychological health and well-being as well as symptoms. Hierarchical regressions reveal that the OFS shows incremental validity greater than the admission GAF score in predicting length of stay. The results also showed that the OFS demonstrates interrater reliability in the excellent range (intraclass correlation coefficient(1,2)) of 0.88. Clinical implications of the use of this tool and areas of future research are discussed.
Asunto(s)
Conducta del Adolescente/psicología , Pacientes Internos/psicología , Servicio de Psiquiatría en Hospital/normas , Escalas de Valoración Psiquiátrica/normas , Adolescente , Adulto , Femenino , Humanos , Masculino , Servicio de Psiquiatría en Hospital/tendencias , Reproducibilidad de los ResultadosRESUMEN
Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.
Asunto(s)
Apoptosis , Resistencia a Antineoplásicos , Factor 4E Eucariótico de Iniciación/metabolismo , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/patología , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/metabolismo , Transducción de Señal , Animales , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Progresión de la Enfermedad , Factor 4E Eucariótico de Iniciación/genética , Factor 4G Eucariótico de Iniciación/metabolismo , Femenino , Linfoma de Células B/metabolismo , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Inhibidores de Proteínas Quinasas , Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoAsunto(s)
Enfermedades del Recién Nacido , Parotiditis , Infecciones Estafilocócicas , Lactante , Recién Nacido , Humanos , Recien Nacido Prematuro , Parotiditis/diagnóstico por imagen , Parotiditis/tratamiento farmacológico , Antibacterianos/uso terapéutico , Infecciones Estafilocócicas/tratamiento farmacológico , Enfermedades del Recién Nacido/tratamiento farmacológico , SupuraciónAsunto(s)
Seno Pericraneal , Senos Craneales , Cabello , Humanos , Recién Nacido , Cuero Cabelludo , Seno Pericraneal/diagnóstico por imagen , CráneoRESUMEN
The major component of the epidermis, keratinocytes, must continuously proliferate and differentiate to form the mechanical and water permeability barrier of the skin. Our previous data have suggested a potential role in these processes for phospholipase D (PLD), an enzyme that hydrolyzes phospholipids to generate phosphatidic acid. In the presence of primary alcohols, PLD also catalyzes a transphosphatidylation reaction to produce phosphatidylalcohols, and this characteristic has been exploited to monitor the activity of PLD in intact cells. In this report, PLD was demonstrated to utilize the physiological alcohol glycerol to form phosphatidylglycerol (PG) in vitro. In intact primary murine epidermal keratinocytes treated for 24 h with elevated extracellular Ca(2+) levels, but not 1,25-dihydroxyvitamin D(3), incubation with radioactive glycerol resulted in an increase in PLD-mediated radiolabeled PG production. This effect was dose-dependent and biphasic, with maximal PG formation detected after exposure to an intermediate (125 microM) Ca(2+) concentration. Furthermore, the biphasic nature of the response was due, in part, to a corresponding biphasic change in glycerol uptake. Finally, short-term treatment of keratinocytes with phorbol 12-myristate 13-acetate (PMA) failed to increase PG synthesis and inhibited glycerol uptake. Since (1) PMA is reported to activate PLD-1 to a greater extent than PLD-2, (2) 1,25-dihydroxyvitamin D(3) increases the expression/activity of PLD-1 in keratinocytes, and (3) PLD-2 is co-localized with a glycerol channel in keratinocyte membrane microdomains, we speculate that radiolabeled PG production from radioactive glycerol is a measure of PLD-2 activation in these cells. Our results also suggest that PLD-mediated PG synthesis may be regulated at the level of both PLD activity and alcohol substrate availability via changes in glycerol uptake.
Asunto(s)
Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Fosfatidilgliceroles/biosíntesis , Fosfolipasa D/metabolismo , Animales , Calcitriol/farmacología , Calcio/farmacología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Células Epidérmicas , Glicerol/metabolismo , Queratinocitos/enzimología , Ratones , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
Diseased skin often exhibits a deregulated program of the keratinocyte maturation necessary for epidermal stratification and function. Protein kinase D (PKD), a serine/threonine kinase, is expressed in proliferating keratinocytes, and PKD activation occurs in response to mitogen stimulation in other cell types. We have proposed that PKD functions as a pro-proliferative and/or anti-differentiative signal in keratinocytes and hypothesized that differentiation inducers will downmodulate PKD to allow differentiation to proceed. Thus, changes in PKD levels, autophosphorylation, and activity were analyzed upon stimulation of differentiation and proliferation in primary mouse keratinocytes. Elevated extracellular calcium and acute 12-O-tetradecanoylphorbol-13-acetate (TPA) treatments induced differentiation and triggered a downmodulation of PKD levels, autophosphorylation at serine 916, and activity. Chronic TPA treatment stimulated proliferation and resulted in a recovery of PKD levels, autophosphorylation, and activity. Immunohistochemical analysis demonstrated PKD localization predominantly in the proliferative basal layer of mouse epidermis. Co-expression studies revealed a pro-proliferative, anti-differentiative effect of PKD on keratinocyte maturation as monitored by increased and decreased promoter activities of keratin 5, a proliferative marker, and involucrin, a differentiative marker, respectively. This work describes the inverse regulation of PKD during keratinocyte differentiation and proliferation and the pro-proliferative/anti-differentiative effects of PKD co-expression on keratinocyte maturation.
