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Background: Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in patients treated with first-line anti-EGFR monoclonal antibody-based therapy. Patients and methods: In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by next generation sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using beads, emulsion, amplification, and magnetics digital PCR (BEAMing). Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing. Results: A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression-free survival of RAS mutant and wild-type patients according to tissue (7.9 versus 12.6 months; P = 0.004) and liquid biopsy testing (7.8 versus 13.8 moths; P < 0.001) were comparable. Similar findings were observed for the median overall survival of RAS mutant and wild-type patients based on tissue (22.1 versus 35.8 months; P = 0.016) and plasma (19.9 versus 35.8 months; P = 0.013) analysis. Conclusion: This study indicates that RAS testing of liquid biopsy results in a similar outcome when compared with tissue testing in mCRC patients receiving first-line anti-EGFR monoclonal antibodies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Biopsia Líquida/métodos , Proteínas Proto-Oncogénicas p21(ras)/genética , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cetuximab/administración & dosificación , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Mutación , Metástasis de la Neoplasia , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
The human X chromosome contains â¼ 1600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations. Current diagnostic tests employ polymerase chain reaction (PCR)-based technologies; however, alterations remain undetermined in 10% of patients. Furthermore, carrier testing in females is limited or unavailable. High-resolution X chromosome-targeted CGH microarray was applied to test for rearrangements in males with BCM and female carriers from three unrelated families. Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR. In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene. The application of high-resolution X-chromosome microarray in clinical diagnosis brings significant advantages in detection of small aberrations that are beyond the resolution of clinically available aCGH analysis and which can improve molecular diagnosis of the known conditions and unravel previously unrecognized X-linked diseases.
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Aberraciones Cromosómicas , Cromosomas Humanos X , Defectos de la Visión Cromática/diagnóstico , Defectos de la Visión Cromática/genética , Enfermedades Genéticas Ligadas al Cromosoma X , Heterocigoto , Puntos de Rotura del Cromosoma , Deleción Cromosómica , Hibridación Genómica Comparativa , Consanguinidad , Orden Génico , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , LinajeRESUMEN
Bardet-Biedl syndrome (BBS, MIM 209900) is a heterogeneous autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. The disorder is also associated with diabetes mellitus, hypertension, and congenital heart disease. Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although BBS is rare in the general population (<1/100,000), there is considerable interest in identifying the genes causing BBS because components of the phenotype, such as obesity and diabetes, are common. We and others have demonstrated that BBS6 is caused by mutations in the gene MKKS (refs. 12,13), mutation of which also causes McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly, and congenital heart defects). MKKS has sequence homology to the alpha subunit of a prokaryotic chaperonin in the thermosome Thermoplasma acidophilum. We recently identified a novel gene that causes BBS2. The BBS2 protein has no significant similarity to other chaperonins or known proteins. Here we report the positional cloning and identification of mutations in BBS patients in a novel gene designated BBS4.
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Síndrome de Bardet-Biedl/genética , Obesidad/genética , Proteínas/genética , Clonación Molecular , Consanguinidad , Etiquetas de Secuencia Expresada , Humanos , Proteínas Asociadas a Microtúbulos , Datos de Secuencia Molecular , MutaciónRESUMEN
The angiogenic factors sFlt-1 and PlGF play an established role in the detection of preeclampsia (PE). Recent data suggest that sEng might contribute to the pathogenesis of PE. However, only a few studies so far have addressed its role.This monocentric cross-sectional study of high-risk pregnancies aims to compare the levels of sFlt-1/PlGF ratio and sEng depending on different placental-related adverse pregnancy outcomes. The statistical analysis takes into account Pearson's correlation coefficient between angiogenic factors, the area under the curve estimates (AUCs) for detection, and adjusted odds ratios (aOR) with 95% confidence intervals (95%-CIs). The analysis included 206 patients: 60 controls, 90 PE (59 EOPE, 35 LOPE), 94 FGR, and 35 HELLP cases. Some outcomes overlapped because FGR commonly complicated PE and HELLP syndrome. Serum levels of sFlt-1/PlGF and sEng correlated with each other. Higher levels were observed in HELLP syndrome and EOPE cases. AUCs for sFlt-1/PlGF ratio and sEng were, respectively, 0.915 (95%-Cl 0.87-0.96) and 0.872 (95%-Cl 0.81-0.93) in PE, 0.895 (95%-Cl 0.83-0.96) and 0.878 (95%-Cl 0.81-0.95) in HELLP syndrome, 0.891 (95%-Cl 0.84-0.94), and 0.856 (95%-Cl 0.79-0.92) in FGR.aORsfor sFlt-1/PlGF ratio and sEng were, respectively: 2.69 (95%-Cl 1.86-3.9) and 2.33 (95%-Cl 1.59-3.48) in PE, 2.38 (95%-Cl 1.64-3.44) and 2.28 (95%-Cl 1.55-3.4) in FGR, and 2.10 (95%-Cl 1.45-3.05) and 1.88 (95%-Cl 1.31-2.69) in HELLP syndrome. In addition, the aORs between sFlt-1/PlGF and sEng were very similar but higher for PE and FGR than HELLP syndrome.In conclusion,sEng performed similarly to sFlt-1/PlGF to detect placental dysfunctions.
