RESUMEN
PURPOSE: The purpose of this study is to describe current survivor services provided by COG institutions. METHODS: A 190-question online survey was distributed to 209 COG member institutions over a 5-month period in 2017. Descriptive statistics were used to describe survivor services and explore their changes between 2007 and 2017. RESULTS: Representatives from 153 (73%) institutions completed the survey. Of these, 96% of institutions reported that they provide pediatric cancer survivor care either in a specialized late effects program (75%) or a regular pediatric oncology clinic (24%). However, only 29.8% of institutions reported that > 75% of eligible patients were seen in a survivorship clinic. The most prevalent reported barriers to survivor care were lack of dedicated time (58%) and lack of funding for program development (41%). In 2017, 88% of institutions provided a treatment summary compared to 31% in 2007. CONCLUSION: The majority of COG institutions have dedicated care for pediatric and young adult survivors of childhood cancer; however, at most institutions, < 75% of eligible patients access this care. Research into more efficient technology strategies is needed to ensure all survivors the opportunity to receive appropriate follow-up care. IMPLICATIONS FOR CANCER SURVIVORS: This survey provides a snapshot of the status of late effects services within COG institutions and provides information on residual gaps in services. Next steps should focus on the importance of attendance in a survivorship clinic on the physical health and psychosocial outcomes in cancer survivors.
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Supervivientes de Cáncer , Neoplasias , Adulto Joven , Humanos , Niño , Supervivencia , Neoplasias/terapia , Neoplasias/psicología , Sobrevivientes/psicología , Cuidados PosterioresRESUMEN
Chemotherapy-induced central nervous system (CNS) neurotoxicity presents an unmet medical need. Patients often report a cognitive decline in temporal correlation to chemotherapy, particularly for hippocampus-dependent verbal and visuo-spatial abilities. We treated adult C57Bl/6 mice with 12 × 20 mg kg-1 paclitaxel (PTX), mimicking clinical conditions of dose-dense chemotherapy, followed by a pulse of bromodesoxyuridine (BrdU) to label dividing cells. In this model, mice developed visuo-spatial memory impairments, and we measured peak PTX concentrations in the hippocampus of 230 nm l-1, which was sevenfold higher compared with the neocortex. Histologic analysis revealed a reduced hippocampal cell proliferation. In vitro, we observed severe toxicity in slowly proliferating neural stem cells (NSC) as well as human neuronal progenitor cells after 2 h exposure to low nanomolar concentrations of PTX. In comparison, mature post-mitotic hippocampal neurons and cell lines of malignant cells were less vulnerable. In PTX-treated NSC, we observed an increase of intracellular calcium levels, as well as an increased activity of calpain- and caspase 3/7, suggesting a calcium-dependent mechanism. This cell death pathway could be specifically inhibited with lithium, but not glycogen synthase kinase 3 inhibitors, which protected NSC in vitro. In vivo, preemptive treatment of mice with lithium prevented PTX-induced memory deficits and abnormal adult hippocampal neurogenesis. In summary, we identified a molecular pathomechanism, which invokes PTX-induced cytotoxicity in NSC independent of cell cycle status. This pathway could be pharmacologically inhibited with lithium without impairing paclitaxel's tubulin-dependent cytostatic mode of action, enabling a potential translational clinical approach.
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Trastornos del Conocimiento/prevención & control , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/prevención & control , Paclitaxel/efectos adversos , Animales , Calcio/metabolismo , Calpaína/metabolismo , Caspasa 3/metabolismo , Proliferación Celular/efectos de los fármacos , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/metabolismo , Hipocampo/metabolismo , Humanos , Carbonato de Litio/uso terapéutico , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Ratones , Ratones Endogámicos C57BL , Células-Madre Neurales/efectos de los fármacosRESUMEN
Diminished bone density and skeletal fractures are common morbidities during and following therapy for acute lymphoblastic leukemia (ALL). While cumulative doses of osteotoxic chemotherapy for ALL have been reported to adversely impact bone density, the timing of onset of this effect as well as other changes to bone structure is not well characterized. We therefore conducted a prospective cohort study in pre-adolescent and adolescent patients (10-21years) newly diagnosed with ALL (n=38) to explore leukemia-related changes to bone at diagnosis and the subsequent impact of the first phase of chemotherapy ("Induction"). Using quantitative computerized tomography (QCT), we found that pre-chemotherapy bone properties were similar to age- and sex-matched controls. Subsequently over the one month Induction period, however, cancellous volumetric bone mineral density (vBMD) decreased markedly (-26.8%, p<0.001) with sparing of cortical vBMD (tibia -0.0%, p=0.860, femur -0.7%, p=0.290). The tibia underwent significant cortical thinning (average cortical thickness-1.2%, p<0.001; cortical area-0.4%, p=0.014), while the femur was less affected. Areal BMD (aBMD) concurrently measured by dual-energy X-ray absorptiometry (DXA) underestimated changes from baseline as compared to vBMD. Biochemical evidence revealed prevalent Vitamin D insufficiency and a net resorptive state at start and end of Induction. Our findings demonstrate for the first time that significant alterations to cancellous and cortical bone develop during the first month of treatment, far earlier during ALL therapy than previously considered. Given that osteotoxic chemotherapy is integral to curative regimens for ALL, these results provide reason to re-evaluate traditional approaches toward chemotherapy-associated bone toxicity and highlight the urgent need for investigation into interventions to mitigate this common adverse effect.
