RESUMEN
As part of a high-throughput mutagenesis and phenotyping process designed to discover novel drug targets, we generated and characterized mice with a targeted mutation in Slc24a5, a gene encoding a putative cation exchanger. Upon macroscopic examination, Slc24a5-/- mice were viable, fertile, and indistinguishable by coat color from their heterozygous and wild-type litter mates. Ophthalmoscopic examination revealed diffuse retinal hypopigmentation, and a histologic examination of the eye confirmed the presence of moderate-to-marked hypopigmentation of the retinal pigmented epithelium (RPE), ciliary body, and iris pigment epithelium (IPE). Hypopigmentation was most severe in the anterior layer cells of the IPE, where melanosomes were smaller, paler, and more indistinct than those of the anterior stroma and posterior IPE. The pigment granules of the posterior IPE appeared to be nearly as dark as those in stromal melanocytes; however, both cell layers were thinner and paler than corresponding layers in wild-type mice. Ultrastructural analysis of the RPE, IPE, and ciliary body pigmented cells confirmed that mutation of Slc24a5 results in marked hypopigmentation of melanosomes in optic cup-derived pigmented neuroepithelium in the eyes. Milder reductions in melanosome size and pigmentation were noted in neural crest-derived melanocytes. The severe hypopigmentation of neuroepithelium-derived cells in the eyes resulted in a novel form of ocular albinism in Slc24a5-/- mice. Our findings suggest that SLC24A5 may be a candidate gene for some forms of ocular albinism and for the BEY1/EYCL2 locus previously associated with central brown eye color in humans.
Asunto(s)
Albinismo Ocular/genética , Antiportadores/genética , Hipopigmentación/genética , Albinismo Ocular/ultraestructura , Animales , Modelos Animales de Enfermedad , Femenino , Color del Cabello/genética , Histocitoquímica , Operón Lac/genética , Masculino , Melanosomas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Electrónica de Transmisión , Mutagénesis Sitio-DirigidaRESUMEN
This study aimed to investigate the prevalence of undernutrition in children with cerebral palsy (CP) and to determine the relation with feeding ability. Ninety children with CP from special needs schools were examined. Undernutrition was diagnosed on one or more of the following criteria: weight <2nd centile, triceps or subscapular skinfold measurement <3rd centile, mid-arm circumference <5th centile. Feeding competence was scored with respect to seven specific oromotor tasks using the Multidisciplinary Feeding Profile. Thirty-six participants (40%) had diplegia, 29 (33%) quadriplegia, 13 (14%) hemiplegia, and 12 participants (13%) had dyskinetic CP. Age ranged from 2.6 to 18.7 years (mean 10.8 years). Forty-six percent (41 of 90) were undernourished. In all aspects of feeding, those undernourished had lower feeding competence scores compared to adequately nourished children (p<0.002). Each modality of feeding competence correlated significantly to the centiles of weight, triceps or subscapular skinfold measurement and mid-arm circumference (p<0.02). A positive association of weight, triceps skinfold measurement, and mid-arm circumference with chewing ability was present independent of other feeding modalities (p<0.05). Undernutrition was common in this group and was associated with poorer feeding ability.
Asunto(s)
Parálisis Cerebral/diagnóstico , Conducta Alimentaria , Desnutrición Proteico-Calórica/diagnóstico , Adolescente , Antropometría , Parálisis Cerebral/rehabilitación , Niño , Preescolar , Educación Especial , Femenino , Humanos , Masculino , Irlanda del Norte , Evaluación Nutricional , Desnutrición Proteico-Calórica/rehabilitación , Trastornos Psicomotores/diagnóstico , Trastornos Psicomotores/rehabilitaciónRESUMEN
Although there have been a number of studies in adults, to date there has been little research into sequential antimicrobial therapy (SAT) in paediatric populations. The present study evaluates the impact of a SAT protocol for the treatment of severe lower respiratory tract infection in paediatric patients. The study involved 89 paediatric patients (44 control and 45 SAT). The SAT patients had a shorter length of hospital stay (4.0 versus 8.3 days), shorter duration of inpatient antimicrobial therapy (4.0 versus 7.9 days) with the period of iv therapy being reduced from a mean of 5.6 to 1.7 days. The total healthcare costs were reduced by 52%. The resolution of severe lower respiratory tract infection with a short course of iv antimicrobials, followed by conversion to oral therapy yielded clinical outcomes comparable to those achieved using longer term iv therapy. SAT proved to be an important cost-minimizing tool for realizing substantial healthcare costs savings.