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Síndrome HELLP , Preeclampsia , Humanos , Femenino , Embarazo , Endoglina , Preeclampsia/diagnóstico , Síndrome HELLP/diagnóstico , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Estudios Transversales , Retardo del Crecimiento Fetal , Placenta , Biomarcadores , Factor de Crecimiento PlacentarioRESUMEN
AIM: The melainomania is a psychological and skin syndrome and it expresses the obsessive need of tanned skin in a complete and constant way. We searched for the psycho-patogenetic factors of the syndrome and the psychological and skin ends point useful to evaluate the psychic and skin damages. METHODS: Seventy-two women and 28 men, aged 38-56 years, who were used to a constant photo exposure have been examined. We have considered the psychosocial damages by Rorschach e Machover tests and by psychologist-subject interviews, skin damages by Glogau signs and by echography. Furthermore, the subjects have been submitted to a psychotherapeutic treatment. RESULTS: The tests and the interviews have underlined obsessive lines, dependence, bodily misperception, low index of reality. The Spearman correlations among clinical signs and echographic findings shows high significance. The psychotherapy has reduced the uneasiness in 66 women and 24 men. Each event that produces uneasiness requires a rationalization process that individualizes in successive phases logical justifications for the lived uneasiness and for the perceived consequences. The rational psycho mechanics is a new method that has identified the phase of the thought-deviation and it has planned the corrective therapy. CONCLUSION: The psychological tests, the interviews, the clinical signs and the ultrasound have allowed us to appraise the psychic and skin damages, while the method of the rational psycho mechanics seems to have brought a satisfactory therapeutic result.
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Trastorno Obsesivo Compulsivo , Enfermedades de la Piel/psicología , Baño de Sol/psicología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastorno Obsesivo Compulsivo/diagnóstico , Enfermedades de la Piel/diagnósticoRESUMEN
Primary aldosteronism is the most common form of secondary hypertension and patients with hyperaldosteronism are more prone to premature cardiovascular complications compared to essential hypertensives. The diagnostic flow-chart for the diagnosis of PA is performed in three steps: a) screening; b) confirmation; and c) subtype differentiation. Instead of proceeding directly to subtype classification, the recently published Endocrine Society Guidelines recommend that patients with a positive ARR should undergo a confirmatory test, in order to definitively confirm or exclude the diagnosis of PA. The Guidelines recognize four testing procedures: oral sodium loading, saline infusion, fludrocortisone suppression, and captopril challenge. Herein we discuss the diagnostic protocols for these confirmatory tests and highlight both the advantages and contraindications and we discuss studies in which these confirmatory tests have been compared.