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Hueso Esponjoso/patología , Hueso Cortical/patología , Quimioterapia de Inducción/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Biomarcadores/metabolismo , Densidad Ósea , Hueso Esponjoso/diagnóstico por imagen , Hueso Esponjoso/fisiopatología , Estudios de Casos y Controles , Estudios de Cohortes , Hueso Cortical/diagnóstico por imagen , Hueso Cortical/fisiopatología , Femenino , Humanos , Masculino , Tibia/diagnóstico por imagen , Tibia/metabolismo , Tibia/patología , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
The increased availability of devices for 3D radiological diagnosis allows the more frequent use of CAD/CAM-produced surgical guides for implant placement. The conventional workflow requires a complex logistic chain which is time-consuming and costly. In a pilot study, the workflow of directly milled surgical guides was evaluated. These surgical guides were designed based on the fusion of an optical impression and the radiological data. The clinical use showed that the surgical guides could be accurately placed on the residual dentition without tipping movements. The conventional surgical guides were used as a control for the manual check of the deviation of the implant axis. The direct transfer of the digital planning data allows the fabrication of surgical guides in an external center without the need of physical transport, which reduces the logistic effort and expense of the central fabrication of surgical guides.
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Diseño Asistido por Computadora , Implantación Dental Endoósea/métodos , Arcada Edéntula/diagnóstico por imagen , Modelos Anatómicos , Cirugía Asistida por Computador , Tomografía Computarizada de Haz Cónico , Humanos , Modelos Dentales , Flujo de TrabajoRESUMEN
AIMS: Assessment of the safety, efficacy and effectiveness of growth factors alone or in combination with other technologies in the treatment of DFU including medical, economical, social, ethical and juridical aspects. METHODS: We systematically searched relevant data bases limited to English and German language and publications since 1990. Review and assessment of the quality of publications followed methods conforming to widely accepted standards for evidence-based medicine and health economics. RESULTS: We identified 25 studies comparing becaplermin, rhEGF, bFGF and the metabolically active skin grafts Dermagraft and Apligraf with standard wound care (SWC) alone or extracellular wound matrix. Study duration ranged from 12 to 20 weeks and the study population comprised between 17 and 382 patients. Treatment with becaplermin, rhEGF, Dermagraft and Apligraf resulted in a higher incidence of complete wound closure and shorter time to complete wound healing with statistically significant differences. Regarding the proportion of adverse events there was no difference between treatment groups. The methodological quality of the studies was affected by significant deficiencies. Economic evaluations showed becaplermin being cost-effective. CONCLUSIONS: Add-on therapy with growth factors and active skin substitutes for treating uncomplicated DFU could be an alternative to SWC alone. For explicit recommendations further studies with stronger evidence are necessary.
