RESUMEN
The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.
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Trastorno Autístico/genética , Proteínas Portadoras/genética , Variación Genética , Discapacidad Intelectual/genética , Ubiquitina-Proteína Ligasas/genética , Adolescente , Trastorno Autístico/diagnóstico , Secuencia de Bases , Niño , Estudios de Cohortes , Femenino , Genoma Humano , Humanos , Discapacidad Intelectual/diagnóstico , Cariotipificación , Masculino , Mutación Missense , Fenotipo , Proteolisis , Empalme del ARN , Análisis de Secuencia de ADNRESUMEN
Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder, caused by mutations in FLVCR2. Hallmarks of the syndrome are glomerular vasculopathy in the central nervous system, severe hydrocephaly, hypokinesia and arthrogryphosis. The disorder is considered prenatally lethal. We report the first patients, a brother and a sister, with Fowler syndrome and survival beyond infancy. The patients present a phenotype of severe intellectual and neurologic disability with seizures, absence of functional movements, and no means of communication. Imaging of the brain showed calcifications, profound ventriculomegaly with only a thin edging of the cerebral cortex and hypoplastic cerebellum. Investigation with whole-exome sequencing (WES) revealed, in both patients, a homozygous pathogenic mutation in FLVCR2, c.1289C>T, compatible with a diagnosis of Fowler syndrome. The results highlight the power of combining WES with a thorough clinical examination in order to identify disease-causing mutations in patients whose clinical presentation differs from previously described cases. Specifically, the findings demonstrate that Fowler syndrome is a diagnosis to consider, not only prenatally but also in severely affected children with gross ventriculomegaly on brain imaging.
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Hidranencefalia/diagnóstico , Hidranencefalia/genética , Hidrocefalia/diagnóstico , Hidrocefalia/genética , Proteínas de Transporte de Membrana/genética , Mutación , Receptores Virales/genética , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/genética , Alelos , Encéfalo , Preescolar , Análisis Mutacional de ADN , Exones , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Linaje , Fenotipo , Hermanos , SíndromeRESUMEN
Diastrophic dysplasia (DTD) is an autosomal recessive skeletal dysplasia caused by SLC26A2 mutations. Clinical features include short stature, joint contractures, spinal deformities, and cleft palate. SLC26A2 mutations also result in other skeletal dysplasias, including the milder recessive multiple epiphyseal dysplasia (rMED). DTD is overrepresented in Finland and we speculated that this may have influenced the prevalence and spectrum of SLC26A2-related skeletal conditions also in Sweden. We reviewed the patient registry at Department of Clinical Genetics, Karolinska University Hospital, Stockholm to identify subjects with SLC26A2 mutations. Seven patients from six families were identified; clinical data were available for six patients. All but one patient had one or two copies of the Finnish SLC26A2 founder mutation IVS1+2T>C. Arg279Trp mutation was present in compound heterozygous form in five patients with phenotypes consistent with rMED. Their heights ranged from -2.6 to -1.4 standard deviation units below normal mean and radiographic features included generalised epiphyseal dysplasia and double-layered patellae. Two rMED patients had hypoplastic C2 and cervical kyphosis, a severe manifestation previously described only in DTD. Our study confirms a high prevalence of rMED in Sweden and expands the phenotypic manifestations of rMED.