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Técnicas de Diagnóstico Endocrino , Hiperaldosteronismo/diagnóstico , Estudios de Validación como Asunto , Aldosterona/análisis , Algoritmos , Técnicas de Diagnóstico Endocrino/normas , Fludrocortisona , Humanos , Renina/análisis , Sodio en la DietaRESUMEN
To assist in distinguishing disease-causing mutations from nonpathogenic polymorphisms, we developed an objective algorithm to calculate an "estimate of pathogenic probability" (EPP) based on the prevalence of a specific variation, its segregation within families, and its predicted effects on protein structure. Eleven missense variations in the RPE65 gene were evaluated in patients with Leber congenital amaurosis (LCA) using the EPP algorithm. The accuracy of the EPP algorithm was evaluated using a cell-culture assay of RPE65-isomerase activity The variations were engineered into plasmids containing a human RPE65 cDNA and the retinoid isomerase activity of each variant was determined in cultured cells. The EPP algorithm predicted eight substitution mutations to be disease-causing variants. The isomerase catalytic activities of these RPE65 variants were all less than 6% of wild-type. In contrast, the EPP algorithm predicted the other three substitutions to be non-disease-causing, with isomerase activities of 68%, 127%, and 110% of wild-type, respectively. We observed complete concordance between the predicted pathogenicities of missense variations in the RPE65 gene and retinoid isomerase activities measured in a functional assay. These results suggest that the EPP algorithm may be useful to evaluate the pathogenicity of missense variations in other disease genes where functional assays are not available.
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Proteínas Portadoras/genética , Proteínas del Ojo/genética , Mutación Missense , Algoritmos , Secuencia de Aminoácidos , Secuencia de Bases , Biocatálisis , Proteínas Portadoras/química , Proteínas Portadoras/fisiología , Línea Celular , Cartilla de ADN , ADN Complementario , Proteínas del Ojo/química , Proteínas del Ojo/fisiología , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Linaje , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , cis-trans-IsomerasasRESUMEN
AIM: The aim of this study was to evaluate the clinical significance and the management of fetal borderline lateral cerebral ventriculomegaly. METHODS: Fetuses with a sonographic diagnosis of lateral cerebral ventriculomegaly isolated or associated to other fetal malformations were followed monthly and a review of the English-language literature was made. RESULTS: Of 86 fetuses analyzed, 30 suffered from hydrocephaly (monolateral, bilateral), 56 showed also several other malformations . Chromosomal aberrations is possible also in case of isolated hydrocephaly. Neurological sequelae, mostly a mild to moderate delay in cognitive and/or motor development, is present in 10% of the cases. CONCLUSIONS: In most cases, isolated borderline lateral cerebral ventriculomegaly has no consequence. However, the risk of cerebral maldevelopment, delayed neurological development and, possibly, chromosomal aberrations is increased. The optimum management of these cases remains uncertain.
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Anomalías Múltiples/diagnóstico por imagen , Hidrocefalia/diagnóstico por imagen , Ventrículos Laterales/anomalías , Ultrasonografía Prenatal , Aborto Legal , Adulto , Ventrículos Cerebrales/anomalías , Femenino , Humanos , Valor Predictivo de las Pruebas , Embarazo , Resultado del Embarazo , Segundo Trimestre del Embarazo , Tercer Trimestre del Embarazo , Diagnóstico Prenatal , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
INTRODUCTION: Psoriasis produces functional and aesthetic damages which cause psychosocial discomfort and require new adjustment factors. AIMS: We describe the correlation among discomfort and personality factors as traits, coping, defense mechanism (DM) and resilience in Ps (skin psoriasis) and PsA (psoriatic arthritis) patients. MATERIALS AND METHODS: A random sample, age between 45-60, with 1:1 female/male, includes 3 groups each of 90 subjects: - single psoriasis (Ps, average 50.11, SD 4.9928) - Ps and psoriatic arthritis (PsA, average 50.61, SD 4.8765) - controls (C, average 50.0 and SD 4.8019). We evaluated traits by the 16PF-5, coping by Cope Scale, defence mechanism (DM) by DMRS, dysmorphophobia by BDDE and resilience by CR-RISC scales. Statistical analysis was performed by SPSS 14 version, p < 0.05 and t, F, W and P tests and clinical analysis. RESULTS: We recorded a reduction in traits and coping and an increase in DM, dysmorphophobia and resilience. PsA patients showed a greater distress and adjustment factors than Ps alone. Tests showed a valid significance (p < 0.00001), an effect size from 0.30 to > 0.50 in comparison patients-C and η2 = 1.4 in comparison Ps-PsA. In all patients- controls OR, PAR and NNT registered very high values. DISCUSSION: Reduction in autonomy and imperfections cause an internal damage. The adaptation process searches coping factors (to integrate traits) when lesions appear. It selects DM when stressful dynamics require a further adaptation. Finally it results in adequate resilience when damages and dysmorphophobia are offset by traits, coping and DM. CONCLUSIONS: Clinical signs increase more then traits in severity, coping decrease in resources, resilience and DM grow in use and dismorphophobia just increases in intensity.
