RESUMEN
The congenital vomer defect (CVD) is a rare and still partially unknown condition. Only few cases have been reported in the international literature and the large majority of them appeared to be isolated. We report a case of CVD detected in a 7-year-old girl affected by ectodermal dysplasia clefting syndrome caused by a mutation of the TP63 gene.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Displasia Ectodérmica/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Vómer/anomalías , Anomalías Múltiples/diagnóstico , Niño , Labio Leporino/cirugía , Fisura del Paladar/cirugía , Femenino , Heterocigoto , Humanos , Imagen por Resonancia Magnética/métodos , Mutación , Tabique Nasal/anomalías , Enfermedades Raras , SíndromeRESUMEN
In adults, one-haplotype-mismatched haematopoietic SCT (haploidentical HSCT) is associated with slow immune recovery due to decaying thymic function and extensive T-cell depletion of the graft. Although essential for preventing GVHD, T-cell depletion underlies the major reasons for transplant failure: leukemia relapse and infections, with infection-related mortality accounting for about 40% of non-leukemic deaths. Adoptive T-cell therapy would be helpful for these patients but to administer it without causing GVHD, alloreactive T cells need to be eliminated from donor T lymphocytes before infusion. In a preclinical study, to address this problem, we determined the efficacy of photodynamic purging of alloreactive T cells, by investigating combinations of parameters in order to achieve maximum allodepletion, preservation of T-regulatory cells and of pathogen and leukemia-specific T-cell responses in donor-vs-recipient MLR. We also needed to identify an optimal method to quantify the Ag-specific T-cell repertoires. Optimal procedures were identified. In particular, we compared limiting-dilution analyses (LDA) of proliferating T cells with H(3)-thymidine incorporation by bulk T cells and with flow cytometry CD25 expression, which is accepted as a T-cell activation marker. This study demonstrated that LDA is a reliable, predictable and sensitive method for measuring alloreactive, pathogen- and leukemia-specific T-cell frequencies.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Inmunoterapia Adoptiva/métodos , Activación de Linfocitos/inmunología , Depleción Linfocítica/métodos , Estudios de Cohortes , Epítopos de Linfocito T/inmunología , Haplotipos/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Fotoquimioterapia/métodos , Linfocitos T/inmunologíaRESUMEN
We studied killer-cell Ig-like receptor (KIR)/natural killer (NK)-cell group-2-Ag repertoires on donor-derived NK cells in 28 patients after haploidentical SCT in the first 6 months after SCT and correlated results with EFS. The reconstitution hierarchy of potentially alloreactive, single KIR+ NK cells was the following: HLA-C1 binding>HLA-Bw4 binding>HLA-C2 binding. The differences in reconstitution kinetics of the three potentially alloreactive NK cell subsets prompted an updated analysis of EFS in AML patients transplanted from haploidentical donors in our center. This analysis showed that in haploidentical transplantation for AML, HLA-C group 1 mismatching in the graft vs host direction not only provides a survival advantage over non-NK-alloreactive (KIR ligand-matched) transplants (5-year EFS 67±10% vs 17±5%) but, indeed, also provides the best EFS compared with C2 (35±10%) or Bw4 KIR ligand mismatches (44±17%). In conclusion, we show that the kinetics with which single KIR-expressing NK cells are generated after haploidentical SCT differ between individual KIR receptors and seem to influence survival after haploidentical SCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Células Asesinas Naturales/inmunología , Receptores KIR/inmunología , Haploidia , Humanos , Células Asesinas Naturales/citología , Células Asesinas Naturales/trasplante , Acondicionamiento Pretrasplante/métodos , Trasplante HomólogoRESUMEN
In 2005, the Italian System for Surveillance of Acute Pesticide-Related Illnesses (SIAF) identified 625 cases, among which 520 unintentionally exposed. The majority of these subjects were men (75%) and aged 26-65 years (65%). About 63% of all exposures occurred at work. Severity for these illnesses was low for 94% and moderate for 5%. Four cases were classified as illnesses of high severity. Some 70% of all the reported exposures occurred between May and September. The active ingredients responsible for the largest number of cases were: glyphosate (n. 56), copper sulphate (n. 55), methomyl (n. = 52), metam-sodium (n. 24). Three episodes of collective environmental exposure to soil fumigants involving 23 subjects were also detected.
Asunto(s)
Enfermedades Profesionales/inducido químicamente , Plaguicidas/efectos adversos , Vigilancia de la Población , Adulto , Anciano , Femenino , Humanos , Italia , Masculino , Persona de Mediana EdadRESUMEN
The survival rate of children and adolescents with cancer has improved dramatically in the last decades so that the prospect of survival in adulthood is today a realistic expectation for about 70% of the treated patients. However, the deleterious impact that chemotherapy and radiotherapy have on the reproductive function and future fertility could compromise the quality of life of the survivors in adulthood. The interest of the scientific community on this topic is increasing and focused on a more accurate evaluation of the reproductive risk among cancer treated children and on the development of less aggressive therapies. In the present review, some information about the long-term effects on the male reproductive function, particularly vulnerable to the cancer therapies, are reported from clinical and experimental studies. Furthermore, the concern about the development of pharmacological treatments and assisted reproductive techniques that might preserve or restore the fertility potential in children being treated with gonadotoxic cancer therapy, is discussed. These new strategies are still under experimentation and deeper knowledges on the functional development of the gonads during infancy, both in human and animals models are required. On the other hand, the future clinical application of these strategies in children rise important ethical and legal problems.