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Pie Diabético/tratamiento farmacológico , Pie Diabético/terapia , Factor de Crecimiento Epidérmico/uso terapéutico , Medicina Basada en la Evidencia , Factores de Crecimiento de Fibroblastos/uso terapéutico , Factor de Crecimiento Derivado de Plaquetas/uso terapéutico , Piel Artificial , Terapia Combinada , Pie Diabético/economía , Factor de Crecimiento Epidérmico/efectos adversos , Factor de Crecimiento Epidérmico/economía , Factores de Crecimiento de Fibroblastos/efectos adversos , Factores de Crecimiento de Fibroblastos/economía , Humanos , Factor de Crecimiento Derivado de Plaquetas/efectos adversos , Factor de Crecimiento Derivado de Plaquetas/economía , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/economía , Proteínas Recombinantes/uso terapéutico , Piel Artificial/efectos adversos , Piel Artificial/economía , Evaluación de la Tecnología BiomédicaRESUMEN
Studies on 3,4-methylenedioxymethamphetamine ("ecstasy")-induced neurotoxicity mainly focus on damage of serotonergic terminals. Less attention has been given to neuronal cell death produced by 3,4-methylenedioxymethamphetamine and other amphetamines in areas including the cortex, striatum and thalamus. In the present study we investigated 3,4-methylenedioxymethamphetamine-induced neurotoxicity in neuronal serum free cultures from rat cortex. Since 3,4-methylenedioxymethamphetamine intake induces hyperthermia in both animals and humans, the experiments were performed under normal (36.5 degrees C) and hyperthermic conditions (40 degrees C). Our findings showed a dose-, time- and temperature-dependent apoptotic cell death induced by 3,4-methylenedioxymethamphetamine in cortical neurons. 3,4-Methylenedioxymethamphetamine-induced damage was potentiated under hyperthermia. The neurotoxicity was reduced by the serotonin 2A-receptor antagonists, ketanserin and (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol hydrochloride, in both normothermic and hyperthermic conditions. (+/-)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride, a model agonist for the serotonin 2A-receptor, also induced a dose- and time-dependent apoptotic cell death. Again, protection was provided by ketanserin and (2R,4R)-5-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ethyl]-1-methyl-3-pyrrolidinol hydrochloride against (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced neurotoxicity, thereby indicating that the 3,4-methylenedioxymethamphetamine stimulation of the serotonin 2A-receptor leads to neurotoxicity. This study provides for the first time evidence that direct 3,4-methylenedioxymethamphetamine serotonin 2A-receptor stimulation leads to neuronal cortical death. alpha-Phenyl-N-tert-butyl nitrone a free radical scavenger and the nitric oxide synthase inhibitor Nomega-nitro-L-arginine as well as the NMDA-receptor antagonist MK-801 provided protection under normothermia and hyperthermia, thereby suggesting the participation of free radicals in 3,4-methylenedioxymethamphetamine-induced cell death. Since 3,4-methylenedioxymethamphetamine serotonin 2A-receptor agonistic properties lead to neuronal death, clinically available atypical antipsychotic drugs with serotonin 2A-antagonistic properties could be a valuable therapeutic tool against 3,4-methylenedioxymethamphetamine-induced neurodegeneration.
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Apoptosis/efectos de los fármacos , Alucinógenos/toxicidad , Hipertermia Inducida , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Neuronas/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Animales , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Depuradores de Radicales Libres/farmacología , Inmunohistoquímica , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Wistar , Serotoninérgicos/farmacología , Factores de TiempoRESUMEN
To investigate the relevance of *NO and oxyradicals in the blood-brain barrier (BBB), differentiated and well-proliferating brain capillary endothelial cells (BCEC) are required. Therefore, rat BCEC (rBCEC) were transfected with immortalizing genes. The resulting lines exhibited endothelial characteristics (factor VIII, angiotensin-converting enzyme, high prostacyclin/thromboxane release rates) and BBB markers (gamma-glutamyl transpeptidase, alkaline phosphatase). The control line rBCEC2 (mock transfected) revealed fibroblastoid morphology, less factor VIII, reduced gamma-glutamyl transpeptidase, weak radical defence, low prostanoid metabolism, and limited proliferation. Lines transfected with immortalizing genes (especially rBCEC4, polyoma virus large T antigen) conserved primary properties: epitheloid morphology, subcultivation with high proliferation rate under pure culture conditions, and powerful defence against reactive oxygen species (Mn-, Cu/Zn-superoxide dismutase, catalase, glutathione peroxidase, glutathione) effectively controlling radical metabolism. Only 100 microM H2O2 overcame this defence and stimulated the formation of eicosanoids similarly as in primary cells. Some BBB markers were expressed to a lower degree; however, cocultivation with astrocytes intensified these markers (e.g., alkaline phosphatase) and paraendothelial tightness, indicating induction of BBB properties. Inducible NO synthase was induced by a cytokine plus lipopolysaccharide mixture in all lines and primary cells, resulting in *NO release. Comparing the cell lines obtained, rBCEC4 are stable immortalized and reveal the best conservation of properties from primary cells, including enzymes producing or decomposing reactive species. These cells can be subcultivated in large amounts and, hence, they are suitable to study the role of radical metabolism in the BBB and in the cerebral microvasculature.
