Responsabilidad por lesiones prenatales. Fundamento, Wrongful Life y tendencias. (Especial atención al derecho suizo) / Responsibility for prenatal injuries. Bases, wrongful life and trends

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Translocaciones cromosómicas en los linfomas no-Hodking (Parte II) / Chromosomal translocations in non-Hodking`s lymphomas. Part II

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Translocaciones cromosómicas en los linfomas no Hodking (Parte I) / Chromosomal translocations in non-Hodking`s lymphomas (Part I)

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A putative susceptibility locus on chromosome 18 is not a major contributor to human selective IgA deficiency: evidence from meiotic mapping of 83 multiple-case families.

Previous reports of an association between constitutional chromosome 18 abnormalities and low levels of IgA suggested that this chromosome contains a susceptibility locus for selective IgA deficiency (IgAD), the most frequent Ig deficiency in humans. IgAD is genetically related to common variable immunodeficiency (CVID), characterized by a lack of additional isotypes. Our previous linkage analysis of 83 multiple-case IgAD/CVID families containing 449 informative pedigree members showed a significantly increased allele sharing in the chromosome region 6p21 consistent with allelic associations in family-based and case-control studies and provided the evidence for a predisposing locus, termed IGAD1, in the proximal part of the MHC. We have typed the same family material at 17 chromosome 18 marker loci with the average intermarker distance of 7 cM. A total of 7633 genotypes were analyzed in a nonparametric linkage analysis, but none of the marker loci exhibited a significantly increased allele sharing in affected family members. In addition, reverse painting and deletion mapping of a panel of constitutional chromosome 18 deletions/translocations showed the presence of IgA-deficient and IgA-proficient patients with the same abnormality and did not reveal a region commonly deleted. The linkage analysis of chromosome 8 and 21 regions involved in reciprocal translocations t(8;18) and t(18;21), which were identified in two patients lacking IgA, did not disclose a significant allele sharing. Although these results do not exclude the presence of a minor predisposing locus on this chromosome, such a putative locus would confer a population risk of developing IgAD/CVID much lower than IGAD1.

Ikaros sets thresholds for T cell activation and regulates chromosome propagation.

T cell activation involves the sustained accumulation of T cell receptor (TCR) and IL-2 receptor (IL-2R) mediated signaling events that promote cell cycle entry and progression. The Ikaros family of nuclear factors regulate this process by providing thresholds overcome by receptor signaling. T cells with reduced levels of Ikaros activity require fewer TCR engagement events for activation, exhibit a greater proliferative response to IL-2, and are less sensitive to inhibitors of TCR and IL-2R signaling. Upon T cell activation, Ikaros proteins localize in a higher-order chromatin structure where they colocalize with components of the DNA replication machinery. Proliferating T cells with reduced Ikaros activity display chromosome abnormalities. We propose that participation of Ikaros in higher-order chromatin structures controls cell cycle transitions and restricts DNA replication.

[The characteristics of the distribution of HLA antigens in the families of children with aneuploid chromosomal pathology]. / Osoblyvosti rozpodilu HLA-antyheniv v sim'iakh ditei z aneuploïdnoiu khromosomniuiu patolohiieiu.

Search of possible immunogenetic markers of tendency to form aneuploid offspring was carried out. We have studied HLA-antigens distribution among families with Down syndrome and Turner syndrome children and among families with miscarriages. The disposition to reproduction of affected offspring is associated with following HLA-antigens: B40, B41 and B51. The most typical haplotypes among families with affected offspring were: A2B27, A2B40, A2B51, A9B51, A10B8, A10B40. The HLA-antigens distribution among families with miscarriages supports evidence, that certain haplotypes can contribute to aneuploidy in progeny.

Antibody deficiency in Wolf-Hirschhorn syndrome.

We identified antibody deficiencies in 9 of 13 infection-prone children with Wolf-Hirschhorn syndrome (4p-monosomy). Eight of the immunodeficient children were identified by a questionnaire sent to 190 families with an affected child. Two of the children had common variable immunodeficiency, one had IgA and IgG2 subclass deficiency, three had IgA deficiency, and three had impaired polysaccharide responsiveness. T-cell immunity was normal. The association of antibody defects with Wolf-Hirschhorn syndrome suggests a regulatory gene within the deleted chromosome region that affects the B cell system.

