A short in-frame deletion in NTRK1 tyrosine kinase domain caused by a novel splice site mutation in a patient with congenital insensitivity to pain with anhidrosis

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis. It is caused by mutations in the NTRK1 gene, which encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF). -- Case Presentation: We present the case of a female patient diagnosed with CIPA at the age of 8 months. The patient is currently 6 years old and her psychomotor development conforms to her age (RMN, SPECT and psychological study are in the range of normality). PCR amplification of DNA, followed by direct sequencing, was used to investigate the presence of NTRK1 gene mutations. Reverse transcriptase (RT)-PCR amplification of RNA, followed by cloning and sequencing of isolated RT-PCR products was used to characterize the effect of the mutations on NTRK1 mRNA splicing. The clinical diagnosis of CIPA was confirmed by the detection of two splice-site mutations in NTRK1, revealing that the patient was a compound heterozygote at this gene. One of these alterations, c.574+1G > A, is located at the splice donor site of intron 5. We also found a second mutation, c.2206-2 A > G, not previously reported in the literature, which is located at the splice acceptor site of intron 16. Each parent was confirmed to be a carrier for one of the mutations by DNA sequencing analysis. It has been proposed that the c.574+1G > A mutation would cause exon 5 skipping during NTRK1 mRNA splicing. We could confirm this prediction and, more importantly, we provide evidence that the novel c.2206-2A > G mutation also disrupts normal NTRK1 splicing, leading to the use of an alternative splice acceptor site within exon 17. As a consequence, this mutation would result in the production of a mutant NTRK1 protein with a seven aminoacid in-frame deletion in its tyrosine kinase domain. --Conclusions: We present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor. The possible phenotypical implications of this mutation are discussed.

Increased expression of cystine/glutamate antiporter in multiple sclerosis

Background: Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS). Intriguingly, glutamate level in plasma and cerebrospinal fluid of MS patients is elevated, a feature which may be related to the pathophysiology of this disease. In addition to glutamate transporters, levels of extracellular glutamate are controlled by cystine/glutamate antiporter x(c)(-), an exchanger that provides intracellular cystine for production of glutathione, the major cellular antioxidant. The objective of this study was to analyze the role of the system x(c)(-) in glutamate homeostasis alterations in MS pathology. -- Methods: Primary cultures of human monocytes and the cell line U-937 were used to investigate the mechanism of glutamate release. Expression of cystine glutamate exchanger (xCT) was quantified by quantitative PCR, Western blot, flow cytometry and immunohistochemistry in monocytes in vitro, in animals with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, and in samples of MS patients. -- Results and discussion: We show here that human activated monocytes release glutamate through cystine/glutamate antiporter x(c)(-) and that the expression of the catalytic subunit xCT is upregulated as a consequence of monocyte activation. In addition, xCT expression is also increased in EAE and in the disease proper. In the later, high expression of xCT occurs both in the central nervous system (CNS) and in peripheral blood cells. In particular, cells from monocyte-macrophage-microglia lineage have higher xCT expression in MS and in EAE, indicating that immune activation upregulates xCT levels, which may result in higher glutamate release and contribution to excitotoxic damage to oligodendrocytes. -- Conclusions: Together, these results reveal that increased expression of the cystine/glutamate antiporter system x(c)(-) in MS provides a link between inflammation and excitotoxicity in demyelinating diseases.

Los programas de apoyo a la creación de spin-offs académicas en las universidades españolas: una comparación internacional

XXII,1021 p.