Asunto(s)
Antineoplásicos/efectos adversos , Gónadas/efectos de los fármacos , Antineoplásicos/uso terapéutico , Niño , Humanos , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/epidemiología , Masculino , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND: Allogeneic hematopoietic transplantation relies on T-cell alloreactions for engraftment and the GvL effect. In HLA haplotype-mismatched transplants, extensive T-cell depletion of the graft is essential to prevent GvHD. This raises the question of whether mismatched transplants exert any GvL effect, and whether it will ever be possible to reduce the intensity of preparative regimens. Natural killer (NK) cells are negatively regulated by MHC Class I-specific inhibitory receptors. Mismatched transplants may therefore trigger NK-cell alloreactivity. METHODS: The effects of NK-cell alloreactivity were evaluated in clinical transplantation and in murine transplant models. RESULTS: In clinical hematopoietic stem-cell transplants, HLA Class I disparities driving NK-cell alloreactions in the GvH direction eliminate AML relapse and graft rejection, while protecting patients from GvHD. In murine MHC mismatched transplant models, the pre-transplant infusion of donor-versus-recipient alloreactive NK cells conditioned the recipients to BMT, and reduced GvHD. DISCUSSION: NK-cell alloreactivity may thus provide a novel, powerful tool for enhancing the efficacy and safety of allogeneic hematopoietic transplantation.
Asunto(s)
Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Inmunidad Innata , Animales , Modelos Animales de Enfermedad , Genes MHC Clase I , Enfermedad Injerto contra Huésped/inmunología , Antígenos HLA/inmunología , Neoplasias Hematológicas/inmunología , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Trasplante HomólogoRESUMEN
This review is based primarily on the recent epidemiological studies conducted in occupational settings in order to explore the relationship between exposures to chemical agents and the possible effects on male reproductive function. The paper examines evidence of the effects of metals, solvents, pesticides and dioxin. The effects considered are primarily the possible alterations of sperm quality and reduction of fertility. Many studies have identified small groups of workers with exposures to these agents, presenting some alteration in the spermatological or fertility profile, but the results are difficult to replicate in other settings with different individuals and different levels of exposure. From examination of the concentrations of environmental and occupational pollutants in the blood and in the seminal fluid of exposed individuals, it appears that, in general, the concentrations are much lower in the seminal fluid and in sperm cells, making this a less useful marker of exposure.
Asunto(s)
Infertilidad Masculina/etiología , Metales Pesados/efectos adversos , Exposición Profesional/efectos adversos , Plaguicidas/efectos adversos , Solventes/efectos adversos , Biomarcadores/análisis , Humanos , Masculino , Metalurgia , Reproducción/fisiologíaRESUMEN
This study investigated the role of natural killer (NK) cells as effectors of an immune response against autologous cells modified by gene therapy. T lymphocytes were transduced with LXSN, a retroviral vector adopted for human gene therapy that carries the selectable marker gene neo, and the autologous NK response was evaluated. We found that (i) infection with LXSN makes cells susceptible to autologous NK cell-mediated lysis; (ii) expression of the neo gene is responsible for conferring susceptibility to lysis; (iii) lysis of neo-expressing cells is clonally distributed and mediated only by NK clones that exhibit human histocompatibility leukocyte antigen (HLA)-Bw4 specificity and bear KIR3DL1, a Bw4-specific NK inhibitory receptor; and (iv) the targets are cells from HLA-Bw4(+) individuals. Finally, neo peptides anchoring to the Bw4 allele HLA-B27 interfered with KIR3DL1-mediated recognition of HLA-B27, i.e., they triggered NK lysis. Moreover, neo gene mutations preventing translation of two of the four potentially nonprotective peptides reduced KIR3DL1(+) NK clone-mediated autologous lysis. Thus, individuals expressing Bw4 alleles possess an NK repertoire with the potential to eliminate autologous cells modified by gene therapy. By demonstrating that NK cells can selectively detect the expression of heterologous genes, these observations provide a general model of the NK cell-mediated control of viral infections.