Chromosomal abnormalities in nodal and extranodal CD30+ anaplastic large cell lymphomas: infrequent detection of the t(2;5) in extranodal lymphomas.

To determine the significance of the t(2;5)(p23;q35) translocation in nodal and extranodal anaplastic large cell lymphoma (ALCL), we performed cytogenetic, molecular genetic, and immunohistochemical analyses of tumor tissues from 11 patients with CD30+ ALCL. Three of five patients with nodal ALCL had additional infiltration of the skin. Six patients had extranodal ALCL, two had primary intestinal ALCL, three had a primary cutaneous ALCL, and one had osseous ALCL. Cytogenetic investigation detected the t(2;5) in all patients with nodal ALCL but not extranodal ALCL. Tumor cells in t(2;5)+ lesions also stained immunohistochemically for p80NPM/ALK, whereas no staining for p80NPM/ALK was detected in extranodal ALCL. Two extranodal lesions had NPM/ALK fusion transcripts detected by nested reverse transcriptase-polymerase chain reaction. Fluorescence in situ hybridization analysis of these two lymphomas showed in one case a significant number (4%) of cells with a split hybridization signal, indicative of disruption of the NPM gene. Additional recurrent breakpoints observed in extranodal ALCL were 1p36, 6p25, and 8q24. Loss of genetic material occurred at 6q in one extranodal ALCL. Our results suggest that the t(2;5) more frequently plays a pathogenetic role in primary nodal than in extranodal ALCL and that this translocation may not be the primary event in some CD30+ ALCL.

Cellular characteristics of peripheral blood lymphocytes and tumour-infiltrating lymphocytes in patients with gynaecological tumours.

Immunotherapy of gynaecological cancer with tumour-infiltrating lymphocytes (TIL) or peripheral blood lymphocytes (PBL) has become a valid treatment modality with varying degrees of success in obtaining an antitumour response. TIL consist of lymphocytes, mainly T cells and minor populations of natural killer cells or B cells. Conventional cytogenetic studies of tumour cells from patients with breast and ovarian cancer have shown multiple chromosomal abnormalities including chromosomes 7 and 12. This study was designed to analyse the surface further, as well as investigate the intracellular, characteristics of TIL by multicolour flow cytometry and the cytogenetic features by fluorescence in situ hybridization. Tumour cell, peripheral blood and TIL samples from 25 patients (15 ovarian tumours, 8 breast cancers, 1 uterine sarcoma, 1 cervical carcinoma) were analysed for their phenotype, the expression of major cytokines [interleukin-2 (IL-2), IL-4 and interferon gamma (IFN gamma)], their proliferation rate, their cytotoxic ability and for the presence of numerical aberrations of chromosomes 7 and 12. All the tumour cells showed a high frequency of numerical aberration in chromosomes 7 and 12, especially trisomies or tetrasomies and combined aberrations. Trisomies of both chromosomes also occured at a low percentage in TIL and PBL. The phenotyping of TIL and PBL revealed rather similar subsets of lymphocytes. In both, T cells were the major population, with TIL containing a slightly increased CD4/CD8 ratio. The cytokine pattern showed a predominance of IL-4 production in TIL and of IFN gamma in PBL, indicating that, in TIL, cellular immunity is downregulated, whereas in PBL the cytotoxic immune response predominates. This is in accordance with the cytotoxic ability of TIL, which is weakened in comparison to PBL. Cellular characteristics revealed some disadvantages in the use of TIL for cancer treatment, explaining ineffective clinical results. The search for specific antitumour lymphocytes requires carefully designed experiments in order to define effective anticancer cells and thereby improve immunologically mediated tumour therapy.

A variant of the Nijmegen breakage syndrome with unusual cytogenetic features and intermediate cellular radiosensitivity.

We report the first Italian case of Nijmegen breakage syndrome (NBS). The proband is an immunodeficient, microcephalic, 11 year old boy with a "bird-like" face. He developed a T cell rich B cell lymphoma. Spontaneous chromosomal instability was detected in T and B lymphocytes and fibroblasts; chromosomes 7 and 14 were only sporadically involved in the rearrangements and no clonal abnormality was present. The patient appeared to be sensitive both to ionising radiation and to bleomycin, although his sensitivity did not reach the level of AT reference cells. After bleomycin treatment, inhibition of DNA synthesis was low when compared with normal cells, but higher than observed in an AT reference strain. Moreover, cell cycle analysis, after drug exposure, showed a progressive reduction in the percentage of S phase cells, but the G1 arrest, found in normal cells, was not observed. On clinical evaluation our patient shares features with NBS subjects, but cytogenetic and cell biological data do not completely overlap with those reported in Nijmegen breakage syndrome. The ethnic origin of our patient might account for these differences, as expression of different allelic forms at the NBS locus.