Asunto(s)
Queratinocitos/citología , Queratinocitos/enzimología , Proteína Quinasa C/metabolismo , Animales , Animales Recién Nacidos , Especificidad de Anticuerpos , Células COS , Calcitriol/farmacología , Calcio/farmacología , Agonistas de los Canales de Calcio/farmacología , Carcinógenos/farmacología , Diferenciación Celular/fisiología , División Celular/fisiología , Chlorocebus aethiops , Espacio Extracelular/efectos de los fármacos , Queratina-15 , Queratina-5 , Queratinocitos/efectos de los fármacos , Queratinas/genética , Ratones , Ratones Endogámicos ICR , Fosforilación , Regiones Promotoras Genéticas/fisiología , Proteína Quinasa C/genética , Proteína Quinasa C/inmunología , Precursores de Proteínas/genética , Acetato de Tetradecanoilforbol/farmacología , Transglutaminasas/metabolismoAsunto(s)
Proteína C-Reactiva/análisis , Fluconazol/administración & dosificación , Enfermedades Renales , Micosis , Sepsis Neonatal/diagnóstico , Ultrasonografía/métodos , Antifúngicos/administración & dosificación , Femenino , Humanos , Recién Nacido , Recien Nacido Prematuro , Enfermedades Renales/sangre , Enfermedades Renales/diagnóstico , Enfermedades Renales/tratamiento farmacológico , Micosis/sangre , Micosis/diagnóstico , Micosis/tratamiento farmacológico , Resultado del TratamientoAsunto(s)
Cistoscopía/métodos , Riñón/diagnóstico por imagen , Riñón Displástico Multiquístico/diagnóstico por imagen , Micción/fisiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Riñón Displástico Multiquístico/patología , Riñón Displástico Multiquístico/cirugía , Guías de Práctica Clínica como Asunto , Valor Predictivo de las Pruebas , Procedimientos Quirúrgicos UrológicosAsunto(s)
Quistes/patología , Hipospadias/diagnóstico , Enfermedades del Pene/congénito , Pene/patología , Enfermedades Uretrales/congénito , Tratamiento Conservador/métodos , Humanos , Recién Nacido , Masculino , Enfermedades del Pene/patología , Resultado del Tratamiento , Enfermedades Uretrales/patologíaRESUMEN
Targeted cancer therapies exploit the continued dependence of cancer cells on oncogenic mutations. Such agents can have remarkable activity against some cancers, although antitumor responses are often heterogeneous, and resistance remains a clinical problem. To gain insight into factors that influence the action of a prototypical targeted drug, we studied the action of imatinib (STI-571, Gleevec) against murine cells and leukemias expressing BCR-ABL, an imatinib target and the initiating oncogene for human chronic myelogenous leukemia (CML). We show that the tumor suppressor p53 is selectively activated by imatinib in BCR-ABL-expressing cells as a result of BCR-ABL kinase inhibition. Inactivation of p53, which can accompany disease progression in human CML, impedes the response to imatinib in vitro and in vivo without preventing BCR-ABL kinase inhibition. Concordantly, p53 mutations are associated with progression to imatinib resistance in some human CMLs. Our results identify p53 as a determinant of the response to oncogene inhibition and suggest one way in which resistance to targeted therapy can emerge during the course of tumor evolution.
Asunto(s)
Proteínas de Fusión bcr-abl/metabolismo , Leucemia/metabolismo , Leucemia/patología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Benzamidas , Línea Celular Tumoral , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Trasplante de Células Madre Hematopoyéticas , Humanos , Mesilato de Imatinib , Leucemia/tratamiento farmacológico , Leucemia/genética , Ratones , Ratones Noqueados , Mutación/genética , Trasplante de Neoplasias , Piperazinas/farmacología , Pirimidinas/farmacología , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Much data in the literature suggest a role for protein kinase C (PKC) in regulating keratinocyte proliferation and differentiation. Nevertheless, the exact role of this family of isoenzymes is unclear, since PKC agonists (e.g., phorbol esters) are known to stimulate expression of both proliferative and differentiative markers in keratinocytes. Similarly, PKC inhibitors have been demonstrated both to inhibit [2-[1-3(aminopropyl)indol-3-yl]-3(1-methyl-1H-indol-3-yl)maleimide, acetate (Ro 31-7549) and 3-[1-[3-(amidinothio)propyl-1H-indol-3-(1-methyl-1H-indol-3yl) maleimide (Ro 31-8220)] and to induce (staurosporine) keratinocyte differentiation. In this study, we examined the role of the PKC inhibitor, Gödecke 6976 (Gö6976) [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo (3,4-c)-carbazole], on keratinocyte proliferation, as measured by DNA synthesis, and differentiation, as monitored by transglutaminase activity. This compound is reported to be selective for the conventional PKC isoforms, of which keratinocytes express only PKCalpha, and for protein kinase D (PKD; also known as PKCmu). We report that Gö6976 stimulated transglutaminase activity. Consistent with this effect, Gö6976 also potently inhibited [(3)H]thymidine incorporation (a half-maximal inhibitory concentration of approximately 0.1 microM). In addition, Gö6976 (1 microM) was able to enhance the stimulation of transglutaminase activity by 1,25-dihydroxyvitamin D(3) but had no effect on D(3)-induced expression of keratin-1. Conversely, Gö6983 [2-[1-(3-dimethylaminopropy)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl)maleimide], a similar compound that also selectively inhibits conventional PKCalpha, but not PKD, had little or no effect on DNA synthesis or transglutaminase activity (up to 1 microM). The effect of Gö6976 was not due to cytotoxicity as its effect on thymidine incorporation was largely reversible, and its stimulation of transglutaminase activity could be inhibited by another general PKC inhibitor, bisindolylmaleimide I. Therefore, our results suggest a proproliferative, antidifferentiative role for PKD in epidermal maturation.