RESUMEN
Recessive CRB2 mutations were recently reported to cause both steroid resistant nephrotic syndrome and prenatal onset ventriculomegaly with kidney disease. We report two Ashkenazi Jewish siblings clinically diagnosed with ciliopathy. Both presented with severe congenital hydrocephalus and mild urinary tract anomalies. One affected sibling also has lung hypoplasia and heart defects. Exome sequencing and further CRB2 analysis revealed that both siblings are compound heterozygotes for CRB2 mutations p.N800K and p.Gly1036Alafs*43, and heterozygous for a deleterious splice variant in the ciliopathy gene TTCB21. CRB2 is a polarity protein which plays a role in ciliogenesis and ciliary function. Biallelic CRB2 mutations in animal models result in phenotypes consistent with ciliopathy. This report expands the phenotype of CRB2 mutations to include lung hypoplasia and uretero-pelvic renal anomalies, and confirms cardiac malformation as a feature. We suggest that CRB2-associated disease is a new ciliopathy syndrome with possible digenic/triallelic inheritance, as observed in other ciliopathies. Clinically, CRB2 should be assessed when ciliopathy is suspected, especially in Ashkenazi Jews, where we found that p.N800K carrier frequency is 1 of 64. Patients harboring CRB2 mutations should be tested for the complete range of ciliopathy manifestations.
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Proteínas Portadoras/genética , Ciliopatías/genética , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Mutación , Niño , Preescolar , Ciliopatías/diagnóstico por imagen , Ciliopatías/fisiopatología , Femenino , Heterocigoto , Humanos , Judíos/genética , Masculino , Linaje , Fenotipo , HermanosRESUMEN
We evaluated the latest pathological criteria for completion right hemicolectomy (RHC) in patients with appendiceal neuroendocrine tumors (ANETs) with emphasis on the size of the primary tumor. Data of 28 consecutive patients who underwent RHC for ANETs in three tertiary hospitals were reviewed retrospectively to assess the indications for completion RHC. 10/28 patients were found to have residual disease (36%). In 8/28 patients (29%), the tumor diameter was <1 cm (mean 0.7 ± 0.2 cm, range 0.5-0.9 cm); the indications for RHC included: tumor presence in surgical margins (1 patient), extensive mesoappendiceal invasion (EMI) (1 patient), vascular invasion (VI) (3 patients), Ki-67 ≥2% (3 patients); residual disease was present in 1 patient (3.5%). In 13/28 patients (46%), the tumor diameter was ≥1 and <2 cm (mean 1.30 ± 0.2 cm, range 1.0-1.8 cm); the indications for RHC were: EMI (2 patients), VI (2 patients), Ki-67 ≥2% (2 patients); residual disease was present in 5 patients (18%). In 7/28 patients (25%), the tumor diameter was ≥2 cm (mean 2.5 ± 0.7 cm, range 2.0-4.0 cm). In this final subgroup, RHC was an accepted practice irrespective of other pathologic findings: the tumor was present in surgical margins in 2 patients, in 5 patients VI was demonstrated, and Ki-67 ≥2% was found in 5 patients; residual disease was present in 4 patients (14%). Using the latest European Neuroendocrine Tumor Society criteria for RHC, residual disease may be missed in 18% of ANET patients.
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Neoplasias del Apéndice/diagnóstico , Neoplasias del Apéndice/terapia , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/terapia , Adolescente , Adulto , Manejo de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Protein-losing gastroenteropathies are characterized by an excessive loss of serum proteins into the gastrointestinal tract, resulting in hypoproteinemia (detected as hypoalbuminemia), edema, and, in some cases, pleural and pericardial effusions. Protein-losing gastroenteropathies can be caused by a diverse group of disorders and should be suspected in a patient with hypoproteinemia in whom other causes, such as malnutrition, proteinuria, and impaired liver protein synthesis, have been excluded. In this paper, we present a case of protein-losing enteropathy in a 22-year-old immunocompetent male with a coinfection of CMV and Hp.
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OBJECTIVE: Heparanase, an endoglycosidase that cleaves heparan sulphate, is frequently expressed in carcinomas and was suggested to play a role in cell invasion and metastasis. We investigated whether heparanase expression may serve as a reliable marker to discriminate benign mesothelial cells from malignant cells shed into body cavities. METHODS AND RESULTS: Cytological smears of effusions from 51 hospitalized patients were immunostained for heparanase. Strong immunoreactivity was noted in 35 of 40 (88%) carcinoma samples and in all three malignant mesothelioma cases. Only rare (<3%) reactive mesothelial cells were noted showing a faint negligible staining. Specificity was 100%, sensitivity 88%, and positive and negative predictive values were 100% and 89% respectively. CONCLUSIONS: Our results suggest that heparanase may be of value as a complementary component in a diagnostic panel of markers, contributing to its reliability and accuracy.
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Glucuronidasa/biosíntesis , Neoplasias/enzimología , Adenocarcinoma/diagnóstico , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/metabolismo , Epitelio/enzimología , Epitelio/patología , Matriz Extracelular/metabolismo , Exudados y Transudados/citología , Exudados y Transudados/enzimología , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/enzimología , Neoplasias Gastrointestinales/patología , Glucuronidasa/metabolismo , Humanos , Neoplasias/diagnóstico , Neoplasias/patología , Estudios RetrospectivosRESUMEN
Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting beta cells. Islet-infiltrating leukocytes secrete cytokines such as IL-1beta and IFN-gamma, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-kappaB is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-kappaB in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-kappaB protein inhibitor (DeltaNIkappaBalpha), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, islets expressing the DeltaNIkappaBalpha protein were resistant to the deleterious effects of IL-1beta and IFN-gamma, as assessed by reduced NO production and beta-cell apoptosis. This effect was even more striking in vivo, where nearly complete protection against multiple low-dose streptozocin-induced diabetes was observed, with reduced intraislet lymphocytic infiltration. Our results show in vivo that beta cell-specific activation of NF-kappaB is a key event in the progressive loss of beta cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.