Immunodeficiency as a component of recognizable syndromes.

Immunodeficiency occurs in numerous genetic syndromes. While it is the dominant manifestation in primary immunodeficiencies, immune deficits may also be seen in a variety of other recognizable syndromes. Immunodeficiency has been reported in 64 such conditions, adding to the 45 recognized primary immunodeficiencies. These uncommon syndromes with immune defects can present with: (a) growth deficiency (11 syndromes with disproportionate or proportionate short stature), (b) specific organ system dysfunction (18 with gastrointestinal, dermatologic, or neurologic abnormalities), (c) inborn errors of metabolism (13), (d) miscellaneous anomalies (10), or (e) chromosome anomalies (12). In most of the disorders, only some of the affected patients have immune defects. However, in 27 syndromes, immunodeficiency is a constant finding. We briefly review the clinical manifestations of each syndrome and delineate the specific associated immune defects. In most syndromes, the connection between the immune and other defects is unknown. Recognition of these conditions involving both the immune and other organ systems may facilitate accurate diagnosis and management as well as yield information regarding genes critical for the development of the involved systems.

Eastern white pine wood-drying condensate induced cytotoxicity and genotoxicity in human peripheral blood lymphocytes in vitro.

Condensate from eastern white pine, one of the commercially most important species of tree in the northeastern United States, was treated for potential cytotoxicity and genotoxicity in human peripheral blood lymphocytes in the absence of S-9 activation. Cytotoxicity was evaluated by mitotic index (MI) determination and proliferative rate index. Genotoxicity was measured by the chromosome aberration (CA) assay and sister chromatid exchange (SCE) analysis. Both cytotoxic and genotoxic effects were observed with laboratory-generated eastern white pine condensate. The MI data showed an inverse correlation between the MI and treatment dosage. A dose response curve was observed using the CA assay and also with the SCE analysis. The present findings thus corroborate the results from Ames testing and represent the only information currently available on the cytotoxic and genotoxic potential of these chemicals.

Nijmegen Breakage syndrome: a progress report.

We report the findings in the first 30 patients with the Nijmegen Breakage Syndrome (NBS). All had microcephaly from birth, short stature and a 'bird-like' face. Most of them suffered from recurrent respiratory tract infections. Intelligence was normal in half of the patients. Serum immunoglobulins were disturbed in 22/25 patients investigated (IgG deficiency, IgA deficiency, IgG2 and IgG4 deficiency) and T cell defects were found in 23/24 patients tested. The immunodeficiency appears to be more severe than in A-T. Chromosomal aberrations in cultured T lymphocytes occurred preferentially in chromosomes 7 and 14 and at the same breakpoints as in A-T. However, the percentage of chromosome 7 and/or 14 rearrangements was significantly higher in NBS patients than in A-T patients (p < 0.0005). Inv(7) was amongst the most frequently detected aberration in NBS cells as it is in A-T cells. Large clones of cells with rearrangements of chromosome 14 were rare in NBS. Of the first 19 reported patients eight have already developed a malignancy: seven a lymphoma and one a meningioma. It is noteworthy that both the tendency to express rearrangements of chromosomes 7 and 14 and the tendency to develop a malignancy is much higher in NBS than in A-T. Whether there is any causal relationship is as yet unknown.

Leukemia-associated changes identified by quantitative flow cytometry: I. CD10 expression.