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Barrera Hematoencefálica , Encéfalo/irrigación sanguínea , Línea Celular , Endotelio Vascular/citología , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Biomarcadores , Encéfalo/citología , Encéfalo/metabolismo , Capilares/citología , División Celular , Citocinas/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Epoprostenol/metabolismo , Radicales Libres/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Ratas , Ratas Wistar , Tromboxano A2/metabolismoRESUMEN
The major goal of this study was to compare mechanisms of the neuroprotective potential of 17 beta-estradiol in two models for oxidative stress-independent apoptotic neuronal cell death with that in necrotic neuronal cell death in primary neuronal cultures derived from rat hippocampus, septum, or cortex. Neuronal apoptosis was induced either by staurosporine or ethylcholine aziridinium (AF64A), as models for necrotic cell death glutamate exposure or oxygen-glucose deprivation (OGD) were applied. Long-term (20 hr) pretreatment (0.1 microm 17 beta-estradiol) was neuroprotective in apoptotic neuronal cell death induced by AF64A (40 microm) only in hippocampal and septal neuronal cultures and not in cortical cultures. The neuroprotective effect was blocked by the estrogen antagonists ICI 182,780 and tamoxifen and the phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002. In glutamate and OGD-induced neuronal damage, long-term pretreatment was not effective. In contrast, short-term (1 hr) pretreatment with 17 beta-estradiol in the dose range of 0.5-1.0 microm significantly reduced the release of lactate dehydrogenase and improved morphology of cortical cultures exposed to glutamate or OGD but was not effective in the AF64A model. Staurosporine-induced apoptosis was not prevented by either long- or short-term pretreatment. The strong expression of the estrogen receptor-alpha and the modulation of Bcl proteins by 17 beta-estradiol in hippocampal and septal but not in cortical cultures indicates that the prevention of apoptotic, but not of necrotic, neuronal cell death by 17 beta-estradiol possibly depends on the induction of Bcl proteins and the density of estrogen receptor-alpha.
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Apoptosis/efectos de los fármacos , Colina/análogos & derivados , Estradiol/farmacología , Necrosis , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Aziridinas/farmacología , Hipoxia de la Célula/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Colina/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno , Glucosa/deficiencia , Glucosa/metabolismo , Ácido Glutámico/toxicidad , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Neuronas/citología , Neuronas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Wistar , Receptores de Estrógenos/metabolismo , Tabique del Cerebro/citología , Tabique del Cerebro/efectos de los fármacos , Tabique del Cerebro/metabolismo , Estaurosporina/farmacología , Factores de TiempoRESUMEN
To assess the neuroprotective potential of melatonin in apoptotic neuronal cell death, we investigated the efficacy of melatonin in serum-free primary neuronal cultures of rat cortex by using three different models of caspase-dependent apoptotic, excitotoxin-independent neurodegeneration and compared it to that in necrotic neuronal damage. Neuronal apoptosis was induced by either staurosporine or the neurotoxin ethylcholine aziridinium (AF64A) with a delayed occurrence of apoptotic cell death (within 72 h). The apoptotic component of oxygen-glucose deprivation (OGD) unmasked by glutamate antagonists served as a third model. As a model for necrotic cell death, OGD was applied. Neuronal injury was quantified by LDH release and loss of metabolic activity. Although melatonin (0.5 mM) partly protected cortical neurons from OGD-induced necrosis, as measured by a significant reduction in LDH release, it was not effective in all three models of apoptotic cell death. In contrast, exaggeration of neuronal damage by melatonin was observed in native cultures as well as after induction of apoptosis. The present data suggest that the neuroprotectiveness of melatonin strongly depends on the model of neuronal cell death applied. As demonstrated in three different models of neuronal apoptosis, the progression of the apoptotic type of neuronal cell death cannot be withhold or is even exaggerated by melatonin, in contrast to its beneficial effect in the necrotic type of cell death.