Asunto(s)
Terapia Genética , Células Asesinas Naturales/inmunología , Secuencia de Aminoácidos , Células Clonales , Farmacorresistencia Microbiana/genética , Farmacorresistencia Microbiana/inmunología , Marcadores Genéticos/genética , Antígenos HLA-B/genética , Antígenos HLA-B/inmunología , Antígeno HLA-B27/genética , Antígeno HLA-B27/inmunología , Humanos , Kanamicina Quinasa/genética , Datos de Secuencia Molecular , Mutación , Fragmentos de Péptidos/inmunología , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Receptores KIR , Receptores KIR3DL1 , Retroviridae/genética , Linfocitos T/inmunologíaRESUMEN
Because of the expression of inhibitory receptors (KIR) for major histocompatibility complex (MHC) class I allotypes, a person's natural killer (NK) cells will not recognize and will, therefore, kill cells from individuals lacking his/her KIR epitopes. This study investigated the role of NK cell alloreactivity in human HLA haplotype-mismatched hematopoietic stem cell transplantation and, specifically, the role of the three major NK specificities, ie, those for HLA-C group 1, HLA-C group 2, and HLA-Bw4 alleles. In 20 of 60 donor-recipient pairs, KIR epitope incompatibility and functional analyses of donor NK cell clones predicted donor NK cells could cause graft-versus-host (GVH)/graft-versus-leukemia (GVL) reactions. NK cell clones of donor origin were obtained from transplanted recipients and tested for lysis of recipient's cryopreserved pretransplant lymphocytes. Despite the absence of GVH disease, we detected high frequencies of NK clones which killed recipient's target cells. Lysis followed the rules of NK cell alloreactivity, being blocked only by the MHC class I KIR epitope which was missing in the recipient. The alloreactive NK clones also killed the allogeneic leukemia. Transplants from these KIR epitope incompatible donors had higher engraftment rates. Therefore, a GVL effector and engraftment facilitating mechanism, which is independent of T-cell-mediated GVH reactions, may be operational in HLA mismatched hematopoietic cell transplants.
Asunto(s)
Citotoxicidad Inmunológica , Efecto Injerto vs Tumor/inmunología , Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales/inmunología , Leucemia/terapia , Adolescente , Adulto , Niño , Preescolar , Antígenos HLA , Prueba de Histocompatibilidad , Humanos , Isoantígenos/inmunología , Persona de Mediana Edad , Inmunología del Trasplante , Trasplante HomólogoRESUMEN
The fungicide methyl thiophanate (MT), widely used to control some of the most common fungal diseases in crops, is metabolized in animals into benzimidazole compounds, including the well-known reproductive toxicant carbendazim. However, standard toxicological tests did not indicate that MT may cause testicular toxicity and/or embryotoxicity, which are typical effects of many benzimidazoles. In the present study some aspects of the MT potential for reproductive toxicity have been assayed by means of two non-conventional models. Following the oral administration of 700 and 1000 mg kg(-1) body wt. for five consecutive days, short-term testicular toxicity was examined in the B6C3F1 mouse through specific parameters (sperm head count, specific enzyme activities, histopathology on days 3-35 post-dosing). In spite of the high doses administered, none of the testicular parameters examined, including histopathology, showed significant alterations as compared to controls at any time post-dosing. Pregnant CD rat dams were administered orally the limit dose of 650 mg kg(-1) body wt. day(-1) during preimplantation (gestational day or GD 2-5) or peri-implantation (GD 6-9) phases; embryos and adnexa were evaluated morphologically on GD 12 as a window for the early observation of embryotoxicity. Evident maternal toxicity was present in both treated groups, whereas only marginal reductions of the growth of embryos and adnexa were observed. A full understanding of MT toxicology will need more quantitative data on metabolism, including plasma kinetics and dosimetry of carbendazim at the relevant targets. Nevertheless, the absence of any clear-cut effect on a number of specific endpoints may provide reassurance that no further testing of MT is needed with regard to testicular toxicity or embryotoxicity.
Asunto(s)
Carbamatos , Embrión de Mamíferos/efectos de los fármacos , Fungicidas Industriales/toxicidad , Reproducción/efectos de los fármacos , Teratógenos/toxicidad , Testículo/efectos de los fármacos , Tiofanato/toxicidad , Administración Oral , Animales , Bencimidazoles/administración & dosificación , Bencimidazoles/toxicidad , Blastocisto/efectos de los fármacos , Peso Corporal , Femenino , Fungicidas Industriales/administración & dosificación , Edad Gestacional , Masculino , Ratones , Embarazo , Ratas , Testículo/enzimología , Testículo/patología , Tiofanato/administración & dosificaciónRESUMEN
Thiram is a dithiocarbamate compound widely used for industrial processes and agriculture. Animal studies reveal that this compound may affect the male reproductive system. Aim of this study was to test, using sensitive testicular parameters, whether thiram directly affects germinal cells. For this purpose, B6C3F1 mice were intraperitoneally injected with thiram in oil (single dose: 75 mg/kg; repeated five daily doses: 25 mg/kg). Although both treatments were toxic, none of the parameters examined, i.e., testis weight, spermatid head number, specific enzyme levels at different times after treatment (14, 28, 35, 56 days) showed significant variations from the controls. On the contrary, in the positive controls (treated with chlorambucil), a marked reduction of sperm head number as well as a decrease of lactate dehydrogenasex and sorbitol dehydrogenase activity levels were evidenced at day 28, with a tendency to recover at day 35. Under these conditions thiram did not cause cytotoxicity on differentiating spermatogonia and on late spermatocyte stages of mice gonads.