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The generation of distinct messenger RNA isoforms through alternative RNA processing modulates the expression and function of genes, often in a cell-type-specific manner. Here, we assess the regulatory relationships between transcription initiation, alternative splicing, and 3' end site selection. Applying long-read sequencing to accurately represent even the longest transcripts from end to end, we quantify mRNA isoforms in Drosophila tissues, including the transcriptionally complex nervous system. We find that in Drosophila heads, as well as in human cerebral organoids, 3' end site choice is globally influenced by the site of transcription initiation (TSS). "Dominant promoters," characterized by specific epigenetic signatures including p300/CBP binding, impose a transcriptional constraint to define splice and polyadenylation variants. In vivo deletion or overexpression of dominant promoters as well as p300/CBP loss disrupted the 3' end expression landscape. Our study demonstrates the crucial impact of TSS choice on the regulation of transcript diversity and tissue identity.
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Empalme Alternativo , Isoformas de ARN , Sitio de Iniciación de la Transcripción , Humanos , Poliadenilación , Regiones Promotoras Genéticas , Isoformas de ARN/metabolismo , ARN Mensajero/metabolismoRESUMEN
PURPOSE: To evaluate Hugo RAS against the Da Vinci system for Robot-Assisted Radical Prostatectomy (RARP) in prostate cancer treatment. METHODS: We compared outcomes of 150 patients with prostate cancer undergoing RARP with either Hugo or Da Vinci systems. Our analysis included operative, postoperative, pathological, and functional outcomes. RESULTS: Both groups had 75 patients. Baseline characteristics and tumor features were similar. Intraoperatively, Da Vinci had a shorter docking time (10.45 vs. 18.62 min, p = 0.02), but total operative times were comparable (145.34 vs 138.95, p = 0.85). Hugo outperformed in neck dissection and lymphadenectomy times (22 vs 13.67 min, p = 0.027 and 37.82 vs 45.77 min, p = 0.025). Postoperative metrics like stay duration, catheter time, and complications showed no significant difference. Functional results, using IPSS and IIEF5, were similar between systems. Six Da Vinci patients (8%) and nine Hugo patients (12%) experienced social incontinence (p = 0.072). Pathological outcomes like T stage, Gleason Score, and nodes removed were alike. However, Hugo had more positive surgical margins (20% vs. 10.67%, p = 0.034). CONCLUSIONS: RARP outcomes using Hugo RAS were similar to the Da Vinci system in our study. More research and extended follow-up are required to ascertain long-term oncological and functional results.
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Prostatectomía , Neoplasias de la Próstata , Procedimientos Quirúrgicos Robotizados , Humanos , Prostatectomía/métodos , Masculino , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/patología , Persona de Mediana Edad , Estudios Prospectivos , Anciano , Resultado del TratamientoRESUMEN
BACKGROUND: Plantar ulcers, which commonly occur in leprosy patients, tend to recur increasing physical disability. The aim of this study is to identify both the bacteriological profile of these ulcers and the antibiotic susceptibility of the isolated bacteria. MATERIALS AND METHODS: 68 leprosy patients with chronic ulcers attending the in-patient department of Gambo General Hospital, West Arsi, were included in this study. Proper sample collection, inoculation on culture media, and final identification using biochemical methods were undertaken. RESULTS: 66 patients (97.1%) had a positive culture. A total of 81 microorganisms were isolated. Multiple organisms (two or more) were isolated in 15 (22.7% out of positive culture) patients. The main isolation was Proteus spp (30.9%), followed by Escherichia coli (21.0%), Staphylococcus aureus (18.5%) and Pseudomonas aeruginosa (9.9%). In the total number of the isolated bacteria, the antibiotics with less resistance were gentamicin (18.5%), fosfomycin (22.2%) cefoxitin (24.7%), ceftriaxone (25.9%) ciprofloxacin (25.9%), and amoxicillin-clavulanic acid (28.49%). CONCLUSION: The bacteriological study of plantar ulcers of leprosy patients revealed Enterobacteriaceae and S. aureus as the main pathogens involved in such infections. The results of this study may guide empirical therapy in a rural area hospital where culture and susceptibility testing facilities are scarce.
