RESUMEN

Galloway-Mowat syndrome is a rare condition that is likely hereditary though the underlying offending gene has not been identified, and is characterized by microcephaly and severe nephrotic syndrome culminating in childhood death. Some of the reported cases have abnormalities in neuronal migration and intractable seizures, but many of the described cases focus on the renal pathology and emphasize a diversity of clinical and pathological features. The case described herein includes a thorough neuropathological description, and when the neuroradiology and neuropathology of the previously published cases is scrutinized, a fairly consistent clinical and neuropathological phenotype emerges.

Asunto(s)

Encéfalo/patología , Epilepsia/complicaciones , Microcefalia/complicaciones , Muerte Celular/fisiología , Epilepsia/patología , Hernia Hiatal/complicaciones , Hernia Hiatal/patología , Humanos , Lactante , Masculino , Microcefalia/patología , Nefrosis/complicaciones , Nefrosis/patología

Asunto(s)

Mastocitosis Sistémica/tratamiento farmacológico , Pirimidinas/uso terapéutico , Tiazoles/uso terapéutico , Adulto , Dasatinib , Femenino , Humanos , Masculino , Mastocitosis Sistémica/genética , Persona de Mediana Edad

RESUMEN

In vitro and in vivo experimental studies suggest that the transcription factor NF-kappaB plays a role in tubulointerstitial injury. We investigated possible cellular and molecular mechanisms involving NF-kappaB activation in the progression of tubulointerstitial lesions in human lupus nephritis (LN). Paraffin-embedded renal biopsies from 50 patients with LN and six control patients with minimal change disease (MCD) were examined by Southwestern histochemistry for in situ detection of active NF-kappaB and AP-1. Immunohistochemistry was performed to examine the expression of NF-kappaB, AP-1, and NF-kappaB regulatory proteins (IkappaB-alpha, p-IkappaB-alpha, and IKK-alpha proteins), as well as NF-kappaB and AP-1 downstream target proinflammatory molecules (ICAM-1, TNF-alpha, IL-1beta, IL-6, and GM-CSF) and NF-kappaB upstream signaling molecules (CD40 and CD40L). We observed extensive upregulation of activated NF-kappaB in renal tubular cells and interstitial cells, in parallel with overactivation of transcription factor AP-1 in LN, as compared with normal controls and MCD. Tubular expression of activated NF-kappaB correlated well with the degree of tubulointerstitial histopathological indices and/or renal function. Tubulointerstitial IKK-alpha expression was specifically upregulated in LN. IkappaB-alpha and p-IkappaB-alpha were detected only in interstitial cells in LN. Tubulointerstitial expression levels of NF-kappaB and AP-1 downstream inflammatory molecules and NF-kappaB upstream signaling molecules CD40 and CD40L were markedly enhanced in LN as compared with MCD or normal controls and were associated with tubulointerstitial histopathological indices and/or renal function. The results suggest that altered IKK-alpha expression and NF-kappaB activation along with AP-1 overexpression may play a pathogenic role in tubulointerstitial injury in human LN mediated through a network of downstream proinflammatory molecules.

Asunto(s)

Túbulos Renales/metabolismo , Nefritis Lúpica/patología , FN-kappa B/metabolismo , Adulto , Antígenos CD40/genética , Antígenos CD40/inmunología , Antígenos CD40/metabolismo , Ligando de CD40/genética , Ligando de CD40/inmunología , Ligando de CD40/metabolismo , Citocinas/genética , Citocinas/metabolismo , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Quinasa I-kappa B/genética , Quinasa I-kappa B/inmunología , Quinasa I-kappa B/metabolismo , Inmunohistoquímica , Inflamación/metabolismo , Inflamación/patología , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/inmunología , Molécula 1 de Adhesión Intercelular/metabolismo , Túbulos Renales/inmunología , Nefritis Lúpica/metabolismo , Masculino , FN-kappa B/genética , FN-kappa B/inmunología , Fosforilación , Transducción de Señal/inmunología , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/inmunología , Factor de Transcripción AP-1/metabolismo