We have compared CD10 antigen expression in normal fetal bone marrow with that of B-linage acute lymphoblastic leukemia (ALL). Both quantitative indirect immunofluoresence (QIFI) and direct immunofluorescence (IF) tests with Quantum beads were used to convert median fluorescence intensity (MFI) values into numbers of antigen molecules expressed per cell (AgE). Lymphoid precursors in the fetal marrow and liver expressed 3-12.5 x 10(3) CD10 molecules/cell with an upper limit of 5 x 10(4)/cell (MaxAgE). The median CD10 AgE in the different cases of acute B-lineage ALL were variable and ranged from undetectable to very high values (> 1.8 x 10(5). In 24 of the 72 cases (33%) tested with QIFI the median CD10 AgE was above the highest values seen in normal samples (> 5 x 10(4)/cell). An additional 23.6% of cases had higher median values than the normal median CD10 AgE. Next, CD10 antigen was quantitated in 78 cases during the routine multiparameter analysis of B-lineage leukemia using CD10/class II/CD34 3-color IF test or CD10/TdT 2-color IF test. The aberrant overexpression was confirmed in 43.6% of ALL cases. The CD10bright display suggested ALL diagnosis even when few cells were available for study, e.g., in early relapse and in ALL masquerading as aplastic anemia. The levels of CD10 expression were maintained in relapse. In addition, different CD10 levels were associated with the various chromosomal alterations: high CD10 levels (> 3 x 10(4)/cell) with hyperdiploidy, low CD10 levels (1.8-4 x 10(3)/cell) with the t(1;19) and undetectable levels (< 1.2 x 10(3)/cell) with the t(4;11) translocations.(ABSTRACT TRUNCATED AT 250 WORDS)

Detección de heterocigotos de ataxia telangiectasia por la sensibilidad a la radiación ionizante / Detection of heterocygotic with patients with ataxia telangiectasia show chromosomic rupture

Investigaciones recientes han demostrado que los pacientes homocigotos y heterocigotos de ataxia telangiectasia (AT) tienen rompimientos cromosómicos. De acuerdo con esta característica se diseñó el estudio inducido rompimientos cromosómicos en células granulocíticas de pacientes con diagnóstico de AT, heterocigotos obligados de AT y comparados con un grupo de individuos sanos. A todos los pacientes se les cuantificó el número de rompimientos cromosómicos con 14 dosis de radiación 125 kv, 125 mA. Los resultados sugieren diferencias significativas en el número de alteraciones estructurales cromosómicas inducidas por la radiación en los granulocitos de heterocigotos de ataxia telangiectasia similares a las alteraciones estructurales de los linfocitos de pacientes con AT y se demuestra que estas alteraciones se presentan preferentemente en un cromosoma del grupo C de homocigotos y heterocigotos de AT

Long-term prognostic importance of primary Ki-1 (CD30) antigen expression and anaplastic morphology in adult patients with diffuse large-cell lymphoma.

BACKGROUND: We retrospectively assessed the long-term prognostic importance of primary CD30 antigen expression and of anaplastic large-cell morphology (ALCL) in adult patients with previously untreated diffuse large-cell lymphoma (DLCL), including cases of immunoblastic lymphoma, and identified their clinical features. MATERIALS AND METHODS: We examined available archival paraffin-embedded or frozen pathologic material and medical records of adult patients with previously untreated DLCL seen at M.D. Anderson Cancer Center (MDACC) between January 1978 and May 1989. RESULTS: Sixty-seven cases of DLCL and seven cases of IBL (a total of seventy-four heretofore referred to as DLCL) were identified. Twenty-two of the 74 patients were positive for the CD 30 antigen. For these 22 patients the rates of complete remission, survival, and time to treatment failure (TTF) were 86%, 82%, and 77%, respectively, at 81 months. When compared with the group of 54 patients which stained negative for CD 30, the long term survival of CD 30-positive DLCL was favorable (82% vs. 49%, p = 0.08). ALCL morphology was present in two-thirds of the patients with CD 30-positive DLCL but did not affect survival and TTF rates. Among patients with CD 30-positive DLCL, 16 patients without skin involvement were younger and had a low failure rate (13%) compared with six patients with skin involvement who were older and had a high failure rate (50%); however, the latter group had a more indolent course after failure and thus both groups had similar survival rates. CONCLUSIONS: Primary CD 30 positivity is associated with a favorable long-term prognosis in adult patients with DLCL treated with doxorubicin-containing chemotherapy. ALCL morphology among these patients does not affect the outcome. Patients with CD30-positive DLCL and skin involvement have a higher failure rate than those without skin involvement, but similar overall survival.

Immunophenotype of mitotic cells with clonal chromosome abnormalities demonstrating multilineage involvement in acute myeloid leukemia.