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Proteínas de Transporte de Anión/genética , Mutación , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Alelos , Huesos/patología , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Estudios Retrospectivos , Transportadores de Sulfato , SueciaRESUMEN
Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
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Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Estudios de Asociación Genética , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/genética , Mutación , Proteínas de Neoplasias/genética , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/genética , Facies , Femenino , Humanos , Masculino , Fenotipo , Análisis de Secuencia de ADNRESUMEN
We have investigated three patients with 21q deletions, two with developmental delay, dysmorphic features and internal organ malformations, and one with cognitive function within the normal range but with some deficits in gross and fine motor development. All aberrations were characterized by array-comparative genomic hybridization (array-CGH). In addition, extensive fluorescence in situ hybridization (FISH) mapping on metaphase chromosomes and mechanically stretched chromosomes was performed on patient 1 who had an extremely complex intrachromosomal rearrangement with 16 breakpoints, four deletions and four duplications. Patients 2 and 3 had interstitial deletions comprising 21q21.1-21q22.11 and 21q11.2-21q21.3, respectively. Partial deletions of 21q are rare and these patients display a highly variable phenotype depending on the size and position of the deletion. A review of the literature identified 38 cases with pure 21q deletions. Twenty-three of these had reliable mapping data. The combined information of present and previous cases suggests that the ITSN1 gene is involved in severe mental retardation in patients with 21q deletion. In addition, a critical region of 0.56 Mb containing four genes, KCNE1, DSCR1, CLIC6 and RUNX1, is associated with severe congenital heart defects, and deletions of the most proximal 15-17 Mb of 21q is associated with mild or no cognitive impairment, but may lead to problems with balance and motor function.
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Deleción Cromosómica , Trastornos de los Cromosomas/diagnóstico , Cromosomas Humanos Par 21 , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Hibridación Genómica Comparativa , Femenino , Humanos , MasculinoRESUMEN
The purpose of this study was to investigate the relative importance of mechanisms behind the effect of food on the intestinal absorption and bioavailability for low solubility compounds by applying a porcine single-pass perfusion model. Nanoparticle suspensions of the model compounds, danazol and cyclosporine were perfused through the jejunum in isotonic fluid alone (control) and isotonic fluid with a P-glycoprotein (P-gp) inhibitor (verapamil) or dietary and endogenous lipids added. The drugs were also administered as saturated solutions in the isotonic fluid containing lipids. Administration of cyclosporine together with verapamil increased the absorption compared to the control (1.6 times) suggesting an effect on jejunal permeability. However, addition of dietary lipids to the media led to a 50% reduction in the absorption of cyclosporine indicating lack of major effects by P-gp inhibition by lipids in vivo. The absorption of danazol was increased (2.6 times) when administered as a nanosuspension in lipid containing media compared to the control, but decreased (60%) when administered as a solution in the same media. This shows how important dissolution of the drug nanoparticles is in drug absorption. The difference in the effect of lipids in the absorption of cyclosporine and danazol when administered as nanosuspensions may be due to different distribution to the colloidal structures present in the media, thereby rendering the drugs' different diffusion rates in the perfused segment. In conclusion, solubilisation seems to be a more important factor than P-gp inhibition as an explanation for the food-drug interaction observed for several low solubility drugs. In addition, the partition into different colloidal structures seems to play a major role in the dissolution and absorption of poorly soluble drugs.
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Ciclosporina/farmacocinética , Danazol/farmacocinética , Alimentos , Absorción Intestinal , Yeyuno/metabolismo , Animales , Disponibilidad Biológica , Tamaño de la Partícula , Perfusión , Solubilidad , PorcinosRESUMEN
The environmental contributions to autism spectrum disorder (ASD) and their informative content for diagnosing the condition are still largely unknown. The objective of this study was to investigate associations between early medical events and ASD, as well as autistic traits, in twins, to test the hypothesis of a cumulative environmental effect on ASD risk. A total of 80 monozygotic (MZ) twin pairs (including a rare sample of 13 twin pairs discordant for clinical ASD) and 46 dizygotic (DZ) twin pairs with varying autistic traits, were examined for intra-pair differences in early medical events (for example, obstetric and neonatal factors, first year infections). First, differences in early medical events were investigated using multisource medical records in pairs qualitatively discordant for ASD. The significant intra-pair differences identified were then tested in relation to autistic traits in the remaining sample of 100 pairs, applying generalized estimating equations analyses. Significant association of the intra-pair differences in the MZ pairs were found for the cumulative load of early medical events and clinical ASD (Z=-2.85, P=0.004) and autistic traits (ß=78.18, P=0.002), as well as infant dysregulation (feeding, sleeping abnormalities, excessive crying and worriedness), when controlling for intelligence quotient and attention deficit hyperactivity disorder comorbidity. The cumulative load of early medical events in general, and infant dysregulation in particular, may index children at risk of ASD owing to non-shared environmental contributions. In clinical practice, these findings may facilitate screening and early detection of ASD.