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Adaptación Psicológica , Actitud Frente a la Salud , Mecanismos de Defensa , Psoriasis/psicología , Resiliencia Psicológica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psoriasis/complicaciones , Estrés Psicológico/complicaciones , Estrés Psicológico/psicologíaRESUMEN
INTRODUCTION: Female genitalis lichen sclerosus (FGLS) occurs on skin and mucous membranes and shows inflammatory lesions, chronic atrophic, itching and pain. These physical damages produce a decline in sex and a resulting relational couple discomfort. AIM: We describe the discomfort and the relationship between physical and psychological damage. MATERIALS AND METHODS: A random sample, between 35-55 years (average 44.55, SD 6.00) includes 2 groups of 55 subjects: - the first with LSAG diagnosis since 24 months - the latter with controls. We evaluated personality by the MMPI-2, discomfort by short SF-36, couple relationship by ISS, coping by Cope and resilience by CR-RISC scales. Statistical analysis was performed by SPSS 14 version. P-values <0.05, 95% confidence limits, t, F, W and P tests and two by two table, compare two rates and Cohort/RTC were employed. RESULTS: Discomfort makes same personality factors changed. 50 FGLS recorded higher scores than 50 controls in MMIP-2, ISS and CD-RISC scales, lower in ISF-36 and COPE scale. Statistical tests show a valid significance (p<0.00001), a 94.3% of exposed with outcome, an etiological fraction in exposed of 96,15% and a 26 risk / prevalence ratio. DISCUSSION: The psychological distress arises as a result of somatic damage and reduces expression and thought of self. Lesion and pain produce depression, anxiety, negative emotionality and decline of sex. High values of t, F and W tests indicate a good validity of results. CONCLUSIONS: The psychological distress grows from somatic damages and, in progressive way, it reduce expressions and thoughts of ego in increasingly tight limits: through successive stages, it involves social relations, couple relationships and individual identity.
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Adaptación Psicológica , Actitud Frente a la Salud , Liquen Escleroso y Atrófico/psicología , Dolor/psicología , Estrés Psicológico/psicología , Adulto , Trastornos de Ansiedad/complicaciones , Trastornos de Ansiedad/psicología , Trastorno Depresivo/complicaciones , Trastorno Depresivo/psicología , Femenino , Humanos , Italia , Liquen Escleroso y Atrófico/complicaciones , Persona de Mediana Edad , Dolor/etiología , Personalidad , Prurito/etiología , Prurito/psicología , Resiliencia Psicológica , Estrés Psicológico/etiologíaRESUMEN
Dysfunction of the retinal pigment epithelium (RPE), its loss, or separation from the underlying neural retina results in severe photoreceptor degeneration. Pigment epithelium-derived factor (PEDF) is a glycoprotein with reported neuroprotective and differentiation properties that is secreted in abundance by RPE cells. The "pooling" of PEDF within the interphotoreceptor matrix places this molecule in a prime physical location to affect the underlying neural retina. The purpose of this study was to analyze the morphogenetic activity of PEDF in a model of photoreceptor dysmorphogenesis induced by removal of the RPE. Eyes were dissected from embryonic Xenopus laevis, and the RPE was removed before culturing in medium containing PEDF, PEDF plus anti-PEDF antibodies, or medium alone. Control retinas were maintained with an adherent RPE. Light and electron microscopic analysis was used to examine retinal ultrastructure. Opsin was localized immunocytochemically and quantified as an index of outer segment membranous material and photoreceptor protein expression. Removal of the RPE resulted in an aberrant assembly of photoreceptor outer segments, loss of fine subcellular ultrastructure in photoreceptors, and a reduction in opsin protein levels when compared with control retinas. The addition of PEDF prevented the dysmorphic photoreceptor changes induced by RPE removal. In particular, photoreceptor ultrastructure, outer segment membrane assembly, and steady-state levels of opsin were equivalent to control conditions. Anti-PEDF antibodies completely blocked the morphogenetic activity of PEDF. These results indicate that PEDF is able to mimic the supportive role of the RPE on photoreceptors during the final stages of retinal morphogenesis.