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Apoptosis , Caspasas/metabolismo , Colina/análogos & derivados , Melatonina/farmacología , Neuronas/efectos de los fármacos , Tiourea/análogos & derivados , Animales , Antioxidantes/farmacología , Aziridinas , Inhibidores de Caspasas , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Óxidos N-Cíclicos , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Depuradores de Radicales Libres/farmacología , Radicales Libres/metabolismo , Glucosa/deficiencia , Glucosa/metabolismo , Hipoxia/metabolismo , Necrosis , Neuronas/patología , Óxidos de Nitrógeno/farmacología , Ratas , Ratas Wistar , Estaurosporina/farmacología , Tiourea/farmacologíaRESUMEN
The involvement of nitric oxide in neurodegenerative processes still remains incompletely characterized. Although nitric oxide has been reported to be an important mediator in neuronal degeneration in different models of cell death involving NMDA-receptor activation, increasing evidence for protective mechanisms has been obtained. In this study the role of nitric oxide was investigated in a model of NMDA-independent, delayed apoptotic cell death, induced by the neurotoxin ethylcholine aziridinium ethylcholine aziridinium both in vivo and in vitro. For the in vivo evaluation rats received bilateral intracerebroventricular injections of ethylcholine aziridinium (2nmol/ventricle) or vehicle. In the hippocampus a transient decrease in nitric oxide synthase activity occurred, reaching its lowest levels three days after ethylcholine aziridinium treatment (51.7+/-9.8% of controls). The decrease coincided with the maximal reduction in choline acetyltransferase activity as marker for the extent of cholinergic lesion. The effect of pharmacological inhibition of nitric oxide synthase was tested by application of various nitric oxide synthase inhibitors with different selectivity for the nitric oxide synthase-isoforms. Unspecific nitric oxide synthase inhibition resulted in a significant potentiation of the loss of choline acetyltransferase activity in the hippocampus measured seven days after ethylcholine aziridinium application, whereas the specific inhibition of neuronal or inducible nitric oxide synthase was ineffective. These pharmacological data are suggestive for a neuroprotective role of nitric oxide generated by endothelial nitric oxide synthase. In vitro experiments were performed using serum-free primary neuronal cell cultures from hippocampus, cortex and septum of E15-17 Wistar rat embryos. Ethylcholine aziridinium-application in a range of 5-80microM resulted in delayed apoptotic neurodegeneration with a maximum after three days as confirmed by morphological criteria, life-death assays and DNA laddering. Nitric oxide synthase activity in harvested cells decreased in a dose- and time-dependent manner. Nitric oxide production as determined by measurement of the accumulated metabolite nitrite in the medium was equally low in controls and in ethylcholine aziridinium treated cells (range 0.77-1.86microM nitrite). An expression of inducible nitric oxide synthase messenger RNA could not be detected by semiquantitative RT-PCR 13h after ethylcholine aziridinium application. The present data indicate that in a model of delayed apoptotic neurodegeneration as induced by ethylcholine aziridinium neuronal cell death in vitro and in vivo is independent of the cytotoxic potential of nitric oxide. This is confirmed by a decrease in nitric oxide synthase activity, absence of nitric oxide production and absence of inducible nitric oxide synthase expression. In contrast, evidence for a neuroprotective role of nitric oxide was obtained in vivo as indicated by the exaggeration of the cholinergic lesion after unspecific nitric oxide synthase inhibition by N-nitro-L-arginine methylester.
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Apoptosis/fisiología , Aziridinas/toxicidad , Colina/análogos & derivados , Lóbulo Frontal/fisiología , Hipocampo/fisiología , Degeneración Nerviosa/fisiopatología , Neuronas/fisiología , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico/fisiología , Animales , Apoptosis/efectos de los fármacos , Aziridinas/administración & dosificación , Células Cultivadas , Corteza Cerebral/citología , Ventrículos Cerebrales/efectos de los fármacos , Ventrículos Cerebrales/fisiología , Colina/administración & dosificación , Colina/toxicidad , Colina O-Acetiltransferasa/metabolismo , Feto , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/fisiopatología , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Inyecciones Intraventriculares , Masculino , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/patología , Neuronas/citología , Neuronas/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II , Ratas , Ratas Sprague-Dawley , Tabique del Cerebro/citología , Toxinas Biológicas/toxicidadRESUMEN
Pneumococcal meningitis resulting from Streptococcus pneumoniae has a death rate of 28% in adults. In severe head injury and stroke, inflammatory changes and intracranial hypertension are improved by induced hypothermia, which also is neuroprotective. We hypothesized that moderate hypothermia ameliorates inflammatory changes in experimental pneumococcal meningitis. Wistar rats were cooled systemically, and meningitis was induced by pneumococcal cell wall components. The increase of regional cerebral blood flow in the meningitis animals was blocked by hypothermia at 6 hours. The reduction of intracranial pressure correlated with temperature. The influx of leukocytes into the cerebrospinal fluid and levels of tumor necrosis factor alpha in the cerebrospinal fluid were decreased. Cooling the animals 2 hours after meningitis induction to 30.5 degrees C was also protective. We conclude that hypothermia is a new adjuvant approach to reduce meningitis-induced changes, in particular intracranial pressure, in the early phase of the disease.