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Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Islotes Pancreáticos/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Transporte Activo de Núcleo Celular/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Citocinas , ADN/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Doxiciclina/farmacología , Resistencia a Medicamentos/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Interferón gamma/farmacología , Interleucina-1/farmacología , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Linfocitos/citología , Ratones , Ratones Transgénicos , Mutación/genética , FN-kappa B/metabolismo , Unión Proteica , Estreptozocina/farmacología , Técnicas de Cultivo de TejidosRESUMEN
Natural killer T (NKT) lymphocyte cells are a subset of regulatory lymphocytes with important immunemodulatory effects. Our aim was to evaluate the effect of transplantation of NKT lymphocytes on graft versus host disease (GVHD) in a murine model of semiallogeneic BMT. GVHD was generated by infusion of 2 x 107 splenocytes from C57BL/6 donor mice into irradiated (C57BL/6 x Balb/c)F1 recipient mice. Adoptive transfer of increasing numbers of DX5+ cells was performed. Recipient mice were followed for histological parameters of GVHD-associated liver, bowel, and cutaneous injury. Intrahepatic and intrasplenic lymphocytes were isolated and analyzed by FACS for CD4+ and CD8+ subpopulations. It was seen that adoptive transfer of 4.5 x 106 DX5+ cells significantly alleviated GVHD-related hepatic, bowel, and cutaneous injury, and improved survival (85% survival on day 28). In contrast, depletion of DX5+ cells led to severe GVHD-associated multiorgan injury and 100% mortality. A direct correlation with the number of transplanted DX5+ cells was noted (maximal effect with transplantation of 4.5 x 106 DX5+ cells). Tolerance induction was associated with an increased peripheral CD4/CD8 ratio, intrahepatic trapping of CD8 lymphocytes and a shift towards a Th2-type cytokine profile, manifested by decreased IL-12/IL10, IL-12/IL-4, IFNgamma/IL-10, and IFNgamma/IL-4 ratios. Transplantation of DX5+ cells holds promise as a novel therapeutic measure for GVHD.
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Traslado Adoptivo/métodos , Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/prevención & control , Células Asesinas Naturales/trasplante , Animales , Trasplante de Médula Ósea/métodos , Relación CD4-CD8 , Citocinas/análisis , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Tolerancia Inmunológica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Animales , Bazo/citología , Linfocitos T , Células Th2 , Trasplante HomólogoRESUMEN
A patient is described who had severe hyperplastic gastropathy as the presenting manifestation of systemic lupus erythematosus (SLE). Aggressive immunosuppressive therapy with systemic corticosteroids and immunoglobulins resulted in complete remission of lupus, and a prompt clinical and radiological regression of hyperplastic gastropathy. Hyperplastic gastropathy is an uncommon gastric illness, which is usually idiopathic but rarely is associated with Helicobacter pylori infection, cytomegalovirus infection or lymphocytic gastritis. Three previous case reports have noted a response of idiopathic hyperplastic gastropathy to systemic corticosteroid treatment, yet none of the presented patients had a systemic inflammatory disease. The presented case is the first in the medical literature in which hyperplastic gastropathy is directly linked to the development of clinical and laboratory manifestations of SLE. We suggest that hyperplastic gastropathy be added to the list of rare gastrointestinal manifestations of SLE, and that autoimmune disease be considered a possible cause of hyperplastic gastropathy. As such, any patient with symptomatic idiopathic hyperplastic gastropathy accompanied by other evidence of systemic inflammation should be considered for SLE evaluation and immunosuppressive treatment.
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Gastritis Hipertrófica/etiología , Lupus Eritematoso Sistémico/diagnóstico , Gastropatías/etiología , Adulto , Antiinflamatorios/uso terapéutico , Diagnóstico Diferencial , Femenino , Humanos , Hidrocortisona/uso terapéutico , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Gastropatías/diagnóstico , Tomografía Computarizada por Rayos XRESUMEN
Graft-versus-host disease (GVHD) is the major obstacle for successful allogeneic stem cell transplantation (SCT). Morbidity and mortality are high, and novel therapeutic strategies are required. Current therapy, which is based mainly on immunosuppression, is associated with a high degree of complications. Immune hyporesponsiveness induced by oral antigen administration has recently been shown to prevent the development of chronic GVHD (cGVHD) in a murine model. The aim of the present study was to evaluate whether it is possible to induce tolerance and to alleviate GVHD in a semiallogeneic transplantation model in mice. GVHD was generated by infusing 2 x 10(7) splenocytes from C57BL/6 donor mice into (C57BL/6 x Balb/c)F1 recipient mice, which received 7 Gy (60)Co total body irradiation (TBI) prior to transplantation. Oral tolerance was induced by feeding recipient F1 mice with five oral doses of proteins, 50 micro g/mouse, extracted from C57BL/6 splenocytes on alternate days following transplantation. In vitro mixed lymphocyte reaction (MLR) from tolerized and nontolerized mice was performed. Recipient mice were followed for chimerism, and for clinical and histological parameters of GVHD. Induction of tolerance was documented by a significant reduction in MLR response of tolerated vs nontolerated splenocytes. A significant alleviation of the clinical and pathological manifestation of GVHD was observed in the liver, small bowel, and skin. Tolerance induction did not jeopardize engraftment. These results may constitute a step towards reducing the frequency of GVHD via manipulation of the immune system.