Deficient protein kinase C-dependent Na+/H+ exchanger activity in T cells from bone marrow transplantation recipients

The early Na+/H+ exchanger-mediated alkalinization of intracellular pH (pHi) was analyzed in peripheral blood T cells from 23 bone marrow transplantation (BMT) recipients (17 allogeneic and 6 autologous) and a group of 13 healthy controls, in response to stimulation of protein kinase C (PKC) with a phorbol ester. In parallel we evaluated the proliferative response of peripheral blood T cells to an anti-CD3 mAb in the presence of either IL-2 or PMA. The pHi increase (delta pHi) observed in control samples ranged from 0.14 to 0.23 pH units (X +/- SD = 0.17 +/- 0.03). In 10 allogeneic and four autologous BMT recipients the delta pHi was under the lower limit of the control range (range: 0.01 to 0.09, X +/- SD = 0.05 +/- 0.02), whereas the remaining nine cases responded similarly to control samples (range: 0.14 to 0.24, X +/- SD = 0.17 +/- 0.04). The response of the Na+/H+ antiporter to a PKC-independent osmotic stimulation appeared to be normal, thus indicating that the intrinsic Na+/H+ exchanger activity was unaltered. The anti-CD3 induced proliferative response of the group of samples displaying a suboptimal delta pHi, was significantly lower (p less than 0.01) than that detected in control samples. T cell proliferation in samples from BMT recipients displaying a normal delta pHi was undistinguishable from the control group (p greater than 0.05). Our results provide the first evidence for a defective early metabolic event, closely related to PKC activity, in T cells from BMT recipients displaying a low proliferative response to T cell mitogens.This work was supported by Grants from INSALUD-FISS (88/1737) and CAICYT 840456.Peer Reviewe

Simple but Precise Engineering of Functional Nanocapsules through Nanoprecipitation

International audienceA general, rapid, and undemanding method to generate at will functional oil-filled nanocapsules through nanoprecipitation is reported. On the basis of polymer and hexadecane/water/acetone phase diagrams, the composition can be set so that polymer chains preferentially stick at the interface of the oil droplets to create nanocapsules. The nanocapsules can be decorated with biorelevant molecules (biotin, fluorescent tags, metal nanoparticles) within the shell and loaded with hydrophobic molecules in a simple one-pot procedure

Prevalence of atherogenic dyslipidemia, related factors and level of lipid control in the general population of Galicia: GALIPEMIAS study

[Resumen] Objetivos. GALIPEMIAS es un estudio diseñado para establecer la prevalencia de las dislipemias familiares en la población general de Galicia. El objetivo del presente estudio fue determinar la prevalencia de dislipemia aterogénica (DA), su relación con otros factores de riesgo cardiovascular (RCV) y el grado de control lipídico. Métodos. Estudio transversal realizado en la población general mayor de 18 años de edad residente en Galicia, y con tarjeta sanitaria del Servicio Gallego de Salud (N = 1.000). Selección de la muestra mediante muestreo aleatorizado por conglomerados. Se analizó la prevalencia de DA ajustada por edad y sexo, y las variables relacionadas. Resultados. La prevalencia de DA ajustada por edad y sexo fue de un 6,6% (IC 95%: 5,0-8,3). La hipertensión arterial, la glucemia basal alterada, la diabetes mellitus tipo 2 y la enfermedad cardiovascular aterosclerótica fueron más frecuentes en individuos con DA que en el resto de la población. El 47,5% de los sujetos con DA presentaba un RCV alto o muy alto. Recibían fármacos hipolipemiantes el 38,9% (30,5% estatinas) de los participantes con DA (46,1% de los de alto y el 71,4% de los de muy alto RCV). El 25,4% de los sujetos con DA presentaban niveles de cLDL en objetivo, siendo todos ellos de bajo o moderado RCV. Conclusiones. La prevalencia de DA en la población general adulta de Galicia no es despreciable, se relacionó con varios factores de RCV y la enfermedad cardiovascular aterosclerótica. A pesar de ello, estuvo infradiagnosticada e infratratada.[Abstract] Objectives: GALIPEMIAS is a study designed to establish the prevalence of familial dyslipidemia in the general population of Galicia. The objective of the present study was to assess the prevalence of atherogenic dyslipidemia (AD), its relationship with other cardiovascular risk (CVR) factors, and the degree of lipid control. Methods: Cross-sectional study carried out in the general population over 18 years of age residing in Galicia and with a health card from the Galician Health Service (N=1,000). Selection of the sample by means of random sampling by conglomerates. The AD prevalence adjusted for age and sex and the related variables were analyzed. Results: The prevalence of AD adjusted for age and sex was 6.6% (95% CI: 5.0-8.3%). Arterial hypertension, altered basal glycemia, type 2 diabetes mellitus and cardiovascular disease were more frequent in subjects with AD than in the rest of the population. 47.5% of the subjects with AD had a high or very high CVR. Lipid-lowering drugs were received by 38.9% (30.5% statins) of the participants with AD (46.1% of those with high and 71.4% of those with very high CVR). 25.4% of the subjects with AD had target LDL-c levels, all of them with low or moderate CVR. Conclusions: The prevalence of AD in the general adult population of Galicia is not negligible, and it was related to several CVR factors and cardiovascular disease. Despite this, this lipid alteration was underdiagnosed and undertreated

Homozygous Nonsense Mutations in TWIST2 Cause Setleis Syndrome

The focal facial dermal dysplasias (FFDDs) are a group of inherited developmental disorders in which the characteristic diagnostic feature is bitemporal scar-like lesions that resemble forceps marks. To date, the genetic defects underlying these ectodermal dysplasias have not been determined. To identify the gene defect causing autosomal-recessive Setleis syndrome (type III FFDD), homozygosity mapping was performed with genomic DNAs from five affected individuals and 26 members of the consanguineous Puerto Rican (PR) family originally described by Setleis and colleagues. Microsatellites D2S1397 and D2S2968 were homozygous in all affected individuals, mapping the disease locus to 2q37.3. Haplotype analyses of additional markers in the PR family and a consanguineous Arab family further limited the disease locus to ∼3 Mb between D2S2949 and D2S2253. Of the 29 candidate genes in this region, the bHLH transcription factor, TWIST2, was initially sequenced on the basis of its known involvement in murine facial development. Homozygous TWIST2 nonsense mutations, c.324C>T and c.486C>T, were identified in the affected members of the Arab and PR families, respectively. Characterization of the expressed mutant proteins, p.Q65X and p.Q119X, by electrophoretic mobility shift assays and immunoblot analyses indicated that they were truncated and unstable. Notably, Setleis syndrome patients and Twist2 knockout mice have similar facial features, indicating the gene's conserved role in mammalian development. Although human TWIST2 and TWIST1 encode highly homologous bHLH transcription factors, the finding that TWIST2 recessive mutations cause an FFDD and dominant TWIST1 mutations cause Saethre-Chotzen craniocynostosis suggests that they function independently in skin and bone development