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Antibacterianos/farmacología , Bacterias Aerobias/efectos de los fármacos , Bacterias Aerobias/aislamiento & purificación , Farmacorresistencia Bacteriana , Úlcera del Pie/microbiología , Lepra/complicaciones , Lepra/patología , Adolescente , Adulto , Anciano , Bacterias Aerobias/clasificación , Estudios Transversales , Enterobacteriaceae/clasificación , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/aislamiento & purificación , Etiopía , Femenino , Hospitales Rurales , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Prospectivos , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/aislamiento & purificación , Adulto JovenRESUMEN
BACKGROUND: Robot-assisted partial nephrectomy (RAPN) has emerged as the preferred approach for T1 renal-cell-carcinoma. As new robotic platforms like Hugo RAS emerge, we seek to understand their potential in achieving similar RAPN outcomes as the established Da Vinci system. METHODS: A prospective single-center comparative study was conducted, and 50 patients selected for RAPN were enrolled (25 Da Vinci Xi; 25 Hugo RAS). The choice of robotic system was based solely on hospital logistics criteria. Surgeries were performed by expert surgeons. Demographic data, tumor characteristics, operative details and postoperative outcomes were collected. SPSS version 22.0 was used for statistical analyses. RESULTS: The average age of patients was 62.52±9.47 years, with no significant differences in median age, sex, and nephrometry scores between groups. Da Vinci group showed a significantly shorter docking time (12.56 vs. 20.08 min; P<0.01), while other intraoperative measures like console time and warm ischemia time were similar. The Hugo RAS group had a shorter renorraphy time (14.33 vs. 18.84 min; P=0.024). Postoperative outcomes and surgical margin positivity showed no significant differences. Each group had one patient (4%) who developed major surgical complications (Clavien IIIa). Trifecta rates were comparable between both groups (Da Vinci 88% vs. Hugo RAS 84%; P=0.93). CONCLUSIONS: Initial findings suggest similar perioperative outcomes for RAPN when using Hugo RAS compared to the Da Vinci system. Further research with long-term follow-up is necessary to evaluate oncological and functional outcomes.
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Carcinoma de Células Renales , Neoplasias Renales , Nefrectomía , Procedimientos Quirúrgicos Robotizados , Humanos , Procedimientos Quirúrgicos Robotizados/métodos , Procedimientos Quirúrgicos Robotizados/instrumentación , Nefrectomía/métodos , Nefrectomía/instrumentación , Femenino , Persona de Mediana Edad , Estudios Prospectivos , Masculino , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Resultado del Tratamiento , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Anciano , Tempo OperativoRESUMEN
BACKGROUND: Benign prostatic hyperplasia (BPH) commonly causes lower urinary tract symptoms (LUTS) in men. Holmium (HoLEP) and thulium (ThuLEP) laser enucleation are established techniques for BPH treatment. Thulium fiber laser (TFL) for prostate enucleation (ThuFLEP) shows promising outcomes. METHODS: A prospective randomized multicenter study was conducted. Patients with BPH and LUTS unresponsive to medical therapy were enrolled. Preoperative, surgical, perioperative and postoperative data were recorded with follow-up at 3 and 6 months. The primary outcome was functional improvement, and the secondary outcome was safety in terms of complications. RESULTS: Two hundred patients were included (HoLEP 100, ThuFLEP 100). No significant baseline difference was found between groups. At 3 and 6 months we found statistically significant improvements from baseline for both HoLEP and ThuFLEP in efficacy: International Prostatic Symptoms Score (IPSS), IPSS-Quality of Life (QoL), maximum urinary flow rate (Q
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Láseres de Estado Sólido , Hiperplasia Prostática , Tulio , Humanos , Masculino , Hiperplasia Prostática/cirugía , Estudios Prospectivos , Anciano , Láseres de Estado Sólido/uso terapéutico , Persona de Mediana Edad , Terapia por Láser/métodos , Terapia por Láser/instrumentación , Terapia por Láser/efectos adversos , Resultado del Tratamiento , Síntomas del Sistema Urinario Inferior/cirugía , Síntomas del Sistema Urinario Inferior/etiología , Calidad de Vida , Prostatectomía/métodos , Prostatectomía/efectos adversos , HolmioRESUMEN