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Proteínas del Ojo , Neuronas/metabolismo , Epitelio Pigmentado Ocular/metabolismo , Proteínas/metabolismo , Retina/metabolismo , Opsinas de Bastones/biosíntesis , Serpinas/metabolismo , Animales , Anticuerpos/farmacología , Bovinos , Relación Dosis-Respuesta a Droga , Inmunohistoquímica , Técnicas In Vitro , Morfogénesis/efectos de los fármacos , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/farmacología , Neuronas/efectos de los fármacos , Neuronas/ultraestructura , Células Fotorreceptoras de Vertebrados/efectos de los fármacos , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/ultraestructura , Epitelio Pigmentado Ocular/citología , Epitelio Pigmentado Ocular/embriología , Proteínas/antagonistas & inhibidores , Proteínas/farmacología , Retina/embriología , Retina/ultraestructura , Segmento Externo de la Célula en Bastón/metabolismo , Serpinas/farmacología , Xenopus laevisRESUMEN
PURPOSE: To determine the disease expression in heterozygotes for mutations in the RP1 gene, a newly identified cause of autosomal dominant retinitis pigmentosa (adRP). METHODS: Screening strategies were used to detect disease-causing mutations in the RP1 gene, and detailed studies of phenotype were performed in a subset of the detected RP1 heterozygotes using electroretinography (ERG), psychophysics, and optical coherence tomography (OCT). RESULTS: Seventeen adRP families had heterozygous RP1 changes. Thirteen families had the Arg677ter mutation, whereas four others had one of the following: Pro658 (1-bp del), Ser747 (1-bp del), Leu762-763 (5-bp del), and Tyr1053 (1-bp del). In Arg677ter RP1 heterozygotes, there was regional retinal variation in disease, with the far peripheral inferonasal retina being most vulnerable; central and superior temporal retinal regions were better preserved. The earliest manifestation of disease was rod dysfunction, detectable as reduced rod ERG photoresponse maximum amplitude, even in heterozygotes with otherwise normal clinical, functional, and OCT cross-sectional retinal imaging results. At disease stages when cone abnormalities were present, there was greater rod than cone dysfunction. Patients with the RP1 frameshift mutations showed similarities in phenotype to those with the Arg677ter mutation. CONCLUSIONS: Earliest disease expression of RP1 gene mutations causing adRP involves primarily rod photoreceptors, and there is a gradient of vulnerability of retinopathy with more pronounced effects in the inferonasal peripheral retina. At other disease stages, cone function is also affected, and severe retina-wide degeneration can occur. The nonpenetrance or minimal disease expression in some Arg677ter mutation-positive heterozygotes suggests important roles for modifier genes or environmental factors in RP1-related disease.
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Proteínas del Ojo/genética , Mutación , Retinitis Pigmentosa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Adaptación a la Oscuridad/fisiología , Electrorretinografía , Femenino , Humanos , Masculino , Proteínas Asociadas a Microtúbulos , Persona de Mediana Edad , Fenotipo , Células Fotorreceptoras de Vertebrados/fisiología , Retinitis Pigmentosa/fisiopatología , Tomografía/métodos , Campos Visuales/fisiologíaRESUMEN
PURPOSE: We have previously shown that lactose, but not mannose, promotes the assembly of nascent photoreceptor outer segments in the absence of the retinal pigment epithelium (RPE). The purpose of the present study was to determine if, in addition to the improved outer segment assembly observed in the presence of lactose, biosynthetic changes in Muller cells could also be detected. METHODS: The RPE was removed from intact isolated Xenopus embryonic eyes that were allowed to complete differentiation in Niu-Twitty medium, Niu-Twitty with mannose, or Niu-Twitty with lactose. Control retinas matured in vitro with an adherent RPE. Retinal morphology was evaluated for organized folding of outer segment membranes and cell loss. In addition, the expression of three Muller cell proteins, glial fibrillary acidic protein (GFAP), cellular retinaldehyde-binding protein (CRALBP), and glutamine synthetase, was examined. RESULTS: In control retinas, GFAP is undetectable, CRALBP heavily immunolabels Muller cells, and radial patterns of glutamine synthetase immunoreactivity are present. In the absence of the RPE, Muller cells upregulate GFAP expression, CRALBP labeling is present at a slightly reduced level, and glutamine synthetase immunolabeling is negligible. Neither mannose nor lactose modify significantly the expression of CRALBP. Similarly, both compounds completely prevent the upregulation of GFAP. However, normal glutamine synthetase expression was observed only in the presence of lactose, but not in the presence of mannose. Statistical analyses of slot blot-based protein quantification confirmed our immunochemical results. CONCLUSIONS: In RPE-deprived retinas supplemented with lactose, Muller cells were morphologically normal. The proper photoreceptor outer segment morphogenesis observed under these conditions was uniquely associated with normal levels of glutamine synthetase expression. The exact significance of this finding with respect to photoreceptor outer segment morphogenesis is unknown. We suggest that glutamine synthetase may be a marker of Muller cell metabolic or structural integrity that may reflect the enhanced ability of these cells, in the presence of lactose, to support photoreceptor outer segment morphogenesis.