RESUMEN

The mechanism of renal cell apoptosis involves transcriptional activation of the inducible nitric oxide synthase (iNOS) gene by nuclear factor (NF)-kappaB. The role of apoptosis in mediating tubulointerstitial injury in human lupus nephritis (LN) remains unclear. We examined the relationship between alterations in NF-kappaB activation and iNOS expression levels and the degree of apoptosis in both glomerular and tubulointerstitial compartments of subjects with LN. Studies were done in renal biopsies from 49 patients with LN and 10 normal kidney tissues. Apoptotic and proliferating cells were identified by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and staining with anti-proliferating cell nuclear antigen antibody, respectively. Nuclear factor-kappaB and iNOS expression was examined by Southwestern histochemistry and immunohistochemistry, respectively. Glomerular cell apoptosis and proliferation increased concomitantly in LN. Glomerular apoptosis correlated with the activity index, the degree of proliferation, and the level of glomerular overexpression of iNOS and activated NF-kappaB in LN. Tubular cell apoptosis correlated with the activity and chronicity indices, the degree of tubular atrophy, and decline in renal function at the time of biopsy. Tubular expression of iNOS and activated NF-kappaB correlated with tubular cell proliferation in LN. Nuclear factor-kappaB activation accompanied overexpression of iNOS in both glomerular and tubulointerstitium compartments in LN. Apoptosis of renal cells associated with NF-kappaB activation and iNOS overexpression may play an important role in mediating chronic renal injury, especially tubulointerstitial lesions that may manifest clinically as progressive renal insufficiency.

Asunto(s)

Apoptosis , Proliferación Celular , Nefritis Lúpica/enzimología , Nefritis Lúpica/fisiopatología , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Mesangio Glomerular/enzimología , Mesangio Glomerular/metabolismo , Humanos , Inmunohistoquímica , Túbulos Renales/enzimología , Túbulos Renales/metabolismo , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo II/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , Estudios Retrospectivos , Activación Transcripcional

RESUMEN

We report a rare presentation of a nested variant of urothelial carcinoma with liver and bone metastases in a 74-year-old man admitted to the hospital with bilateral hydronephrosis and acute renal failure. At cystoscopy, both ureters were obstructed, with the right ureter narrowed along its entire length. Subsequent histopathologic examination from the ureteral resection revealed nested variant of urothelial carcinoma. Bilateral stents were placed, and the patient survived 12 months with a good partial response to chemotherapy. A total of 76 cases of nested variant of urothelial carcinoma have been reported worldwide. Our patient was the first, to our knowledge, to present with bilateral hydronephrosis and tumor extension along one ureter.

Asunto(s)

Neoplasias Óseas/secundario , Carcinoma de Células Transicionales/secundario , Neoplasias Hepáticas/secundario , Neoplasias Ureterales/patología , Anciano , Neoplasias Óseas/patología , Carcinoma de Células Transicionales/clasificación , Carcinoma de Células Transicionales/patología , Resultado Fatal , Humanos , Neoplasias Hepáticas/patología , Masculino

RESUMEN

Nuclear Factor-kappaB (NF-kappaB) has been suggested to play a role in the cellular and molecular mechanisms underlying glomerular injury. We investigated the potential role of NF-kappaB activation in the pathogenesis of glomerular injury in 31 patients with class III-V lupus nephritis (LN), 14 patients with non-proliferative proteinuric glomerulopathy and six normal controls. The expression of NF-kappaB subunits p65 and p50, and the NF-kappaB regulated proinflammatory mediators tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) as well as CD68 and synaptopodin was examined by Southwestern histochemistry (SWH) or immunohistochemistry. In contrast to non-proliferative glomerulopathy and normal controls, NF-kappaB activation (both p65 and p50) was enhanced in glomerular endothelial, mesangial cells or infiltrating cells in class IV LN, along with upregulation of TNF-alpha, IL-1beta, IL-6 and ICAM-1 expression. Glomerular endothelial and mesangial activation of NF-kappaB and mesangial ICAM-1 expression correlated with disease activity and the level of glomerular macrophage infiltration. Podocyte NF-kappaB overactivation (predominantly p65) paralleled podocyte expression of TNF-alpha and IL-1beta in patients with LN and non-proliferative glomerulopathy. Podocyte staining scores of NF-kappaB and p65 were positively correlated with the severity of proteinuria in LN and non-proliferative glomerulopathy. These results suggest a pathogenic role for NF-kappaB in glomerular injury by multiple mechanisms.

Asunto(s)

Glomérulos Renales/patología , Nefritis Lúpica/patología , FN-kappa B/biosíntesis , Proteinuria/patología , Adulto , Femenino , Humanos , Inmunohistoquímica/métodos , Molécula 1 de Adhesión Intercelular/análisis , Interleucina-1beta/análisis , Interleucina-6/análisis , Glomérulos Renales/metabolismo , Nefritis Lúpica/metabolismo , Masculino , Persona de Mediana Edad , Subunidad p50 de NF-kappa B/análisis , Proteinuria/metabolismo , Factor de Transcripción ReIA/análisis , Factor de Necrosis Tumoral alfa/análisis