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Hipotermia Inducida , Meningitis Neumocócica/terapia , Animales , Líquido Cefalorraquídeo/citología , Circulación Cerebrovascular , Presión Intracraneal , Masculino , Meningitis Neumocócica/líquido cefalorraquídeo , Meningitis Neumocócica/fisiopatología , Ratas , Ratas Wistar , Factores de Tiempo , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeoRESUMEN
Metanephric adenoma is a recently characterized renal tumor that generally occurs in adults and has an excellent prognosis. To date, only one atypical metanephric adenoma has been reported to metastasize. The authors report a case of typical metanephric adenoma that arose in the left kidney of a 7-year-old girl that was associated with metastases to the para-aortic, hilar, and aortic bifurcation lymph nodes. The tumor was 9.5 cm and was composed entirely of epithelial elements arranged in tubules, short papillae, and glomeruloid bodies with scattered psammoma bodies. No atypia and only rare mitotic activity were present. Immunohistochemically, the tumor was negative for epithelial membrane antigen, negative for keratin AE1, and focally positive for both keratin CAM5.2 and cytokeratin 7. Tumor cytogenetics revealed a normal diploid karyotype, and disomy of chromosomes 7 and 17 was confirmed by fluorescence in situ hybridization. The authors conclude that tumors with histologic, immunohistochemical, and genetic features characteristic of typical metanephric adenoma can present with metastatic disease.
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Adenoma/patología , Neoplasias Renales/patología , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Adenoma/química , Adenoma/cirugía , Biomarcadores de Tumor/análisis , Niño , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Cariotipificación , Riñón/diagnóstico por imagen , Neoplasias Renales/química , Neoplasias Renales/cirugía , Tomografía Computarizada por Rayos XRESUMEN
We report on a patient with ocular-ectodermal syndrome who was previously described in 1993 [Am J Med Genet (1993) 45:764-766]. This boy has now developed additional manifestations, including giant cell granulomas and non-ossifying fibromas. This adds to the list of phenotypic manifestations of this condition.
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Anomalías del Ojo , Fibroma/complicaciones , Granuloma de Células Gigantes/complicaciones , Anomalías Cutáneas , Preescolar , Humanos , Masculino , SíndromeRESUMEN
TNF-alpha, inducible NO synthase (iNOS), and ICAM-1 are considered to be key proteins in the inflammatory response of most tissues. We tested the hypothesis that cell walls of Streptococcus pneumoniae (PCW), the most common cause of adult bacterial meningitis, induce TNF-alpha, iNOS, and ICAM-1 expression in rat primary brain microvascular endothelial cell cultures. We detected TNF-alpha mRNA by RT-PCR already 1 h after stimulation with PCW, while TNF-alpha protein peaked at 4 h (9.4 +/- 3.6 vs 0.1 +/- 0.1 pg/microgram protein). PCW induced iNOS mRNA 2 h after stimulation, followed by an increase of the NO degradation product nitrite (18.1 +/- 4 vs 5.8 +/- 1.8 at 12 h; 18.1 +/- 4 vs 5.8 +/- 1.8 pmol/microgram protein at 72 h). The addition of TNF-alpha Ab significantly reduced nitrite production to 62.2 +/- 14.4% compared with PCW-stimulated brain microvascular endothelial cells (100%). PCW induced the expression of ICAM-1 (measured by FACS), which was completely blocked by TNF-alpha Ab (142 +/- 18.6 vs 97.5 +/- 12.4%; 100% unstimulated brain microvascular endothelial cells). Cerebral endothelial cells express TNF-alpha mRNA as well as iNOS mRNA and release the bioactive proteins in response to PCW. PCW-induced NO production is mediated in part by an autocrine pathway involving TNF-alpha, whereas ICAM-1 expression is completely mediated by this autocrine loop. By these mechanisms, cerebral endothelial cells may regulate critical steps in inflammatory blood-brain-barrier disruption of bacterial meningitis.