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Trastorno Autístico/psicología , Ambiente , Gemelos Dicigóticos , Gemelos Monocigóticos , Adolescente , Adulto , Puntaje de Apgar , Asma/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Trastorno del Espectro Autista/epidemiología , Trastorno del Espectro Autista/psicología , Trastorno Autístico/epidemiología , Peso al Nacer , Presentación de Nalgas/epidemiología , Hemorragia Cerebral/epidemiología , Niño , Eccema/epidemiología , Epilepsia/epidemiología , Trastornos de Ingestión y Alimentación en la Niñez/epidemiología , Femenino , Sufrimiento Fetal/epidemiología , Gastroenteritis/epidemiología , Cardiopatías Congénitas/epidemiología , Humanos , Hidrocefalia/epidemiología , Hiperbilirrubinemia Neonatal/epidemiología , Hipersensibilidad/epidemiología , Hipoglucemia/epidemiología , Masculino , Microcefalia/epidemiología , Otitis Media/epidemiología , Terapia por Inhalación de Oxígeno , Embarazo , Pielonefritis/epidemiología , Sepsis/epidemiología , Trastornos del Sueño-Vigilia/epidemiología , Suecia/epidemiología , Trombocitopenia/epidemiología , Trastornos de la Visión/epidemiología , Adulto JovenRESUMEN
The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.
Asunto(s)
Ciliopatías/genética , Predisposición Genética a la Enfermedad , Proteínas Asociadas a Microtúbulos/genética , Músculo Esquelético , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Cerebelo/anomalías , Cerebelo/fisiopatología , Niño , Preescolar , Ciliopatías/fisiopatología , Anomalías del Ojo/genética , Anomalías del Ojo/fisiopatología , Femenino , Homocigoto , Humanos , Lactante , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/fisiopatología , Masculino , Músculo Esquelético/anomalías , Mutación , Síndromes Orofaciodigitales/genética , Síndromes Orofaciodigitales/fisiopatología , Linaje , Fenotipo , Retina/anomalías , Retina/fisiopatologíaRESUMEN
Quantitation of estrogen receptor has been performed in cytosol prepared from 75 specimens of breast cancer tissue from patients who had not received hormonal therapy. The study was performed in order to compare an immunoassay (Abbott Laboratories, North Chicago, IL) with our currently used method for estrogen receptor analysis based on isoelectric focusing of [3H]estradiol-receptor complex in polyacrylamide gels. Using linear regression analysis, a regression coefficient (slope) of 1.30 and a correlation coefficient of 0.75 were calculated. The differences in results between the two methods are probably partly explained by the fact that the ligand-based method only measures unoccupied receptor, whereas the immunoassay detects the total amount of receptor, resulting in generally slightly higher concentrations with the latter method. However, in five of 75 specimens the ligand-based method gave a considerably higher concentration of estrogen receptor. This was most probably explained by partial proteolysis resulting in the formation of receptor fragment(s), which was undetectable with the immunoassay but detectable with the ligand-based method. These observations underline the importance of careful handling of specimens during the whole immunoassay procedure.
