Factores de riesgo y protección de la conducta antisocial en adolescentes / Risk and protective factors for antisocial behavior used by adolescents

Existe un amplio consenso entre los investigadores y el público en general acerca de la naturaleza multicausal de la conducta antisocial. Cualquier abordaje preventivo y/o de intervención de estas conductas debe asentarse necesariamente en la identificación y evaluación de cuáles son los factores de riesgo responsables del inicio y el mantenimiento de las mismas. Es necesario realizar una integración de los diferentes factores implicados, tanto ambientales como individuales (factores psicológicos y de socialización) para apreciar la idoneidad de un abordaje multidimensional de los determinantes de la conducta antisocial en adolescentes. Se discuten, además, las implicaciones preventivas de la revisión realizada para la población adolescente escolar y en riesgo (AU)

Marcadores bioquímicos de cromosomopatía durante el embarazo / Biochemical marked of chromosomopathy during pregnancy

La edad materna como único criterio se utilizó para seleccionar las gestaciones de alto riesgo de aneuploidía en los inicios de la amniocentesis para diagnóstico prenatal. La introducción del cribado bioquímico de segundo trimestre (alfafetoproteína + hCG) permitió en la década de 1990 duplicar la detección prenatal del síndrome de Down del 30 al 65 por ciento, manteniendo la misma tasa de falsos positivos, según han mostrado los amplios estudios prospectivos poblacionales. Aumentar hasta el 90 por ciento los diagnósticos parece estar a nuestro alcance si se combina la translucencia nucal con los marcadores bioquímicos de primer trimestre (PAPP-A+ hCG) (AU)

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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Genes and inheritance.

The information gained from the Human Genome Project and related genetic research will undoubtedly create significant changes in healthcare practice. It is becoming increasingly clear that nurses in all areas of clinical practice will require a fundamental understanding of basic genetics. This article provides the oncology nurse with an overview of basic genetic concepts, including inheritance patterns of single gene conditions, pedigree construction, chromosome aberrations, and the multifactorial basis underlying the common diseases of adulthood. Normal gene structure and function are introduced and the biochemistry of genetic errors is described.

Chromosomal changes pattern and gene amplification in T cell non-Hodgkin's lymphomas.

T cell non-Hodgkin's lymphomas are a heterogeneous group of lymphomas with poor prognosis, and whose genetic alterations are not well understood. Comparative genomic hybridization (CGH) is a technique that allows the identification of DNA imbalances without cytogenetic studies. We have studied 37 samples from 29 T cell non-Hodgkin's lymphomas (25 peripheral and four lymphoblastic lymphomas) by CGH in order to detect DNA sequence copy number changes of putative importance in the biology and prognosis of these neoplasms. We detected abnormal CGH profiles in 16/27 (59%) of samples at diagnosis, a ratio that increased to 66% (23/37) when we included the relapsed samples. The most common recurrent changes were gains related to the X chromosome, either the whole chromosome or partially the Xq26-27 bands (19%). Other recurrent changes included gains of bands 9q34, gains of chromosomes 17, 19, and 20, and complete or partial deletions of chromosome 13 (10%). Cancer-related genes located at Xq26-28 region were analyzed by Southern blot and fluorescence in situ hybridization (FISH). Low level amplification of some of these genes was detected by this technique confirming the results obtained by CGH in this region. The detection of abnormal CGH profiles in these T cell lymphomas could have clinical implications. Patients with abnormal CGH profiles showed significant associations with advanced stage of disease, overexpression of P53, and higher proliferative index.

[Problems posed by the diagnosis and prenatal management of facial clefts]. / Problèmes posés par le diagnostic et la prise en charge prénatale des fentes faciales.

OBJECTIVE: To identify the difficulties in relation to prenatal diagnosis of cleft lip and/or palate. To provide useful clue to the clinician in order to evaluate prognosis and for prenatal management of this malformation. PATIENTS AND METHODS: Retrospective study of all cases managed in our fetal medicine unit between January 1991 and December 1999. During this study period 64 cases of fetal cleft lip and/or palate were retrospectively reviewed. From June 1995, all cases were prospectively recorded, giving us the opportunity to compare the performance of three ultrasound signs for associated secondary cleft palate. RESULTS: The mean gestational age at diagnosis was 26 weeks. Associated ultrasound abnormalities were detected in 42% of cases. Chromosome analysis was performed in all fetuses with associated ultrasound findings and in 39% of fetuses with isolated facial clefts. All fetuses with isolated cleft were chromosomally normal, whereas 15 of the 26 with additional abnormalities had chromosomal defects. Prospective assessment of three ultrasound signs of associated secondary cleft palate was considered possible in 57% of facial clefts. Sensitivity of these signs was respectively 78% (interruption of the secondary palate midline linear echo in a sagittal view), 87% (abnormal oro-nasopharyngeal fluid flow with color Doppler imaging) and 31% for ancillary signs (amniotic fluid excess and non-visualized fetal stomach) for the prediction of associated cleft palate. Only the absence of the three signs to rule out secondary cleft palate. CONCLUSION: Prenatal diagnosis of cleft lip and/or palate must draw attention to associated sonographic malformations. When cleft lip and/or palate is isolated, amniocentesis is recommended apart from selected cases. Secondary palate involvement is difficult to ascertain during pregnancy.