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Proteínas Portadoras/biosíntesis , Proteína Ácida Fibrilar de la Glía/biosíntesis , Glutamato-Amoníaco Ligasa/biosíntesis , Lactosa/farmacología , Neuroglía/efectos de los fármacos , Epitelio Pigmentado Ocular/fisiología , Animales , Células Cultivadas , Técnicas de Cocultivo , Inmunohistoquímica , Manosa/farmacología , Morfogénesis , Neuroglía/citología , Neuroglía/metabolismo , Epitelio Pigmentado Ocular/citología , Retina/embriología , Regulación hacia Arriba , Xenopus laevisRESUMEN
PURPOSE: To investigate 20 patients affected with Bardet-Biedl (BB) syndrome and compare them to an age-matched group of 70 non-syndromic patients with retinitis pigmentosa (RP) to identify hallmarks peculiar to the BB phenotype. METHODS: Patients were examined clinically and with functional tests (color vision, kinetic perimetry, electroretinography, ocular motility tests). Fundus findings were numerically graded for statistical purposes. RESULTS: Recurrent ocular features in BB patients were early and severe reduction of visual acuity, constantly altered color vision, high incidence of strabismus and nystagmus, mild-to-severe atrophic changes of the optic disc, and frequently absent or minimal pigmentary retinal changes. Visual acuity was more closely correlated to optic disc than to macular conditions. These findings were remarkably different from non-syndromic RP. CONCLUSIONS: This investigation further suggests that retinopathy in BB syndrome has features distinctive from those in non-syndromic RP. The early occurrence of optic disc atrophy in the BB syndrome, even in those patients with healthy maculas, suggests that optic atrophy could often be primary in nature and might play a major role in decreasing central vision in BB patients. Variability of some findings is in line with the documented heterogeneity of the BB syndrome.
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Anomalías Múltiples/genética , Hipogonadismo/genética , Discapacidad Intelectual/genética , Trastornos de la Motilidad Ocular/genética , Atrofia Óptica/genética , Polidactilia/genética , Retinitis Pigmentosa/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Niño , Diagnóstico Diferencial , Electrorretinografía , Femenino , Fondo de Ojo , Humanos , Hipogonadismo/diagnóstico , Discapacidad Intelectual/diagnóstico , Masculino , Trastornos de la Motilidad Ocular/diagnóstico , Trastornos de la Motilidad Ocular/fisiopatología , Atrofia Óptica/diagnóstico , Atrofia Óptica/fisiopatología , Fenotipo , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/fisiopatología , Síndrome , Agudeza Visual , Campos VisualesRESUMEN
AIMS: To assess the effects of the nitric oxide donor 5-isosorbide mononitrate (ISMO) on blood flow in the optic nerve head (ON flow) and choroid (Ch flow). METHODS: Laser Doppler flowmetry was used to measure ON flow and Ch flow in 12 normal subjects by aiming the laser beam at the fovea and at the temporal rim, respectively. In a double masked, randomised, crossover design, each subject received orally on separate days either 20 mg of 5-isosorbide mononitrate (ISMO) or placebo. Ch flow and ON flow were determined monocularly at baseline and 1 hour after dosing. In the last six subjects, additional measurements were obtained at 3 hours. Mean arterial blood pressure (BPm), heart rate, and intraocular pressure (IOP) were monitored, and ocular perfusion pressure (PP) was estimated. RESULTS: No significant changes in ON flow, PP, IOP, or BPm were observed following placebo. Following ISMO, ON flow increased from baseline by 19.8% (SEM 9.3%) at 1 hour (paired t test, p = 0.058) and by 33.1% (7.5%) at 3 hours (p = 0.007). Compared with the changes following placebo, statistically significant increases in ON flow were observed both at 1 (p = 0.050) and 3 hours (p = 0.041) after ISMO treatment. Compared with placebo, PP decreased significantly 1 hour after ISMO dosing (p = 0.039), mainly as a function of reduced BPm. A significant inverse correlation (R = -0.618; p = 0.032) was observed between the percentage changes in PP and ON flow 1 hour following ISMO administration, but not after placebo. No significant change in foveal Ch flow was documented. CONCLUSIONS: These results suggest that, in normal subjects, ISMO increases significantly ON flow but not Ch flow. The inverse correlation observed between PP and ON flow suggests that the same mechanism(s) responsible for systemic vasodilatation and blood pressure decrease may also cause the ON flow increase.