Eleven patients with acute myeloid leukemia (AML) were studied with a technique that simultaneously identifies cytogenetic abnormality and immunophenotype of the same mitotic cell. To determine the cell lineages with abnormal karyotypes, monoclonal antibodies in the alkaline phosphatase-antialkaline phosphatase (APAAP) detection procedure were used. The granulocytic/monocytic lineage was involved in the leukemic process in all 11 patients. In nine patients, we also detected abnormal karyotypes in the erythrocytic and/or megakaryocytic lineages. All four patients with secondary AML showed involvement of the granulocytic/monocytic, erythrocytic, and megakaryocytic lineages into the leukemic process, as compared with five of seven patients with de novo AML. One patient with trisomy 8 showed erythrocytic participation in the leukemic process, but in another the erythrocytic lineage had only normal karyotypes. Thus, in AML, the chromosome abnormalities apparently usually originate at the multipotent progenitor cell stage, since in addition to granulocytic/monocytic lineages, erythrocytic and/or megakaryocytic lineages were also involved. Some patients show involvement of granulocytic/monocytic lineages only, however, suggesting that the target cell belongs to a more mature committed progenitor cell stage.

Alteraciones del cromosoma 1 en pacientes pediátricos con leucemia / Alterations of the chromosome 1 in pediatrics patients with leukemia

El estudio citogenético en la médula ósea de 61 pacientes pediátricos con hemopatías malignas mostró que 36 (59 por ciento) tenían un cariotopo anormal al momento del diagnóstico. De éstos, 15 tenían anormalidades estructurales y en ocho el cromosoma 1 estaba involucrado en alguno de los rearreglos. El objetivo del presente etudio fue analizar las alteraciones del cromosoma 1 y el estado clínico de los pacientes porque otros autores han observado la aparición de estos rearreglos en enfermos con recaída o en estado terminal. En tres casos la alteración en la que participaba el cromosoma 1 fueron primarias; y en los restantes fueron cambios clonales secundarios que aparecen durante la evolución de la enfermedad. Al momento del diagnóstico, cinco de estos pacientes tenían cuentas elevadas de leucocitos o enfermedad extramedular y la respuesta al tratamiento en general fue mala. Se asume que la alta frecuencia de alteraciones del cromosoma 1 en la población estudiada se debe a que los pacientes llegan al Instituto para su diagnóstico y tratamiento cuando su padecimiento está avanzado, existe evolución clonal de las células leucémicas y el pronóstico es malo.

Cytogenetic survey in systemic sclerosis: correlation of aneuploidy with the presence of anticentromere antibodies.

Previous cytogenetic studies of patients with systemic sclerosis have obtained conflicting results regarding the presence of chromosomal anomalies. We studied 38 patients and 15 controls to determine whether these inconsistencies were due to differences in the subgroups of patients who were studied. Because many patients with systemic sclerosis produce autoantibodies to protein antigens that have been implicated in chromosome structure and function, we further hypothesized that the presence of these autoantibodies might correlate with the presence of chromosomal anomalies. Patients were classified into clinical subgroups based on the extent of their disease. Their sera were assayed for autoantibodies to topoisomerase I and centromere proteins (CENP-A, CENP-B, and CENP-C) by immunoblotting. Cytogenetic analyses for aneuploidy and chromosome breaks were performed. Anticentromere antibody positive (ACA+) patients had significantly more aneuploidy than either ACA negative (ACA-) patients or controls (P = 0.041). Although the patient group, when considered as a whole, had significantly greater aneuploidy than the control group (P < 0.005), patients who were ACA--did not have more aneuploidy than the controls had. Patients with Type I disease (sclerodactyly), the majority of whom were ACA+, also had significantly more aneuploidy than did either the controls or patients with Type III (diffuse) disease, most of whom were ACA- (P < 0.005). ACA+ patients also had more chromatid breaks than the controls had (P < 0.05). The correlation between the presence of ACAs and chromosomal aneuploidy suggests that aneuploidy may be the result of nondisjunction secondary to centromeric dysfunction. In support of this hypothesis, the ACA+ patients who had antibodies to CENP-C exhibited more chromosomal aneuploidy than did either anti-CENP-A or anti-CENP-B positive patients (P < 0.048). Unlike CENP-A and CENP-B, which are present at both functional and inactivated centromeres, CENP-C is present at the kinetochore of functional centromeres.