In mammals, the cytokine IL-7 is a key regulator of various aspects of lymphocyte differentiation and homeostasis. Because of the difficulty of identifying cytokine homologs in lower vertebrates and the paucity of assay systems and reagents, the degree of functional conservation of cytokine signaling pathways, particularly those pertaining to lymphocyte development, is unclear. In this article, we report on the analysis and characterization of three zebrafish mutants with severely impaired thymopoiesis. The identification of affected genes by positional cloning revealed components of the IL-7 signaling pathway. A presumptive null allele of the zebrafish homolog of the IL-7Rα-chain causes substantially reduced cellularity of the thymus but spares B cell development in the kidney. Likewise, nonsense mutations in the zebrafish homologs of janus kinases JAK1 and JAK3 preferentially affect T cell development. The functional interactions of the cytokine receptor components were examined in the three groups of fish hetero- or homozygous for either il7r and jak1, il7r and jak3, or jak1 and jak3 mutations. The differential effects on T cell development arising from the different genotypes could be explained on the basis of the known structure of the mammalian IL-7R complex. Because IL-7 signaling appears to be a universal requirement for T cell development in vertebrates, the mutants described in this article represent alternative animal models of human immunodeficiency syndromes amenable to large-scale genetic and chemical screens.
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Evolución Molecular , Receptores de Interleucina-7/genética , Transducción de Señal/inmunología , Linfocitos T/citología , Pez Cebra/inmunología , Animales , Interleucina-7/fisiología , Mutación , Especificidad de Órganos , Linfocitos T/inmunología , Timo/citología , Timo/crecimiento & desarrolloRESUMEN
Mutation in the protocadherin 19 (PCDH19) gene is an increasingly recognized cause of epilepsy in females. This disorder is frequently associated with mental retardation and psychiatric features. We describe two unrelated females with novel PCDH19 missense mutations. One was de novo, and the other was inherited from her unaffected father. Both had mild mental impairment but had remarkable behavioral problems. We reviewed the cognitive and behavioral profiles of previously reported PCDH19-positive cases. Intellectual disability appeared in 75% of patients, ranging from borderline to severe. More than half of the individuals presented behavioral disturbances, which could be divided into two different groups: autistic and non-autistic. The majority of patients with autism already had some degree of cognitive impairment. It appears that seizures tend to diminish or even stop in adolescence, so non-epileptic problems can become the most important and disabling issue in adult patients with PCDH19 mutation.
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Síntomas Conductuales/etiología , Cadherinas/genética , Trastornos del Conocimiento/etiología , Epilepsia/complicaciones , Epilepsia/genética , Mutación/genética , Síntomas Conductuales/genética , Niño , Trastornos del Conocimiento/genética , Femenino , Humanos , Pruebas Neuropsicológicas , Protocadherinas , Escalas de Valoración Psiquiátrica , Adulto JovenRESUMEN
Cell-type-specific gene regulatory programs are essential for cell differentiation and function. In animal neurons, the highly conserved ELAV/Hu family of proteins promotes alternative splicing and polyadenylation of mRNA precursors to create unique neuronal transcript isoforms. Here, we assess transcriptome profiles and neurogenesis success in Drosophila models engineered to express differing levels of ELAV activity in the course of development. We show that the ELAV-mediated establishment of a subset of neuronal mRNA isoforms at the onset of neuron differentiation constitutes a developmental bottleneck that cannot be overcome later by the nuclear activation of the paralog found in neurons (FNE). Loss of ELAV function outside of that critical time window results in neurological defects. We find that FNE, when activated early enough, can restore ELAV-dependent neuronal mRNA isoforms and fully rescue development. Our findings demonstrate the essential role of robust cellular strategies to maintain ELAV activity and intact neuronal signatures in neurogenesis and neuronal function.