Asunto(s)
Antibacterianos/administración & dosificación , Bronquitis/tratamiento farmacológico , Neumonía/tratamiento farmacológico , Administración Oral , Combinación Amoxicilina-Clavulanato de Potasio/administración & dosificación , Combinación Amoxicilina-Clavulanato de Potasio/economía , Combinación Amoxicilina-Clavulanato de Potasio/uso terapéutico , Antibacterianos/economía , Antibacterianos/uso terapéutico , Cefixima/administración & dosificación , Cefixima/economía , Cefixima/uso terapéutico , Cefotaxima/administración & dosificación , Cefotaxima/economía , Cefotaxima/uso terapéutico , Niño , Preescolar , Protocolos Clínicos , Esquema de Medicación , Femenino , Costos de la Atención en Salud , Humanos , Lactante , Inyecciones Intravenosas , Tiempo de Internación , Masculino , Resultado del TratamientoRESUMEN
1. Smoking exerts an inflammatory stimulus on lung macrophages, and smokers generally have low intakes of antioxidant micronutrients. This study was performed to investigate the relationship between whole-blood tumour necrosis factor production, plasma interleukin-6 and acute-phase protein concentration and antioxidant vitamins in smokers and non-smokers. 2. Measurement of tumour necrosis factor was conducted in whole blood stimulated with endotoxin (lipopolysaccharide), and interleukin-6 concentrations were measured in the plasma of smokers and non-smokers. Enzyme and dietary antioxidant concentrations and acute-phase proteins were determined in the two groups. 3. Tumour necrosis factor production and plasma interleukin-6 concentrations were 38% (P = 0.01) and 16% (P = 0.07) greater, respectively, in smokers than in non-smokers. Plasma vitamin A and E concentrations were unaffected by smoking; however, a 21% lower plasma vitamin C (P = 0.04) concentration was observed in smokers, than in non-smokers despite a similar intake of this vitamin by the two groups. 4. Concentrations of the acute-phase proteins alpha 1-acid glycoprotein, caeruloplasmin and alpha 2-macroglobulin were increased in the plasma of smokers compared with non-smokers by 39%, 28% and 12% respectively (P < 0.01). Our studies indicate that smokers have a compromised antioxidant status and elevated concentrations of tumour necrosis factor and interleukin-6 as a consequence of smoking. 5. These observations may provide some insight into the biological mechanisms underlying the pathology associated with smoking.
Asunto(s)
Proteínas de Fase Aguda/metabolismo , Antioxidantes/metabolismo , Citocinas/biosíntesis , Fumar/metabolismo , Adulto , Ácido Ascórbico/sangre , Ceruloplasmina/metabolismo , Femenino , Humanos , Interleucina-6/sangre , Masculino , Orosomucoide/metabolismo , Fumar/sangre , Factor de Necrosis Tumoral alfa/metabolismo , alfa-Macroglobulinas/metabolismoRESUMEN
We examined the effects of trichloroethylene (TCE) on the bronchiolar epithelium of mouse lung, using scanning electron microscopy. The lesion elicited by TCE involved predominantly the nonciliated Clara cells of the bronchiolar epithelium. Although there was slight loss of cilia and the mucosal surface exhibited increased deposits of debris throughout the period the tissues were observed, the ciliated cells appeared relatively uninjured. At 24 h following the intraperitoneal administration of TCE (2000 mg/kg) the Clara cells of the bronchiolar epithelium were irregularly distributed on the mucosal surface and reduced in number, indicating loss of cells by exfoliation. The remaining Clara cells appeared deformed and collapsed. This cell population was markedly reduced by seven days after TCE exposure, and the bulging apices characteristic of this cell type were virtually absent, resulting in a flattened epithelial lining. By 15 and 30 days after TCE, reparative processes were evident and micronodules consisting of multiple Clara cells protruded into the airway lumen. The administration of TCE to mice causes severe morphological damage to Clara cells of the bronchiolar epithelium which persists for at least 60 days after chemical exposure.
Asunto(s)
Bronquios/efectos de los fármacos , Tricloroetileno/toxicidad , Animales , Bronquios/ultraestructura , Epitelio/efectos de los fármacos , Epitelio/ultraestructura , Masculino , Ratones , Ratones Endogámicos , Microscopía Electrónica de RastreoRESUMEN
Administration of a single intraperitoneal dose of 1,1-dichloroethylene (125 mg/kg, 1,1-DCE) to mice resulted in bronchiolar injury with selective necrosis of Clara cells. Degenerative changes were manifest in Clara cells as early as 1 h following 1,1-DCE exposure, and were characterized by marked swelling of mitochondria and aggregation of chromatin against the nuclear membrane. Cell death was apparent at 2 h; by 8 h, areas of the bronchiolar epithelium were devoid of lining cells, and at 24 h, the majority of Clara cells were exfoliated. The residual epithelium consisted of flattened cells which formed a thin lining for the airway. Necrosis of Clara cells early in the course of 1,1-DCE exposure coincided with peak covalent binding of [14C]1,1-DCE and significant depression of components of the pulmonary mixed-function oxidase system; cytochrome P-450 and aryl hydrocarbon hydroxylase activity were markedly reduced but not depleted. Liver damage involving centrilobular hepatocytes was observed at 24 h in 30% of treated animals, and coincided with significant inhibition of aryl hydrocarbon hydroxylase activity; cytochrome P-450 content, however, remained unchanged. While changes in the liver evoked by 1,1-DCE were less striking, the results in lung demonstrate positive temporal correlations between structural damage, peak covalent binding and disturbances of monooxygenase enzymes.