[Preimplantation genetic diagnosis. The first experiences in Denmark]. / Praeimplantations genetisk diagnostik. De første erfaringer i Danmark.

INTRODUCTION: Preimplantation genetic diagnosis (PGD) is a possible alternative to prenatal diagnosis, whereby families with serious inherited diseases can avoid having children with the disease. The genetic diagnosis is performed on embryos before implantation and therefore implies IVF. Hence, PGD offers the possibility of transferring embryos without disease, thereby avoiding termination of pregnancy owing to an affected fetus. MATERIAL AND METHODS: Activities at the Centre for Preimplantation Genetic Diagnosis at Aarhus University Hospital since its opening in February 1999 are described. The fluorescent in situ hybridisation (FISH) technique was used for sex selection (hemophilia A and Duchenne's muscular dystrophy) and translocations. The polymerase chain reaction (PCR) was used for cystic fibrosis. RESULTS: Of 20 PGD cycles started, 15 were successful in terms of transference of healthy or carrier embryos. A positive pregnancy test was found after six of 15 embryo transfers (40%) with two subsequent clinical pregnancies. CONCLUSIONS: The present pregnancy rates with PGD are comparable to those following IVF; the clinical pregnancy rate may seem low, but the cycle numbers are small. Preimplantation genetic diagnosis seems to be a realistic alternative for selected genetic diseases, in cases where the couple find abortion unacceptable.

[Detection of submicroscopic chromosome abnormalities by comparative genomic hybridization]. / Påvisning af submikroskopiske kromosomfejl med komparativ genomisk hybridisering.

INTRODUCTION: The purpose was to detect chromosome abnormalities in dysmorphic and mentally retarded individuals with normal karyotypes by means of comparative genomic hybridisation (CGH). MATERIAL AND METHODS: One hundred and forty-four individuals with normal karyotype underwent CGH analysis with a new detection technique where fixed limits are replaced by dynamic standard reference intervals. This method provides improved resolution and thereby detects minor chromosome abnormalities. RESULTS: Fifteen minor abnormalities (10%) and one trisomy 9 mosaic were found. Eleven were interstitial deletions or duplications, which cannot be detected by screening with other cytogenetic techniques. Three were terminal deletions or duplications and one was a terminal unbalanced translocation. DISCUSSION: CGH analysis with dynamic standard reference intervals is a new objective and quantitative method, which is suitable for screening for small chromosome abnormalities that can not be detected by conventional chromosome analysis. The method is recommended for use in the investigation of dysmorphic and mentally retarded individuals, in whom abnormalities are not found by ordinary karyotyping.

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

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Genetic imbalances revealed by comparative genomic hybridization in Ewing tumors.

Ewing tumors are characterized by reciprocal translocations involving the EWS gene on 22q12 fused to ETS transcription-factor family members. Little is known about further aberrations contributing to tumor development and progression. Sixty-two frozen tumors with known EWS rearrangements (52 primary tumors, 10 relapses) of ET patients registered in the EICESS protocol were analyzed by comparative genomic hybridization (CGH). The median number of changes in 52 primary and 10 relapsed cases was 2.5 and 5.0 per tumor (P = 0.153). Frequent abnormalities included gains of chromosomes 8, 12, 20, and 1q and losses of 16q and 19q. Neither number nor type of aberration was associated with histology, tumor size, disease stage, tumor localization, or histologic tumor response to chemotherapy. Among the 52 primary tumors, 26 with Type I fusion (EWS exon 7 to FLI1 exon 6) and 26 with other fusion types had a median of 2.0 and 3.0 aberrations per tumor, respectively (P = 0.031). Combinations of gains of chromosomes 8 and 12, gains of chromosome 20, and either gains of 8q or 18q and losses of 16q and 17p frequently occurred. The cumulative overall survival (OAS) was different between 35 patients with <5 aberrations and 13 patients with > or =5 aberrations (P = 0.009). Univariate analysis showed that patients with gains of 1q, 2q, 12, and 20 or losses of 16q and 17p had significantly lower OAS than those without aberrations. By multivariate analysis, loss of 16q (relative risk [RR] = 5.3; P = 0.0006) was an independent prognostic factor.