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Encéfalo/inmunología , Pared Celular/inmunología , Endotelio Vascular/inmunología , Molécula 1 de Adhesión Intercelular/biosíntesis , Óxido Nítrico Sintasa/biosíntesis , Streptococcus pneumoniae/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Comunicación Autocrina/inmunología , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Células Cultivadas , Dexametasona/farmacología , Relación Dosis-Respuesta Inmunológica , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Guanidinas/farmacología , Sueros Inmunes/farmacología , Cinética , Microcirculación/inmunología , Microcirculación/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Nitroarginina/farmacología , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Regulación hacia Arriba/inmunologíaRESUMEN
Cultured brain microvascular endothelial cells have been used to study blood-brain barrier properties in vitro. Among several endothelial derived factors the gaseous free radical nitric oxide (NO) has been shown to regulate both vascular tone and blood-brain barrier permeability. Due to its short half-life and high reactivity with many other molecules, effects of NO have preferentially been investigated using NO synthase inhibitors, NO donors or, more recently, in NO synthase knock-out animals. In the present study we describe a rapid, sensitive and reliable protocol for chemiluminescence detection of NO2-, the stable oxydation product of NO, from the supernatant of rat cortical endothelial cells in culture. After suppression of inducible NOS activity brain endothelial cells showed low basal NO levels. After stimulation with calcium ionophore NO levels increased and were attenuated again by NOS blockade. NO release was also elicited by bradykinin or acetylcholine, albeit to a lesser extent. This protocol might prove useful to investigate calcium-dependent NO formation in cerebral endothelial cells and blood-brain barrier models in vitro. In principle, the same protocol can be applied to virtually any cell type in culture.
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Corteza Cerebral/metabolismo , Endotelio Vascular/metabolismo , Óxido Nítrico/biosíntesis , Animales , Bovinos , Células Cultivadas , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/citología , Endotelio Vascular/citología , Mediciones Luminiscentes , Microcirculación/fisiología , Ratas , Ratas Wistar , Reproducibilidad de los ResultadosRESUMEN
Cell wall compounds of gram-positive bacteria are capable of inducing the biosynthesis of proinflammatory cytokines in CNS cells in a similar way as lipopolysaccharide (LPS) of gram-negative bacteria does. Astrocytes, which lack the CD14 LPS receptor, have also been shown to respond to LPS-stimulation by increased cytokine synthesis. However, almost nothing is known about signaling steps involved in this process. We have therefore examined signaling events in primary cultures of rat astrocytes and the human astrocytoma cell line U373MG, brought about by LPS and pneumococcal cell walls (PCW). Of particular interest to us was the tyrosine phosphorylation patterns and activation states of three members of the mitogen activated protein kinase (MAPK) family, i.e., extracellular signal-regulated protein kinase (erk)-1, erk-2, and the recently identified p38. We show that LPS and PCW initiate tyrosine phosphorylation and activation of erk-1, erk-2, and p38 in a dose-dependent fashion. Inhibitors of tyrosine phosphorylation were able to alleviate this effect and also blocked cytokine production of astrocytes. Both, LPS- and PCW-induced responses of astrocytic cells required the presence of soluble CD14 (sCD14) present in serum. Unraveling the signaling steps induced by bacterial compounds in cells of the CNS may potentially help to elucidate the pathomechanisms of meningitis and central nervous complications of sepsis and may offer options for novel treatment strategies.
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Astrocitos/enzimología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas Quinasas Activadas por Mitógenos , Animales , Astrocitos/citología , Astrocitos/efectos de los fármacos , Astrocitoma , Proteínas Bacterianas/farmacología , Pared Celular/química , Corteza Cerebelosa/citología , Relación Dosis-Respuesta a Droga , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Genisteína/farmacología , Humanos , Receptores de Lipopolisacáridos/metabolismo , Lipopolisacáridos/farmacología , Proteína Quinasa 1 Activada por Mitógenos , Proteína Quinasa 3 Activada por Mitógenos , Fosforilación , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Streptococcus pneumoniae/química , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/enzimología , Factor de Necrosis Tumoral alfa/metabolismo , Tirosina/metabolismo , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Although tumour necrosis factor alpha is said to play a key role in bacterial meningitis and other CNS diseases, the effects of this pro-inflammatory cytokine have only been studied in part and are incompletely understood. In a rat model, we investigated the effect of intracisternal injection of recombinant rat-specific tumour necrosis factor alpha (5, 35, 70 and 280 microg tumour necrosis factor alpha) (i) alone, (ii) combined with pneumococcal cell wall components, on regional cerebral blood flow, intracranial pressure, white blood cell count in the cerebrospinal fluid, and brain water content. Tumour necrosis factor a dose-dependently caused an increase in regional cerebral blood flow (up to 221 +/- 43% of baseline values) over the six hour observation period and mild cerebrospinal fluid leukocytosis; intracranial pressure and brain water content were unchanged. Hypothesizing that regional cerebral blood flow changes are dependent on nitric oxide, tumour necrosis factor alpha-induced regional cerebral blood flow increase was abolished by Aminoguanidine, a selective inhibitor of inducible nitric oxide synthase. Combination of the lowest tumour necrosis factor alpha dose and a low dose pneumococcal cell wall preparation magnified the inflammatory effect of both. We conclude that intrathecally injected tumour necrosis factor alpha alone results in only minor inflammatory changes, whereas it dramatically augments experimental meningitis.