RESUMEN

In situ hybridization, immunohistochemistry, and TUNEL staining were applied to renal biopsy specimens of immunoglobulin A nephropathy (IgAN) patients to determine the expression of nitric oxide synthase (iNOS) (mRNA and protein), p53, and their potential roles in renal cell apoptosis in relation to the development of pathologic lesions. Fifty-one cases were categorized into four subgroups (A-D) according to the presence of progressive histopathological features. A cell type-specific and differential overexpression of iNOS mRNA and protein was demonstrated in glomerular cells in subgroups (A-C) and was found to correlate well with the upregulation of p53 protein by glomerular endothelium and epithelium in early- and advanced-stage disease. In the tubulointerstitium, induction of iNOS products was evident in damaged tubules in late-stage disease, in parallel with the upregulation of p53 protein levels in these tubules. Increased TUNEL staining observed in glomeruli with progressive lesions and tubules with degenerative changes positively correlated with the expression levels of iNOS and p53 in glomerular endothelium, epithelium, and their overexpression in damaged tubules. Clinicopathologic correlations demonstrated that induction of iNOS products in renal cells was associated with indices of poor renal prognosis in human IgAN. The coupled induction of iNOS and p53 upregulation in intrinsic renal cells of IgAN may be linked with both pro- and anti-apoptotic activities, thus playing an important role in mediating progressive renal injury and determining renal outcome in human IgAN.

Asunto(s)

Apoptosis/fisiología , Glomerulonefritis por IGA/metabolismo , Glomerulonefritis por IGA/patología , Óxido Nítrico Sintasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adolescente , Adulto , Anciano , Enfermedad Crónica , Células Epiteliales/enzimología , Células Epiteliales/patología , Femenino , Regulación Enzimológica de la Expresión Génica , Humanos , Glomérulos Renales/enzimología , Glomérulos Renales/patología , Masculino , Persona de Mediana Edad , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo II , Proteínas Nucleares/metabolismo , Pronóstico , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2 , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba

RESUMEN

The activities of cell cycle regulatory proteins have been reported to be associated with the development of pathological lesions in glomerulonephritis. To assess the cellular mechanisms underlying the mesangial cell proliferation and glomerulosclerosis in progressive human IgA nephropathy (IgAN), we examined the expression of E2F1, Rb, c-Myc, proliferating cell nuclear antigen (PCNA), cyclins (D1, E and A), cyclin-dependent kinase 2 (CDK2) and CDK inhibitors (p21(waf1), p27(kip1), 57(kip2) and p16(ink4a)) by immunohistochemistry in renal biopsy specimens. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) was also performed to detect the presence of apoptosis. In total, 51 cases of IgAN were categorized into four subgroups according to histological severity. A dramatic upregulation of E2F1 expression in mesangial cells was identified in proliferating glomeruli, which correlated well with the proliferation index. High endogenous expression of p27(kip1) and p57(kip2) by podocytes in normal glomeruli and glomeruli with minor lesions was observed to decrease in proliferating and sclerosing glomeruli; this pattern displayed a strong inverse correlation with the mean glomerulosclerosis score and the index of glomerular lesion. Increased apoptotic activity was identified in progressive glomerular lesions of advanced IgAN, which correlated with the proliferative activity in these lesions as assessed by total expression levels of PCNA and CDK2 in glomeruli, E2F1 expression levels in the mesangium, cyclin D1 expression levels in endothelium and the c-Myc glomerular staining score. Our results suggest that the onset and magnitude of mesangial cell proliferation and glomerulosclerosis is associated with the upregulation of E2F1 by mesangial cells and the downregulation of p27(kip1) and p57(kip2) by glomerular epithelial cells. The cell type-specific and coordinated regulation of proliferative and proapoptotic activities of cell cycle regulatory proteins may play an important role in mediating progressive glomerular injury in human IgAN.

Asunto(s)

Proteínas de Ciclo Celular/metabolismo , Glomerulonefritis por IGA/metabolismo , Glomerulonefritis por IGA/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Adolescente , Adulto , Anciano , Apoptosis , División Celular , Regulación hacia Abajo , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Mesangio Glomerular/metabolismo , Mesangio Glomerular/patología , Humanos , Técnicas para Inmunoenzimas , Inmunoglobulina A/clasificación , Inmunoglobulina A/metabolismo , Etiquetado Corte-Fin in Situ , Masculino , Persona de Mediana Edad , Regulación hacia Arriba