Cytogenetic analysis of trophoblasts by comparative genomic hybridization in embryo-fetal development anomalies.

Cytogenetic studies of spontaneous abortions or intrauterine fetal death depend on conventional tissue culturing and karyotyping. This technique has limitations such as culture failure and selective growth of maternal cells. Fluorescent in situ hybridization (FISH) using specific probes permits diagnosis of aneuploidies but is limited to one or a few chromosomal regions. Comparative genomic hybridization (CGH) provides an overview of chromosomal gains and losses in a single hybridization directly from DNA samples. In a prospective study, we analyzed by CGH trophoblast cells from 21 fetuses in cases of spontaneous abortions, intrauterine fetal death or polymalformed syndrome. Six numerical chromosomal abnormalities including one trisomy 7, one trisomy 10, three trisomies 18, one trisomy 21 and one monosomy X have been correctly identified by CGH. One structural abnormality of the long arm of chromosome 1 has been characterized by CGH. One triploidy and two balanced pericentromeric inversions of chromosome 9 have not been identified by CGH. Sexual chromosomal constitutions were concordant by both classical cytogenetic technique and CGH. Contribution of trophoblast analysis by CGH in embryo-fetal development anomalies is discussed.

Identification of chromosomal deficiencies that modify Drosophila mastermind mutant phenotypes.

Mastermind (Mam) is a component of Notch pathway signaling. In combination with the intracellular domain of Notch and Suppressor of Hairless, Mam forms a transcriptional activation complex. We have initiated a genetic approach to identify other loci involved in Mam function. The screen utilizes engineered mutations in Mam that derive from GAL4-UAS-directed expression of dominant negative constructs. When driven at the wing margin, truncated versions of Mam phenocopy Notch pathway mutations. Correlated with these phenotypes is depression of Notch pathway target expression. Strains expressing truncated versions of Mam were tested for genetic interactions with a large collection of chromosomal deficiencies. Genomic segments that enhanced and suppressed the dominant wing phenotype were identified. These regions may contain uncharacterized loci involved in Notch pathway function.

Cardiomyopathy in mice with paternal uniparental disomy for chromosome 12.

Mice inheriting both copies of MMU12 either maternally or paternally demonstrate imprinting effects. Whereas maternal uniparental disomy 12 (matUPD12) fetuses are growth retarded and die perinatally, paternal UPD12 (patUPD12) fetuses die during late gestation and exhibit placentomegaly and skeletal muscle maturation defects. To examine further the developmental consequences of UPD12, we intercrossed mouse stocks heterozygous for Robertsonian translocation chromosomes (8.12) and (10.12). We report that at 13.5-14.5 dg patUPD12 hearts exhibit increased ventricular diameter, thinner, less compact myocardium, and deep intertrabecular recesses when compared to controls. These data provide evidence for cardiac failure, a lethal condition, and suggest a role for an imprinted gene(s) in normal heart development.

Smoking and acute myeloid leukemia: associations with morphology and karyotypic patterns and evaluation of dose-response relations.

This case-control study of tobacco smoking and acute myeloid leukemia (AML), emphasizing specific associations with morphologic and cytogenetic subtypes, comprised smoking histories for 333 cases and 351 controls. Smoking status (ever smokers versus life-long non-smokers) showed no evident effect on AML risk. However, an effect of smoking was indicated at high cumulative smoking doses (pack-years), e.g. 40 pack-years was associated with an odds ratio (OR) of 1.5 [95% confidence interval (CI) 1.0-2.3]. Among morphologic subtypes, the smoking associated OR for acute erythroleukemia was 8.9 (95% CI 1.0-76). No clear associations between smoking and cytogenetic subtypes of AML were observed.

Adult-onset autosomal recessive ataxia with thalamic lesions in a Finnish family.

OBJECTIVE: To describe an unusual kindred with adult-onset ataxia and thalamic lesions detected by brain MRI. METHODS: The authors characterized clinical, laboratory, and pathologic features of the disease and sought linkage to previously recognized ataxia loci. RESULTS: Two sisters and a brother developed progressive ataxia, dysarthria, mild cognitive impairment, and sensorimotor neuropathy at age 30, combined with epilepsy in one sibling. MRI showed symmetric thalamic lesions, changes in brainstem gray matter, and white matter changes in the cerebellum. Autopsy in one of the patients revealed neuronal degeneration with a peculiar vacuolar change in thalamus, probably representing transsynaptic degeneration in response to deafferentation. Neuronal and secondary tract degeneration was observed in the spinal cord, cerebellum, and brainstem suggesting a spinocerebellar degeneration. The disorder appears to be transmitted as an autosomal recessive trait. Genetic and sequence analysis of the FRDA gene and comprehensive laboratory examinations excluded Friedreich's ataxia and other similar recessive diseases. CONCLUSION: Adult-onset recessive ataxia with bilateral thalamic lesions in this family may represent a distinct hereditary spinocerebellar ataxia.