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Proteínas de Drosophila , Animales , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas ELAV/genética , Isoformas de ARN/metabolismo , Drosophila/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas de Unión al ARN/metabolismoRESUMEN
Introduction: Treatment of radio-recurrent prostate cancer (PC) is managed mainly by androgen deprivation therapy. Nonetheless, selected patients could benefit from local salvage treatment options.In this study we present our series of recurrent PC cases submitted to laparoscopic salvage radical prostatectomy (sRP) at our institution. Material and methods: A total of 29 patients with recurrent PC after primary non-surgical treatment were submitted to laparoscopic sRP at our institution, with a mean follow-up time of 7 years. Results: There were 7 post-operative complications Clavien-Dindo grade ≥2. At the end of the follow-up, 58.6% patients presented biochemical recurrence and five-year recurrence-free survival (RFS) was 50%.Positive lymph nodes, high preoperative prostate-specific antigen (PSA) and TNM stage were correlated with worse RFS. Cox regression analysis demonstrated that stage pT3b was independently associated with worse RFS in comparison with stage pT3a or less.At 12 months, pad-free continence or mild incontinence was observed in 62% of the patients. Conclusions: sRP is a technically challenging surgery, and in our series, we were able to perform this procedure with acceptable operative time and limited blood loss.Post-operative complications, functional results and oncological outcomes were similar to other published studies, being our series, to the best of our knowledge, the one with the longest follow-up, of 7 years.sRP is a feasible local treatment with curative intent for radio-recurrent prostate cancer, with good oncological outcomes and reasonable continence rates in selected patients.
RESUMEN
To capture the global gene network regulating the differentiation of immature T cells in an unbiased manner, large-scale forward genetic screens in zebrafish were conducted and combined with genetic interaction analysis. After ENU mutagenesis, genetic lesions associated with failure of T cell development were identified by meiotic recombination mapping, positional cloning, and whole genome sequencing. Recessive genetic variants in 33 genes were identified and confirmed as causative by additional experiments. The mutations affected T cell development but did not perturb the development of an unrelated cell type, growth hormone-expressing somatotrophs, providing an important measure of cell-type specificity of the genetic variants. The structure of the genetic network encompassing the identified components was established by a subsequent genetic interaction analysis, which identified many instances of positive (alleviating) and negative (synthetic) genetic interactions. Several examples of synthetic lethality were subsequently phenocopied using combinations of small molecule inhibitors. These drugs not only interfered with normal T cell development, but also elicited remission in a model of T cell acute lymphoblastic leukaemia. Our findings illustrate how genetic interaction data obtained in the context of entire organisms can be exploited for targeted interference with specific cell types and their malignant derivatives.
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Redes Reguladoras de Genes , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Mutaciones Letales Sintéticas , Linfocitos T/metabolismo , Animales , Modelos Animales de Enfermedad , Epistasis Genética , Fenotipo , Pez CebraRESUMEN
We describe the case of a 74-year-old woman with previous history of gastric signet cell carcinoma who develops bladder metastasis as first sign of recurrence 6 years later. Bladder metastasis due to signet cell carcinoma is extremely rare with only 19 cases reported. Treatment includes radical cystectomy or chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células en Anillo de Sello , Cistectomía/métodos , Neoplasias Gástricas , Neoplasias de la Vejiga Urinaria , Anciano , Carcinoma de Células en Anillo de Sello/patología , Carcinoma de Células en Anillo de Sello/secundario , Quimioterapia Adyuvante/métodos , Femenino , Fluorouracilo/administración & dosificación , Gastrectomía/efectos adversos , Gastrectomía/métodos , Humanos , Inmunohistoquímica , Leucovorina/administración & dosificación , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/patología , Compuestos Organoplatinos/administración & dosificación , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Tomografía Computarizada por Rayos X/métodos , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/secundarioRESUMEN
The MHC class I-related receptor, FcRn, is involved in binding and transporting immunoglobulin G (IgG) within and across cells. In contrast to mouse FcRn, which binds to IgGs from multiple different species, human FcRn is surprisingly stringent in binding specificity. For example, human FcRn does not bind to mouse IgG1 or IgG2a and interacts only weakly with mouse IgG2b. Here, we have used site-directed mutagenesis in combination with interaction (surface plasmon resonance) studies, with the goal of generating human FcRn variants that more closely resemble mouse FcRn in binding specificity. Our studies show that residues encompassing and extending away from the interaction site on the alpha2 helix of FcRn play a significant and most likely indirect role in FcRn-IgG interactions. Further, by combining mutations in the alpha2 helix with those in a non-conserved region of the alpha1 helix encompassing residues 79-89, we have generated a human FcRn variant that has properties very similar to those of mouse FcRn. These studies define the molecular basis for the marked difference in binding specificity between human and rodent FcRn, and give insight into how human FcRn recognizes IgGs.