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Coroides/efectos de los fármacos , Dinitrato de Isosorbide/análogos & derivados , Nervio Óptico/efectos de los fármacos , Vasodilatadores/farmacología , Adulto , Velocidad del Flujo Sanguíneo , Volumen Sanguíneo , Coroides/irrigación sanguínea , Coroides/fisiopatología , Estudios Cruzados , Método Doble Ciego , Humanos , Dinitrato de Isosorbide/farmacología , Nervio Óptico/irrigación sanguínea , Nervio Óptico/fisiopatología , Agudeza Visual/fisiologíaRESUMEN
Two genetically engineered strains of mice were used to characterize murine cone function electroretinographically, without interference of rod-driven responses: (1) mice with a deletion of the gene for the rod transducin alpha-subunit (transducin alpha-/-), and (2) mice with rod arrestin deleted (arrestin -/-). In the first three months of age, both strains have a normal complement of rods and normal rod structure, but transducin alpha-/- mice have no rod-driven responses to light, while rod-driven activity of arrestin -/- mice can be suppressed by a single intense flash for hours. In response to intense flashes the electroretinograms of these strains of mice showed a readily identifiable, pure-cone a-wave of approximately 10 microV saturating amplitude. A 530 nm background that saturates rod responses of wild type mice was found to desensitize the b-wave responses of mice of both transgenic lines, whether the b-waves were driven by photons captured by M- or UV-cone pigments. The desensitizing effect of the 530 nm background on UV-pigment driven responses provides new evidence in support of the hypothesis of functional co-expression of the M-pigment in cones expressing primarily the UV-pigment.
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Arrestina/genética , Células Fotorreceptoras Retinianas Conos/fisiopatología , Enfermedades de la Retina/fisiopatología , Células Fotorreceptoras Retinianas Bastones , Transducina/genética , Animales , Electrorretinografía , Ratones , Ratones Transgénicos , Modelos Animales , Estimulación Luminosa , Enfermedades de la Retina/terapiaRESUMEN
AIMS: To investigate whether plasma levels of endothelin-1 (ET-1), a potent vasoconstricting peptide that is crucial in regulating retinal blood flow, were elevated in patients with retinal vein occlusion (RVO). METHODS: ET-1 plasma concentrations were determined by radioimmunoassays in a double blind fashion in a group of 18 selected patients with RVO, in 20 healthy age matched non-smoking, normoglycaemic, normotensive control subjects, and in 15 patients with uncomplicated essential hypertension in the same age range. RESULTS: Patients with RVO had significantly increased ET-1 plasma levels (14.22 (SD 4.6) pg/ml) compared with both normal subjects (7.90 (1.6) pg/ml; p < 0.05) and hypertensive patients (8.50 (2.9) pg/ml; p < 0.05). The highest concentrations of circulating ET-1 were found in patients with RVO of the ischaemic type (16.97 (3.5) pg/ml; p < 0.01; n = 7). Systemic hypertension alone did not account for the observed increase in plasma ET-1 concentrations. CONCLUSIONS: These findings raise the possibility that the increased circulating ET-1 levels in patients with RVO may be a marker of the occlusive event, thereby suggesting that ET-1 homeostasis may be relevant to RVO pathogenesis and retinal ischaemic manifestations.
