Estudi dels factors mol•leculars i cel•lulars implicats en les alteracions corticals de la Síndrome de down

Investigación producida a partir de una estancia en en el Instituto de Neurociencias de la Universidad Miguel Hernández entre enero y mayo del 2007. El SD o trisomía del cromosoma 21 es la aneuploidía cromosómica más frecuente y constituye la principal causa de retraso mental. Las cuestiones que aún son objeto de debate en el SD son: 1) si pueden existir, entre los genes triplicados, algunos que contribuyan de forma más importante a algunos de los fenotipos observables en SD y, 2) hasta qué punto los fenotipos observados derivan de alteraciones del neurodesarrollo o de alteraciones funcionales en el adulto. Con el fin de abordar esta cuestión nos hemos centrado en las alteraciones cognitivas del SD y hemos realizado la caracterización del papel de Dyrk1A en el desarrollo de una estructura clave para esta función: la corteza cerebral. Los resultados obtenidos muestran que la sobrexpresión de Dyrk1A produce un desajuste proliferativo dando lugar a un retraso en la formación de la subplaca, con consecuencias en la laminación de la placa cortical. Las alteraciones en la corticogénesis van a tener consecuencias en el establecimiento de la conectividad tálamo-cortical que se encuentra marcadamente retrasada. En el hipocampo, los ratones transgénicos mostraron una reducción del grosor de las capas. Estos resultados pueden ser relevantes para el SD, puesto que es similar a lo observado en fetos SD.

Public Health Functions Project Team Minutes (PDF 21 KB)

Minutes of the Meeting of the Public Health Functions Project Team 21 February 2006

Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes.

Inter-individual differences in gene expression are likely to account for an important fraction of phenotypic differences, including susceptibility to common disorders. Recent studies have shown extensive variation in gene expression levels in humans and other organisms, and that a fraction of this variation is under genetic control. We investigated the patterns of gene expression variation in a 25 Mb region of human chromosome 21, which has been associated with many Down syndrome (DS) phenotypes. Taqman real-time PCR was used to measure expression variation of 41 genes in lymphoblastoid cells of 40 unrelated individuals. For 25 genes found to be differentially expressed, additional analysis was performed in 10 CEPH families to determine heritabilities and map loci harboring regulatory variation. Seventy-six percent of the differentially expressed genes had significant heritabilities, and genomewide linkage analysis led to the identification of significant eQTLs for nine genes. Most eQTLs were in trans, with the best result (P=7.46 x 10(-8)) obtained for TMEM1 on chromosome 12q24.33. A cis-eQTL identified for CCT8 was validated by performing an association study in 60 individuals from the HapMap project. SNP rs965951 located within CCT8 was found to be significantly associated with its expression levels (P=2.5 x 10(-5)) confirming cis-regulatory variation. The results of our study provide a representative view of expression variation of chromosome 21 genes, identify loci involved in their regulation and suggest that genes, for which expression differences are significantly larger than 1.5-fold in control samples, are unlikely to be involved in DS-phenotypes present in all affected individuals.

Escalating epidemiology of eosinophilic esophagitis: 21 years of prospective population-based documentation in Olten county

Background and Aims: Eosinophilic Esophagitis (EoE) is detected with a dramatically increasingfrequency during the last decades. However, it is still unknown whether this reflects atrue increase in incidence or just an increased awareness by gastroenterologists. We therefore,prospectively assessed incidence and prevalence of EoE in an epidemiologically well definedindicator area over the last 21 years. Methods: Olten County is an area of approximately90,000 inhabitants without pronounced demographic changes during the last two decades.Two EoE-experienced gastroenterologists and one pathology centre are responsible forcovering the gastroenterological service of the area. No public programs for increasingawareness of EoE were implemented in this region. Since 1989 all individuals with confirmeddiagnosis of EoE living in Olten County were entered prospectively into the database. Results:Forty-six patients (76% males, mean age 41±16 yrs) were diagnosed with EoE between1989 and 2009. Ninety-four percent of patients presented with dysphagia. An average annualincidence rate of 1.88/100,000 was found (range 0-8) with a marked increase in the periodfrom 2004 to 2009. The cumulative EoE prevalence rose up to 35.1/100,000 inhabitantsin 2009. No significant change was observed for the median diagnostic delay, as it was 3years from 1989 to 1998 and 2 years from 1999 to 2009 with age < 40 years representinga risk factor for retarded diagnosis. The number of upper endoscopies per year increasedby 63% in the period from 1999 to 2009 compared to the years 1989 to 1998 which ismarkedly less then the increase in the incidence rate of 150% for the same periods. Conclusions:Over the last 21 years, a significant increase in EoE incidence and prevalence wasfound in an epidemiologically stable indicator region of Switzerland. The constant diagnosticdelay, the number of newly diagnosed EoE cases that was much more pronounced thanthe modest increase of performed upper endoscopies, as well as the lack of EoE awarenessprograms in Olten County indicates a true increase in EoE incidence.