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Mutagénesis Sitio-Dirigida/genética , Receptores Fc/genética , Receptores Fc/metabolismo , Secuencia de Aminoácidos , Animales , Antígenos de Histocompatibilidad Clase I , Humanos , Concentración de Iones de Hidrógeno , Inmunoglobulina G/inmunología , Inmunoglobulina G/metabolismo , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica , Conformación Proteica , Receptores Fc/química , Receptores Fc/inmunología , Alineación de Secuencia , Resonancia por Plasmón de SuperficieRESUMEN
Lymphocytes represent basic components of vertebrate adaptive immune systems, suggesting the utility of non-mammalian models to define the molecular basis of their development and differentiation. Our forward genetic screens in zebrafish for recessive mutations affecting early T cell development revealed several major genetic pathways. The identification of lineage-specific transcription factors and specific components of cytokine signaling and DNA replication and/or repair pathways known from studies of immunocompromised mammals provided an evolutionary cross-validation of the screen design. Unexpectedly, however, genes encoding proteins required for pre-mRNA processing were enriched in the collection of mutants identified here. In both zebrafish and mice, deficiency of the splice regulator TNPO3 impairs intrathymic T cell differentiation, illustrating the evolutionarily conserved and cell-type-specific functions of certain pre-mRNA-processing factors for T cell development.
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Pruebas Genéticas , Precursores del ARN/genética , Procesamiento Postranscripcional del ARN/genética , Linfocitos T/citología , Linfocitos T/metabolismo , Pez Cebra/genética , Empalme Alternativo/genética , Animales , Epistasis Genética , Regulación del Desarrollo de la Expresión Génica , Larva/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación/genética , Especificidad de Órganos/genética , Precursores del ARN/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribonucleoproteínas Nucleares Pequeñas/metabolismo , Transcriptoma/genética , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , beta Carioferinas/deficiencia , beta Carioferinas/metabolismoRESUMEN
A 19-year-old woman was born with congenital hypotonia, generalized weakness, and dysmorphic features. A muscle biopsy performed at age 18 months found that type I fibers were smaller and more numerous than type II fibers, and she was diagnosed with congenital fiber type disproportion. She grew up with moderate motor impairment, but after a stationary period her weakness progressed gradually and she developed a severe ophthalmoplegia. When she was 18 years old a second muscle biopsy still indicated the predominance of type I fibers but also the presence of central nuclei and strong oxidative enzyme activity in the center of most of the fibers; this was compatible with centronuclear myopathy. The diagnostic reconsideration raises questions about the pathogenesis of these diseases and the recognition of congenital fiber type disproportion as a distinct nosologic entity.