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Neoplasias de la Mama/análisis , Receptores de Estrógenos/análisis , Resinas Acrílicas , Adulto , Anciano , Anticuerpos Monoclonales , Estradiol/metabolismo , Femenino , Humanos , Técnicas para Inmunoenzimas , Focalización Isoeléctrica , Persona de Mediana Edad , TritioRESUMEN
We have used DNA fluorescence in situ hybridization (FISH) in combination with morphology to study cell lineage involvement in peripheral blood and bone marrow smears from 15 patients with myelodysplastic syndromes (MDS) and known numerical chromosomal aberrations. Eleven cases were investigated at diagnosis of MDS, and four at transformation to acute myeloid leukemia (MDS-AML). Using conventional cytogenetics, monosomy 7 was detected in nine cases, monosomy 17 in two, and trisomy 8 in five, either as a single aberration or as part of a complex clone. One case had both monosomy 7 and 17. Three biotinylated DNA probes directed against the pericentromeric region of chromosomes 7, 8 and 17, respectively, were used. Bone marrow smears were first stained with May-Grünewald-Giemsa (MGG) for morphologic evaluation, and regions of interest documented by photography. Later the same regions were targeted after hybridization, which allowed FISH analysis of selected bone marrow cells. In each patient between 267 and 921 cells (mean 453) were studied. In most cases a majority of the non-lymphoid bone marrow cells appeared to be of clonal origin, ie showed either monosomy or trisomy by FISH, while in contrast both lymphocytes and plasma cells generally were disomic, ie displayed two fluorescent spots for each probe. The percentages of clonal bone marrow cells differed greatly between patients, but in a single case there was a good agreement between the extent of granulocytic, monocytic and erythrocytic cell lineage involvement. In relation to the clinical stage of MDS, patients with more advanced disease had a significantly higher mean percentage of bone marrow blasts showing monosomy or trisomy, while disomic, possibly non-clonal cells were more frequent among the earlier forms of MDS. In the four cases of MDS-AML nearly all non-lymphoid bone marrow cells belonged to the abnormal clone. The FISH technique offers information regarding the distribution of clonal and non-clonal bone marrow cells in MDS, which might have prognostic and possibly, therapeutic implications.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 7 , Cromosomas Humanos Par 8 , Células Madre Hematopoyéticas/patología , Monosomía , Síndromes Mielodisplásicos/genética , Trisomía , Enfermedad Aguda , Anciano , Anciano de 80 o más Años , Médula Ósea/patología , Diferenciación Celular , Sondas de ADN , Femenino , Granulocitos/patología , Humanos , Hibridación Fluorescente in Situ , Leucemia Mieloide/sangre , Leucemia Mieloide/genética , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/patología , Valores de ReferenciaRESUMEN
BACKGROUND: KBG syndrome is a rare disorder characterized by intellectual disability and associated with macrodontia of the upper central incisors, specific craniofacial findings, short stature and skeletal anomalies. Genetic corroboration of a clinical diagnosis has been possible since 2011, upon identification of heterozygous mutations in or a deletion of the ANKRD11 gene. METHODS: We summarized the height data of 14 adults and 18 children (age range 2-16 years) with a genetically confirmed diagnosis of KBG syndrome. Two of these children were treated with growth hormones. RESULTS: Stature below the 3rd centile or -1.88 standard deviation score (SDS) was observed in 72% of KBG children and in 57% of KBG adults. Height below -2.50 SDS was observed in 62% of KBG children and in 36% of KBG adults. The mean SDS of height in KBG children was -2.56 and in KBG adults -2.17. Two KBG children on growth hormone therapy increased their height by 0.6 and 1 SDS within 1 year, respectively. The former also received a gonadotropin-releasing hormone agonist due to medical necessity. CONCLUSION: Short stature is prevalent in KBG syndrome, and spontaneous catch-up growth beyond childhood appears limited. Growth hormone intervention in short KBG children is perceived as promising.