RESUMEN

Bcl-2 defines a new class of proto-oncogenes that block cell death without promoting cell proliferation. To elucidate the role of Bcl-2 in the development of glomerular lesions in human IgA nephropathy (IgAN), we applied immunohistochemistry coupled with in situ hybridization to detect the expression of Bcl-2 products and their association with Bax, p27(kip1), and p57(kip2) in modulating the apoptotic, proliferative, and sclerotic events in progressive glomerular injury. Glomerular cell apoptosis was examined by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) staining. A total of 51 IgAN cases were categorized into four subgroups (A to D) according to the severity of their histopathological lesions. Creatinine levels, creatinine clearance, and magnitude of proteinuria based on 24-h urine collections at the time of diagnostic renal biopsy were available for the majority of subjects. Bcl-2 expression was observed predominantly in podocytes in IgAN. Podocyte expression of Bcl-2 was found to be upregulated in early-stage disease and downregulated in late-stage disease. Bcl-2 downregulation in progressive IgAN was associated with an increased Bax/Bcl-2 ratio in glomerular epithelial cells and correlated with the downregulation of high endogenous podocyte p27(kip1) and p57(kip2) expression. Bax/Bcl-2 ratios positively correlated with glomerular cell apoptosis and the degree of glomerulosclerosis, whereas p27(kip1) and p57(kip2) expression levels were inversely correlated with mesangial hypercellularity and glomerulosclerosis. Clinicopathologic correlations demonstrated that downregulation of Bcl-2 protein expression was associated with indices of poor renal prognosis in human IgAN. The results suggest that Bcl-2 expression by podocytes may exert modulatory effects on cellular processes that contribute to progressive glomerular injury and play an important role in determining renal outcome in human IgA nephropathy.

Asunto(s)

Regulación hacia Abajo , Células Epiteliales/fisiología , Glomerulonefritis por IGA/genética , Glomérulos Renales/patología , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Adolescente , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Glomerulonefritis por IGA/patología , Humanos , Glomérulos Renales/citología , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Proto-Oncogénicas/biosíntesis , Urotelio/citología , Proteína X Asociada a bcl-2

RESUMEN

Interleukin-12 (IL12) is a cytokine that is secreted by activated phagocytes and dendritic cells and that induces interferon-gamma production by natural-killer and T lymphocytes. It consists of two subunits, p35 and p40, which are encoded by IL12A and IL12B, respectively. The first reported patient with a genetic cytokine disorder was a Pakistani child, who was homozygous for a large loss-of-function deletion (g.482+82_856-854del) in IL12B. This IL12-deficient child suffered from infections caused by bacille Calmette-Guérin (BCG) and Salmonella enteritidis. We herein report 12 additional patients from five other kindreds. In one kindred from India, the same large deletion that was described elsewhere (g.482+82_856-854del) was identified. In four kindreds from Saudi Arabia, a recessive loss-of-function frameshift insertion (g.315_316insA) was found. A conserved haplotype encompassing the IL12B gene suggested that a founder effect accounted for the recurrence of each mutation. The two founder mutational events-g.482+82_856-854del and g.315_316insA-were estimated to have occurred approximately 700 and approximately 1,100 years ago, respectively. Among a total of 13 patients with IL12 deficiency, 1 child had salmonellosis only and 12 suffered from clinical disease due to BCG or environmental nontuberculous mycobacteria. One patient also had clinical disease caused by virulent Mycobacterium tuberculosis, five patients had clinical disease caused by Salmonella serotypes, and one patient had clinical disease caused by Nocardia asteroides. The clinical outcome varies from case to case, since five patients (aged 2-11 years) died of overwhelming infection, whereas eight patients (aged 3-12 years) are still in good health and are not currently taking antibiotics. In conclusion, IL12 deficiency is not limited to a single kindred, shows significant variability of outcome, and should be considered in the genetic diagnosis of patients with mycobacteriosis and/or salmonellosis. To date, two founder IL12B mutations have been identified, accounting for the recurrence of a large deletion and a small insertion within populations from the Indian subcontinent and from the Arabian Peninsula, respectively.

Asunto(s)

Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/microbiología , Interleucina-12 , Interleucinas/deficiencia , Interleucinas/genética , Mutación/genética , Adolescente , Linfocitos B/inmunología , Linfocitos B/metabolismo , Línea Celular Transformada , Niño , Preescolar , Consanguinidad , Femenino , Efecto Fundador , Haplotipos/genética , Herpesvirus Humano 4/fisiología , Humanos , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/fisiopatología , India , Lactante , Subunidad p40 de la Interleucina-12 , Interleucinas/metabolismo , Masculino , Mutagénesis Insercional/genética , Pakistán , Linaje , Fenotipo , Polimorfismo Genético/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Arabia Saudita , Eliminación de Secuencia/genética