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Encéfalo/fisiopatología , Inflamación/fisiopatología , Meningitis Neumocócica/fisiopatología , Factor de Necrosis Tumoral alfa/farmacología , Animales , Agua Corporal/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Pared Celular , Circulación Cerebrovascular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Guanidinas/farmacología , Presión Intracraneal/efectos de los fármacos , Presión Intracraneal/fisiología , Recuento de Leucocitos , Masculino , Ratas , Ratas Wistar , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Flujo Sanguíneo Regional/efectos de los fármacos , Streptococcus pneumoniae , Factor de Necrosis Tumoral alfa/administración & dosificación , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Heparin is a natural proteoglycan that was first described in 1916. In addition to its well characterized effect on blood coagulation, it is becoming clear that heparin also modulates inflammatory processes on several levels, including the interference with leukocyte-endothelium interaction. Anecdotal observations suggest a better clinical outcome of heparin-treated patients with bacterial meningitis. The authors demonstrate that heparin, a glycosaminoglycan, inhibits significantly in the early phase of experimental pneumococcal meningitis the increase of 1) regional cerebral blood flow (125 +/- 18 versus 247 +/- 42%), 2) intracranial pressure (4.5 +/- 2.0 versus 12.1 +/- 2.2 mm Hg), 3) brain edema (brain water content: 78.23 +/- 0.33 versus 79.49 +/- 0.46%), and 4) influx of leukocytes (571 +/- 397 versus 2400 +/- 875 cells/microL) to the cerebrospinal fluid compared with untreated rats. To elucidate the possible mechanism of this observation, the authors investigated for the first time leukocyte rolling in an inflammatory model in brain venules by confocal laser scanning microscopy in vivo. Heparin significantly attenuates leukocyte rolling at 2, 3, and 4 hours (2.8 +/- 1.3 versus 7.9 +/- 3.2/100 microm/min), as well as leukocyte sticking at 4 hours (2.1 +/- 0.4 versus 3.5 +/- 1.0/100 microm/min) after meningitis induction compared with untreated animals. The authors conclude that heparin can modulate acute central nervous system inflammation and, in particular, leukocyte-endothelium interaction, a key process in the cascade of injury in bacterial meningitis. They propose to evaluate further the potential of heparin in central nervous system inflammation in basic and clinical studies.
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Antiinflamatorios/farmacología , Heparina/farmacología , Leucocitos/efectos de los fármacos , Meningitis Bacterianas/sangre , Animales , Edema Encefálico/metabolismo , Adhesión Celular/efectos de los fármacos , Circulación Cerebrovascular/efectos de los fármacos , Heparitina Sulfato/farmacología , Presión Intracraneal/efectos de los fármacos , Leucocitos/fisiología , Masculino , Ratas , Ratas WistarRESUMEN
Using a behavioral paradigm designed to simulate olfactory-guided foraging, the ability of five squirrel monkeys to distinguish iso-amyl acetate from n- and iso-forms of other acetic esters (ethyl acetate to decyl acetate) and from other esters carrying the iso-amyl group (iso-amyl propionate to iso-amyl capronate) was investigated. We found (i) that all five animals were clearly able to discriminate between all odor pairs tested; (ii) a significant negative correlation between discrimination performance and structural similarity of odorants in terms of differences in carbon chain length of both the aliphatic alcohol group and the aliphatic acid group of the esters; and (iii) that iso- and n-amyl acetate were perceived as qualitatively similar despite different steric conformation. Using a triple-forced choice procedure, 20 human subjects were tested on the same tasks in parallel and showed a very similar pattern of discrimination performance compared with the squirrel monkeys. Thus, the results of this study provide evidence of well-developed olfactory discrimination ability in squirrel monkeys for aliphatic esters and support the assumption that human and non-human primates may share common principles of odor quality perception.