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Enfermedades del Desarrollo Óseo/complicaciones , Trastornos del Crecimiento/tratamiento farmacológico , Hormona de Crecimiento Humana/uso terapéutico , Discapacidad Intelectual/complicaciones , Anomalías Dentarias/complicaciones , Anomalías Múltiples , Niño , Facies , Trastornos del Crecimiento/complicaciones , Humanos , Masculino , Resultado del TratamientoRESUMEN
Sepsis and endotoxaemia initiate the generation of thrombin, which is responsible for the conversion of fibrinogen to fibrin, platelet aggregation and acts as an inflammatory mediator affecting numerous types of cells, including myocardial, smooth muscle and endothelial cells. Human Gram-negative septic shock, frequently seen in intensive care units, is a condition with high mortality. This condition can be replicated in the endotoxaemic pig. As many of the toxic effects of sepsis are due to thrombin generation, it was of interest to study, using this porcine experimental septic shock model, whether inhibition of thrombin could alleviate the effects of endotoxaemia. For this purpose melagatran, a direct synthetic thrombin inhibitor with a molecular weight of 429 Da, was employed. Melagatran does not significantly interact with any other enzymes in the coagulation cascade or fibrinolytic enzymes aside from thrombin. Furthermore, melagatran does not require endogenous co-factors such as antithrombin or heparin co-Factor II for its antithrombin effect, which is important, as these inhibitors are often consumed in septic patients. We have shown that melagatran exerts a beneficial effect on renal function, as evaluated by plasma creatinine and urinary output, during experimental septic shock. These effects were most pronounced during the later phase of the experimental period, after the infusion of melagatran had been discontinued. Prevention of intrarenal coagulation may be attributable to this finding. In addition, melagatran had beneficial effects on systemic haemodynamics (left ventricular stroke work index, pulmonary capillary wedge pressure and systemic vascular resistance index) in endotoxaemic pigs. This result may be explained by the ability of melagatran to inhibit thrombin, thereby counteracting thrombin's cellular effects. Thus, it can be seen, using this experimental model of septic shock, that melagatran may help to alleviate some of the damaging effects of endotoxaemia, although more research is required to test this further.
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Glicina/análogos & derivados , Choque Séptico/tratamiento farmacológico , Trombina/antagonistas & inhibidores , Animales , Azetidinas , Bencilaminas , Glicina/uso terapéutico , Humanos , Choque Séptico/sangreRESUMEN
We report on a patient with azoospermia, mild mental retardation, and minor physical anomalies. Chromosome analysis demonstrated the presence of additional material on the long arm of one chromosome 13. Forward chromosome painting using chromosome-specific libraries showed an insertion of material from chromosome 5. Further characterization with flow sorting of the aberrant chromosome and amplification by DOP-PCR followed by reverse chromosome painting showed specific trisomy of 5q12-->q13.3.
Asunto(s)
Aberraciones Cromosómicas/genética , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 5 , Trisomía/diagnóstico , Adulto , Trastornos de los Cromosomas , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Reacción en Cadena de la Polimerasa , Translocación GenéticaRESUMEN
INTRODUCTION: Plasma cell leukaemia is a rare disorder that usually carries an aggressive course with a rapidly fatal outcome. A variety of chromosomal abnormalities have been reported in plasma cell leukaemia but the clinical significance of an abnormal karyotype is still unclear. MATERIALS AND METHODS: We have applied the molecular cytogenetic techniques multicolour spectral karyotyping and microdissection in combination with fluorescence in situ hybridization on metaphases from a patient with primary plasma cell leukaemia and a fatal outcome. RESULTS AND CONCLUSION: The chromosome analysis showed severe hypodiploidy and 12 marker chromosomes. Identification of the structural rearrangements was not possible using routine cytogenetic methods. Utilizing the methods above, all marker chromosomes could be identified in detail and the karyotype was shown to be very complex. Forty-three breakpoints were found, and 25 could be identified at the band level, among others 14q32 where the immunoglobulin heavy chain locus is situated. Thus, these techniques provide the opportunity to resolve very complex chromosomal changes in a way that has not been previously possible and will consequently be of great importance in the search for hot spots that may harbour new cancer genes.