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Endotelina-1/sangre , Oclusión de la Vena Retiniana/sangre , Adulto , Anciano , Biomarcadores/sangre , Método Doble Ciego , Femenino , Humanos , Hipertensión/sangre , Isquemia/etiología , Masculino , Persona de Mediana Edad , Hipertensión Ocular/sangre , Oclusión de la Vena Retiniana/complicaciones , Vasos RetinianosRESUMEN
PURPOSE: The purpose of this randomized double-masked cross-over study was to determine the effects of 20 mg of 5-isosorbide mononitrate (ISMO) on the retinal hemodynamics of young healthy subjects. METHODS: Monochromatic fundus photography and bidirectional laser Doppler velocimetry (BLDV) were used to determine vascular diameters (D), and blood velocity (V(max)) and flow (Q) in retinal veins, respectively. The diameter of the vein [D((vein))] at the same location where BLDV measurements were made, and the diameter of a neighboring artery [D((art) )], were determined from the fundus photographs. Measurements were carried out one and three hours after ISMO dosing, on twelve and six subjects, respectively. Mean blood pressure (BP(m)) and intraocular pressure (IOP) were also monitored, and ocular perfusion pressure (PP) was calculated. Results are expressed in percentage changes (+/- the standard error of the mean). RESULTS: On average, we observed a moderate increase of Q one hour after ISMO dosing (+8.2 +/- 5.4%), but not after placebo (+2.7 +/- 1.6%). This effect of ISMO, which displayed remarkable interindividual variability (95% confidence interval: -3.9%, +20.4%), did not attain statistical significance. D((vein)) and D((art)) were not appreciably affected. No effect was observed three hours after either ISMO or placebo dosing. PP was reduced one hour following ISMO administration, mainly as a function of reduced BP(m), although this variation was not statistically significant. IOP did not change appreciably throughout the duration of the study. CONCLUSIONS: Our findings suggest that, in contrast to the optic nerve head, in which we previously documented consistent and significant increases in blood flow following ISMO administration at both one and three hours, retinal hemodynamics are not equally responsive to a single dose of ISMO at these time points. Marked interindividual variability to the effects of this long-acting nitric oxide donor was documented one hour after administration, but not at three hours. This study further suggests that distinct vascular tissues of the ocular microcirculation respond differently to identical pharmacological challenges.
Asunto(s)
Dinitrato de Isosorbide/análogos & derivados , Vasos Retinianos/efectos de los fármacos , Vasodilatadores/farmacología , Adulto , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Ojo/irrigación sanguínea , Hemodinámica/efectos de los fármacos , Humanos , Presión Intraocular/efectos de los fármacos , Dinitrato de Isosorbide/farmacología , Flujometría por Láser-Doppler , Flujo Sanguíneo Regional/efectos de los fármacos , Vasos Retinianos/fisiología , Factores de TiempoRESUMEN
A study on the determination of environmental hexavalent chromium [Cr(VI)] was carried out in a chromium and zinc plating plant. The atmospheric particulate was collected both on glass wool filters and with an electrostatic sampler; Cr(VI) was determined by the S-diphenylcarbazide method. The filtered and electrostatically collected Cr(VI) was extracted with both 1.4% sulfuric acid and 7% sodium carbonate. Strong interference was observed when extraction was carried out with the acid medium. Alkaline extraction permits 95 +/- 6 (+/- SD)% recovery of the total chromium and has been shown to be suitable in releasing Cr(VI). The analyses of the alkaline samples were carried out with the standard addition method to compensate for a depressive interference of 26 +/- 8 (+/- SD)%. The absorbance decrease of the Cr-S-diphenylcarbazide complex is a time function, and it should be measured within a few minutes of the reagent addition.
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Contaminantes Ocupacionales del Aire/análisis , Contaminantes Atmosféricos/análisis , Cromo/análisis , Metalurgia , Difenilcarbazida , Indicadores y Reactivos , Espectrofotometría , ZincRESUMEN
The authors discuss the problems of emergency treatment of cavernous hemangiomas of the liver. Five cases were observed and treated with different techniques, ligation of the hepatic artery, excision of the mass, embolization of the hepatic artery. The results of these procedures were strongly influenced by the patient's previous state. Treatment was successful in three patients, while the procedure adopted was able to stop the hemorrage in the other two patients. The physical state was very important for the prognosis; the two patients arriving at our Institute in deep shock both died.