Briefing 21: Inequalities in Primary Care in the East of England

This report focuses on inequalities in primary care as indicated by the Quality and Outcomes Framework.

Corneal Opacities in Trisomy 8 Mosaic Syndrome : Clinical, Histologic and Genetic Features

Purpose: To describe the clinical, histologic and genetic findings of corneal opacities in the trisomy 8 mosaic syndrome. Methods: 3 children aged 8 years (Patients A), 6 years (Patients B) and 1 month (Patients C) respectively, were referred with corneal opacities for ophthalmologic evaluation. The 2 older patients had been previously diagnosed with trisomy 8 mosaicism, while the third was diagnosed after the ocular examination. Automated lamellar keratoplasty (ALTK) was performed on the most amblyopic eye. Histopathologic analysis with immunohistochemical markers and cytogenetic studies by FISH using haploid probes for chromosome 8 and chromosome 16 (control) were performed on the excised corneal lesion. Results: All patients presented vascularized corneal opacities involving the superficial stroma, and amblyopia with a bilateral involvement in two of them (Patients A and B). Post-operative follow-up (range 6-20 months) was satisfactory, with the graft remaining clear and improved visual acuity, allowing iso-acuity and stereoscopy in the one month old child (Patients C). The clinically observed corneal opacities corresponded histopathologically to the replacement of the normal anterior corneal stroma by a choristomatous loose richly vascularized connective tissue containing mucopolysacharides. Bowman's membrane was absent. There were no adnexal structures. The overlaying epithelium expressed keratin 3 in all three cases. Keratin 19 was found in the suprabasal epithelial cells in one case but was absent in the other cases. There were no expression of keratin 7 and 1 as well as MUC5AC in the epithelial cells. FISH analysis from 100 interphase cells of the affected tissue and normal conjontival probe revealed normal diploid cells. Conclusions: In this series, the corneal opacities associated with trisomy 8 mosaic syndrome share a common clinical, histopathological and genetic features. ALTK should be considered at diagnosis to prevent amblyopia in these children.

Gm(1,2,4,10,21) and Km(1) factors in vitreous humor.

The presence of Gm(1,2,4,10,21) and Km(1) factors in vitreous humor taken from human corpses was investigated. The results revealed a good agreement between the factors detected in this biological material and in blood. Their presence in vitreous humor is independent of the secretor type.

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Current applications of cardiac magnetic resonance (CMR) imaging offer a wide spectrum of indications in the setting of acute cardiac care. In particular, CMR is helpful for the differential diagnosis of chest pain by detection of myocarditis and pericarditis. Also, takotsubo cardiomyopathy and acute aortic diseases can be evaluated by CMR and are important differential diagnoses in patients with acute chest pain. In patients with restricted windows for echocardiography, CMR is the method of choice to evaluate complications of acute myocardial infarction (AMI). In AMI, CMR allows for a unique characterization of myocardial damage by quantifying necrosis, microvascular obstruction, oedema (=area at risk), and haemorrhage. These capabilities will help us to understand better the pathophysiological events during infarction and will also allow to assess new treatment strategies in AMI. To what extent the information on tissue damage will guide patient management is not yet clear and further research in this field is warranted. In the near future, CMR will certainly become more routine in acute cardiac care units, as manufacturers are now focusing strongly on this aspect of user-friendliness. Finally, in the next decade or so, MRI of other nuclei such as fluorine and carbon might become a clinical reality, which would allow for metabolic and targeted molecular imaging with excellent sensitivity and specificity

Phénotype de la trisomie 9q distale chez un enfant présentant un chromosome surnuméraire remanié [t(X;9)]. [Distal 9q trisomy phenotype in a patient with a supernumerary rearranged chromosome [t(X:9)] (author's transl).]

A child with clinical features associated a trisomy for the distal part of 9q was shown to have the following abnormal chromosome complement : 47,XY,+t)X;9) (Xpter yields Xq24:9q31 yields 9qter), inv 9(p11q13), var 14 (14pQFQ34).