Atypical presentation of dopa-responsive dystonia: generalized hypotonia and proximal weakness.

Dopa-responsive dystonia (DRD) is an autosomal dominant disorder typically presenting as dystonia with diurnal variability. Described is an 8-year-old boy who had had waddling gait, generalized hypotonia, and proximal weakness since early childhood. He responded well to low-dose L-dopa. He had a point mutation of the GTP cyclohydrolase I gene. The patient's father and sister had the same mutation but did not have proximal weakness. GTP cyclohydrolase I deficiency can present with hypotonia and weakness.

Hypodiploidy is a major prognostic factor in multiple myeloma.

Conventional karyotypes performed before any treatment in 208 patients with multiple myeloma were reviewed by the Groupe Français de Cytogénétique Hématologique. A total of 138 patients displayed complex chromosomal abnormalities (CCAs). According to the chromosome number pattern, a first group of 75 patients had a hyperdiploid karyotype. A second group of 63 patients referred to as the hypodiploid group had either pseudodiploid, hypodiploid, or near-tetraploid karyotypes. Of 159 treated patients available for survival analysis, 116 had an abnormal karyotype. The comparison of overall survival (OS) between hyperdiploid and hypodiploid patients showed a highly significant difference (median OS 33.8 vs 12.6 months, respectively, P <.001). The presence of 14q32 rearrangements (36 of 116 patients) worsened the prognosis (median OS 17.6 vs 29.9 months, P <.02). The presence of chromosome 13q abnormalities (13qA, 63 patients) did not modify OS in CCA patients (median OS 20.6 vs 27.8 months, P <.59). However, taking into account the whole series including normal karyotypes, 13qA (63 of 159 patients) had a significant impact on OS (median 20.6 vs 37.1 months, P <.04). In the same way, the presence of a hypodiploid karyotype (52 of 159 patients) had a strong prognostic value (OS 12.8 vs 44.5 months, P <.000 01). A multivariate analysis including stage, beta2-microglobulin, bone marrow plasmocytosis, treatment type, 13qA, and hyperdiploidy and hypodiploidy showed that a hypodiploid karyotype was the first independent factor for OS (P <.001), followed by treatment approach. These results confirm that the chromosome number pattern of malignant plasma cells is a very powerful prognostic factor in newly diagnosed multiple myeloma patients.

Spectral karyotyping analysis of head and neck squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: The genetic content of head and neck squamous cell carcinomas is ill defined. Spectral karyotyping (SKY) is a new technique that allows the simultaneous detection of all chromosomal translocations by labeling each individual chromosome with different fluorescent agents. In the current study we used SKY to analyze cell lines and a primary tumor derived from head and neck squamous cell carcinomas (HNSCC) to delineate recurrent translocations and breakpoints. STUDY DESIGN: Spectral karyotyping analysis of head and neck cancer. METHODS: Two cell lines (MDA886 and MSK922) and one primary tumor in short-term culture were subjected to metaphase growth arrest with colcemide in their exponential growth phase and fixed onto glass slides. Painting probes for each of the autosomes and the sex chromosomes were generated from flow-sorted human chromosomes using sequence-independent DNA amplification. The probes were labeled using a polymerase chain reaction-based reaction and hybridized to metaphase preparations for 2 days at 37 degrees C. Biotinylated probes were detected using avidin Cy5 and digoxigenin-labeled probes with an anti-mouse digoxigenin antibody followed by goat anti-mouse antibody conjugated to Cy5.5. Chromosomes were counterstained with 4,6-diamino-2-phenyliodole (DAPI), and a minimum of five metaphases were captured and analyzed for each case. Breakpoints on the SKY-painted chromosomes were determined by comparison of corresponding DAPI banding. RESULTS: Spectral karyotyping analysis revealed a complex pattern of chromosomal abnormalities. A total of 66 translocations were identified in the three cases, with one new recurrent translocation at (der(4)t(4;20)(q35;?)). Nine complex translocations, involving three or more chromosomes, were identified in these cases. Overall, 96 breakpoints were assigned to metaphase chromosomes and another 74 breakpoints could not be assigned. Breakpoints most commonly involved chromosomes in genetic rearrangements were 1, 3, 5, 8, 13, 16, and 17. CONCLUSIONS: Spectral karyotyping analysis reveals the true complexity of chromosomal aberrations in cell lines derived from head and neck squamous cell carcinomas. The use of SKY, in combination with other techniques, may allow for a more complete assessment of the genetic abnormalities of head and neck cancers and serve as a starting point for gene identification.