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Hipotonía Muscular/patología , Músculo Esquelético/patología , Adolescente , Adulto , Biopsia , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Fibras Musculares de Contracción Rápida/patología , Fibras Musculares de Contracción Lenta/patología , Hipotonía Muscular/congénitoRESUMEN
Macrophagic myofasciitis is an unusual inflammatory myopathy, which has been almost exclusively reported in French adults with diffuse arthromyalgias and asthenia. It is characterized by an infiltrate of densely packed macrophages, with granular periodic-acid-Schiff positive content, on muscle biopsies at the site of vaccination. The presence of aluminum inclusions in these macrophages points to an inappropriate reaction to aluminum used as an adjuvant in some vaccines. Although in adults this entity is well defined, less than 15 cases have been reported in children. This study describes seven children, younger than 3 years of age, with typical lesions of macrophagic myofasciitis on quadriceps muscle biopsy. In five cases, biopsies were performed to exclude mitochondrial pathology. All the children developed hypotonia and motor or psychomotor delay, associated with others symptoms. Abnormal neuroimaging was evident in six cases. Spectrometry studies detected elevated levels of aluminum in muscle in three of four cases tested. Despite the wide use of vaccines in childhood, macrophagic myofasciitis was rarely observed in children and its characteristic histologic pattern could not be correlated with a distinctive clinical syndrome.
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Fascitis/patología , Macrófagos/patología , Miositis/patología , Aluminio/efectos adversos , Biopsia , Preescolar , Fascitis/inmunología , Femenino , Humanos , Cuerpos de Inclusión/patología , Cuerpos de Inclusión/ultraestructura , Lactante , Macrófagos/ultraestructura , Masculino , Microscopía Electrónica , Miositis/inmunología , Músculo Cuádriceps/patología , Vacunación/efectos adversosRESUMEN
Hepatitis B virus (HBV) infection is a worldwide public health problem. There are an estimated 350 million persons with chronic HBV infection that could progress to cirrhosis and hepatocarcinoma with nearly one million deaths per year. In the last few years the therapeutic options in chronic hepatitis B have increased and currently six treatments are authorized: standard interferon (IFN)-alpha, pegylated interferon-alpha (PEG-IFNalpha), lamivudine, adefovir, entecavir, and telbivudine. For the last 25 years, conventional IFNalpha has been used as the treatment of chronic hepatitis B (CHB) and currently PEG-IFNalpha is indicated due to its greater effectiveness. Both drugs are first line options for HBeAg(+) and HBeAg(-) CHB. The advantages of IFNalpha and PEG-IFNalpha are that these drugs are administered for a limited time period, they achieve a higher sustained response rate and do not induce HBV mutants with antiviral resistance. These drugs achieve greater HBeAG and HBsAG clearance due to their antiviral and immunomodulatory activity. PEG-IFNalpha induces sustained biochemical and virological response in approximately one third of patients with HBeAg(+) CHB. The best response to IFNalpha and PEG-IFNalpha is obtained in patients with elevated transaminase levels, moderate viral load and HBV genotypes A and B. The disadvantages of IFNalpha and PEG-IFNalpha are their adverse effects and contraindications. These drugs cannot be administered in patients with decompensated cirrhosis. The combination of nucleos(t)ide analogs with PEG-IFNalpha could achieve much higher sustained response rates; however, which treatment constitutes the most suitable therapeutic strategy requires investigation.
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Antivirales/uso terapéutico , Hepatitis B/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Adenina/administración & dosificación , Adenina/análogos & derivados , Adenina/uso terapéutico , Antivirales/administración & dosificación , Antivirales/efectos adversos , Ensayos Clínicos como Asunto/estadística & datos numéricos , Quimioterapia Combinada , Genotipo , Guanina/administración & dosificación , Guanina/análogos & derivados , Guanina/uso terapéutico , Antígenos e de la Hepatitis B/análisis , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/fisiología , Hepatitis B Crónica/tratamiento farmacológico , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interferón-alfa/farmacología , Lamivudine/administración & dosificación , Lamivudine/uso terapéutico , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Nucleósidos/administración & dosificación , Nucleósidos/uso terapéutico , Organofosfonatos/administración & dosificación , Organofosfonatos/uso terapéutico , Polietilenglicoles/efectos adversos , Polietilenglicoles/uso terapéutico , Pirimidinonas/administración & dosificación , Pirimidinonas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Proteínas Recombinantes , Telbivudina , Timidina/análogos & derivados , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: CXCR3 and CCR5 play a major role in recruiting cytotoxic T cells (Tc) and secreting secondary type 1 cytokines (Tc1) in the liver. HCV could impair their expression as a survival mechanism. The role of these chemokine receptors on CD8+ cells in chronic hepatitis C is analysed. METHODS: Serum, chemokines, peripheral blood and intrahepatic lymphocytes from chronic hepatitis C patients were studied. CXCR3/CCR5 expressing CD8+ cells were quantified by flow-cytometry. Serum chemokines concentration (CXCL10/CCL3) was measured by ELISA. Basal data were correlated with liver inflammation. Longitudinal data were obtained during treatment and correlated with virologic response. RESULTS: CCR5/CXCR3 expressing CD8+ cells were enriched in the liver and correlated with inflammation. Chronic HCV patients presented the same frequency of CCR5(high)/CXCR3(high) expressing CD8+ cells in peripheral blood as in healthy controls but higher serum concentration of CXCL10/CCL3. Treatment with PEG-interferon alpha-2b plus ribavirin increased CCR5(high)/CXCR3(high) expressing CD8+ cells frequency in peripheral blood and decreased CXCL10/CCL3 serum concentration. Increase in CXCR3(high) expressing CD8+ cells after 24 weeks of treatment was correlated with SVR. CONCLUSIONS: In chronic hepatitis C, anti-viral treatment induces an increase in CD8+ cells expressing chemokine receptors associated with Tc1 response and a reduction in their ligands. Achievement of viral control is associated with an increase in CXCR3(high) expressing CD8+ cells during treatment.
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Linfocitos T CD8-positivos/inmunología , Hepacivirus/inmunología , Hepatitis C/inmunología , Hepatitis C/virología , Receptores CCR5/inmunología , Receptores CXCR3/inmunología , Adulto , Muerte Celular/efectos de los fármacos , Muerte Celular/inmunología , Quimiocina CCL3/sangre , Quimiocina CCL3/inmunología , Quimiocina CXCL10/sangre , Quimiocina CXCL10/inmunología , Enfermedad Crónica/terapia , Citocinas/inmunología , Citocinas/metabolismo , Femenino , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Humanos , Interferón-alfa/farmacología , Interferón-alfa/uso terapéutico , Hígado/inmunología , Hígado/fisiopatología , Hígado/virología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Receptores CCR5/sangre , Receptores CXCR3/sangre , Linfocitos T Citotóxicos/inmunología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunologíaRESUMEN
We report a case of symptomatic epidural lipomatosis in an 8-year-old girl with Cushing's syndrome secondary to longstanding high-dose steroid therapy for Crohn's disease. MR imaging of the spine revealed massive diffuse epidural fat compressing the entire spinal cord with T2 prolongation in the central gray matter of the cord suggesting ischemic myelopathy. This finding has not been previously demonstrated on imaging. A proposed mechanism underlying these findings is discussed.
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Lipomatosis/diagnóstico , Compresión de la Médula Espinal/diagnóstico , Niño , Enfermedad de Crohn/complicaciones , Síndrome de Cushing/complicaciones , Diagnóstico Diferencial , Espacio Epidural , Resultado Fatal , Femenino , Humanos , Lipomatosis/etiología , Imagen por Resonancia Magnética , Compresión de la Médula Espinal/etiologíaRESUMEN
Fibromuscular dysplasia (FMD) is a systemic arteriopathy which tends to affect renal arteries followed by cervicocranial vessels. It can lead to cerebral infarction if cephalic arteries are involved. FMD is an unusual cause of stroke in childhood that generally affects the carotid area. Only four cases of vertebral FMD and subsequent stroke have been reported previously and we present the youngest patient of all. A healthy 3-year-old female was admitted to Hospital Doce de Octubre in Madrid, Spain with cerebellar infarction. Angiography disclosed basilar artery thrombosis and typical signs of FMD in both vertebral arteries. No other angiographic alteration was noted in the other vessels studied. Her phenotype and other investigations were unremarkable. The patient was treated with anti-aggregation therapy (aspirin) and the outcome was excellent. Investigation of the occurrence in childhood of this kind of arteriopathy may lead to clarification of its natural history and speculation about its unclear pathogenesis.