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Aberraciones Cromosómicas , Leucemia de Células Plasmáticas/genética , Adulto , Células de la Médula Ósea/patología , Bandeo Cromosómico , Mapeo Cromosómico , Resultado Fatal , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia de Células Plasmáticas/patología , MasculinoRESUMEN
We have applied fluorescence in situ hybridization (FISH) using chromosome-specific libraries from all 24 chromosomes on metaphase spreads from bone marrow cells, in order to resolve the chromosomal changes in leukemic cells from a 10-year-old boy with acute lymphoblastic leukemia (ALL), near-triploidy, and a subsequent poor outcome. The FISH analysis revealed a pattern of chromosome gains and losses that differed from all cases previously described. Most of the affected chromosomes were present in three copies (trisomy for chromosomes 1, 2, 5, 6, 7, 11, 12, 13, 14, 16, 17, 18, 19, 20, and 22), but the patient had four copies of chromosomes 8 and 21, two copies of chromosomes 3, 4, 9, 10, 15, and X, and one Y chromosome. No structural abnormalities could be detected. Thus, the karyotype of the malignant clone was 66,XXY-3,-4,+8,-9,-10,-15,+21.
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Mapeo Cromosómico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Trisomía , Niño , Resultado Fatal , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Ploidias , PronósticoRESUMEN
Continuous intra-aortic balloon occlusion has been reported to improve cerebral blood flow during cardiopulmonary resuscitation (CPR) but not to ameliorate the impaired blood recirculation occurring after restoration of spontaneous circulation (ROSC). Volume expansion with hypertonic solutions may improve recovery of brain function by enhancing post-resuscitation cerebral blood flow. We hypothesised that the combination of these treatments with open-chest CPR would improve cerebral blood flow during CPR, and attenuate post-resuscitation flow disturbances. In 32 anaesthetised piglets, catheters were placed for haemodynamic and blood gas monitoring. Open-chest CPR was initiated after 9 min of ventricular fibrillation. The piglets were treated either with 3 ml kg(-1) hypertonic saline and dextran (HSD) (n = 10), HSD and balloon occlusion (n = 10) or with normal saline (n = 12). After 7 min of CPR, internal defibrillatory shocks were administered to restore spontaneous circulation. Haemodynamic variables, continuous cerebral cortical blood flow, cerebral tissue pH and pCO2 and blood gas parameters were measured during CPR and up to 210 min after ROSC. Higher cerebral perfusion pressure was found in the balloon-HSD group during CPR. This group exhibited less arterial hypertension immediately after ROSC compared with the other groups. Thereafter, a fairly rapid decrease of the perfusion pressures was observed in all groups reaching a minimum level approximately 30 min after ROSC. Cerebral cortical blood flow was significantly higher and cerebral oxygen extraction ratio significantly lower in the balloon-HSD group during CPR, but not after ROSC. In conclusion, a combination of intra-aortic balloon occlusion and HSD administration improves cerebral blood flow and brain oxygen supply during experimental open-chest CPR. In contrast, cerebral blood flow after ROSC was not shown to be influenced by this treatment.
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Isquemia Encefálica/prevención & control , Reanimación Cardiopulmonar , Circulación Cerebrovascular/fisiología , Paro Cardíaco/terapia , Animales , Aorta Torácica , Reanimación Cardiopulmonar/métodos , Cateterismo , Dextranos/uso terapéutico , Cardioversión Eléctrica , Solución Salina Hipertónica/uso terapéutico , Porcinos , Fibrilación VentricularRESUMEN
PURPOSE: Human septic shock can be replicated in the endotoxaemic pig. Endotoxaemia causes a multitude of events, including reduced PaO(2) and increased lipid peroxidation. This study was designed to evaluate the possible effects of a commonly used anaesthetic drug with known antioxidant properties (propofol) during porcine endotoxaemia. METHODS: Ten pigs were anaesthetised and given a 6 h E. coli endotoxin infusion. The animals received, randomly, a supplementary continuous infusion of propofol emulsion (containing 0.005% EDTA) or the corresponding volume of vehicle (controls). Pathophysiologic responses were determined. Non-enzymatic (by measuring plasma 8-iso-PGF(2 alpha) and enzymatic (by measuring plasma 15-keto-dihydro-PGF(2 alpha)) lipid peroxidations were evaluated. Plasma levels of the endogenous antioxidants alpha- and gamma-tocopherols, were also analysed. RESULTS: Endotoxaemia increased plasma levels of 8-iso-PGF(2 alpha) (1st-4th h) and 15-keto-dihydro-PGF(2 alpha) (1st-4th h) significantly more in controls than in the propofol+endotoxin group. PaO(2) was significantly less affected by endotoxin in the propofol treated animals (2nd-4th h). Mean arterial pressure (4th-6th h) and systemic vascular resistance (6th h) were reduced significantly more by endotoxin among the propofol-treated animals. Vitamin E (alpha-tocopherol) increased in all animals, significantly more in the propofol+endotoxin group (1/2-6th h) than in the control group. CONCLUSIONS: Propofol reduced endotoxin-induced free radical mediated and cyclooxygenase catalysed lipid peroxidation significantly. The implication is that propofol counteracts endotoxin-induced deterioration of PaO(2).
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Anestésicos Intravenosos/uso terapéutico , Dinoprost/análogos & derivados , Endotoxemia/fisiopatología , Infecciones por Escherichia coli/fisiopatología , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Propofol/análogos & derivados , Propofol/uso terapéutico , Choque Séptico/sangre , Choque Séptico/tratamiento farmacológico , Vitamina E/fisiología , Animales , Dinoprost/sangre , F2-Isoprostanos/sangre , Inflamación/terapia , Radioinmunoensayo , Porcinos , Vitamina E/sangreRESUMEN
Chromosomal rearrangements in short term cultures from nine cases of non-Hodgkin's lymphomas (NHL) were characterized by G-banding, spectral karyotyping (SKY), and fluorescence in situ hybridization (FISH). Eight of the nine cases showed complex karyotypes with chromosomal aberrations which, in most cases, could not be fully characterized by traditional G-banding analysis alone. Karyotypic abnormalities of special interest were marker chromosomes and chromosomes with added unidentified chromosomal material, as previously non-identified chromosomal translocations were hidden behind these aberrations. SKY and FISH analysis, as a complement to banding analysis, significantly improved the karyotypes in seven of the nine cases and unveiled 21 previously unidentified rearrangements with novel translocation breakpoints. Traditional G-banding alone revealed seven new rearrangements, which were all confirmed by SKY. None of these new aberrations occurred as single clonal rearrangements but as parts of complex karyotypes. Nevertheless, the chromosomal break-point regions identified should be considered as potential hot spots for genes involved in the tumorigenesis of the malignancy.
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Rotura Cromosómica/genética , Cariotipificación/métodos , Linfoma no Hodgkin/genética , Adulto , Anciano , Bandeo Cromosómico/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Espectral/métodosRESUMEN
Ventilation with decelerating inspiratory flow is known to reduce the dead space fraction and to decrease PaCO2. Constant inspiratory flow with an end-inspiratory pause (EIP) is also known to increase the removal of CO2. The aim of the study was to elucidate the effect of the pause/no-flow period while both the pattern and rate of inspiratory flow was unchanged, and when the lung was ventilated with sufficient PEEP to prevent end-expiratory collapse. Surfactant depleted piglets were assigned to decelerating or constant inspiratory flow with 24 breaths per minute (bpm) or 12 bpm, or to constant flow, without and with an end-inspiratory pause of 25%. By adding an EIP the total time without active inspiratory flow of the respiratory cycle was kept unchanged. Gas exchange, airway pressures, functional residual capacity (using sulfurhexafluoride) and haemodynamics (thermo-dye indicator dilution technique) were measured. Irrespective of ventilatory frequency, PaCO2 was lower and serial dead space reduced with decelerating flow, compared with constant inspiratory flow. With an end-inspiratory pause added to constant inspiratory flow, serial dead space was reduced but did not decrease PaCO2. The results of this study corroborate the assumption that total time without active inspiratory flow is important for arterial CO2-tension.