Number of prior episodes and the presence of depressive symptoms are associated with longer length of stay for patients with acute manic episodes

Background: Few studies have analyzed predictors of length of stay (LOS) in patients admitted due to acute bipolar manic episodes. The purpose of the present study was to estimate LOS and to determine the potential sociodemographic and clinical risk factors associated with a longer hospitalization. Such information could be useful to identify those patients at high risk for long LOS and to allocate them to special treatments, with the aim of optimizing their hospital management. Methods: This was a cross-sectional study recruiting adult patients with a diagnosis of bipolar disorder (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) criteria) who had been hospitalized due to an acute manic episode with a Young Mania Rating Scale total score greater than 20. Bivariate correlational and multiple linear regression analyses were performed to identify independent predictors of LOS. Results: A total of 235 patients from 44 centers were included in the study. The only factors that were significantly associated to LOS in the regression model were the number of previous episodes and the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at admission (P < 0.05). Conclusions: Patients with a high number of previous episodes and those with depressive symptoms during mania are more likely to stay longer in hospital. Patients with severe depressive symptoms may have a more severe or treatment-resistant course of the acute bipolar manic episode.

Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer's disease mouse model : mechanism for deficient glutamatergic transmission?

Astrocytes are fundamental for brain homeostasis and the progression and outcome of many neuropathologies including Alzheimer's disease (AD). In the triple transgenic mouse model of AD (3xTg-AD) generalised hippocampal astroglia atrophy precedes a restricted and specific beta-amyloid (A beta) plaque-related astrogliosis. Astrocytes are critical for CNS glutamatergic transmission being the principal elements of glutamate homeostasis through maintaining its synthesis, uptake and turnover via glutamate-glutamine shuttle. Glutamine synthetase (GS), which is specifically expressed in astrocytes, forms glutamine by an ATP-dependent amination of glutamate. Here, we report changes in GS astrocytic expression in two major cognitive areas of the hippocampus (the dentate gyrus, DG and the CA1) in 3xTg-AD animals aged between 9 and 18 months. We found a significant reduction in Nv (number of cell/mm(3)) of GS immunoreactive (GS-IR) astrocytes starting from 12 months (28.59%) of age in the DG, and sustained at 18 months (31.65%). CA1 decrease of GS-positive astrocytes Nv (33.26%) occurs at 18 months. This Nv reduction of GSIR astrocytes is paralleled by a decrease in overall GS expression (determined by its optical density) that becomes significant at 18 months (21.61% and 19.68% in DG and CA1, respectively). GS-IR Nv changes are directly associated with the presence of A beta deposits showing a decrease of 47.92% as opposed to 23.47% in areas free of A beta. These changes in GS containing astrocytes and GS-immunoreactivity indicate AD-related impairments of glutamate homeostatic system, at the advanced and late stages of the disease, which may affect the efficacy of glutamatergic transmission in the diseased brain that may contribute to the cognitive deficiency.

[R_SanMillan_Yuso] Documentación geométrica de las excavaciones arqueológicas realizadas en el Monasterio de Yuso (San Millán de la Cogolla, La Rioja)

[ES] El seguimiento arqueológico se realiza sobre las capillas del la nave Norte de la iglesia más la capilla “de las reliquias”, en total 9 capillas de unos 10 x 10 metros cada una. Los elementos a documentar son las unidades estratigráficas exhumadas que, en gran medida corresponden a enterramientos (fosas y los propios esqueletos).

[G_Oñati_Arantzazu] Documentación fotográfica del Apostolado y la Piedad del exterior del Monasterio de Arantzazu (Oñati, Gipuzkoa)

[ES] Conjunto de figuras en piedra de gran porte (unos 4 metros de altura cada una), lo componen 14 figuras en la zona baja del apostolado y un conjunto de 2 personajes más formando la Piedad en la parte superior. Se trata de formas esquemáticas de perfil redondeado que corresponden artísticamente a una de las corrientes más destacadas del siglo XX.

[S_Ambrona_Insitu] Levantamiento fotogramétrico del yacimiento paleontológico “Museo in situ” de Ambrona (Soria)

[ES] Se trata de un área cubierta de unos 8 x 8 metros (la altura del techo es de unos 2,5 metros en la zona más baja) en la que se disponen varios huesos de diferentes especies entre los que destacan, por su porte, varios colmillos de elefante.

[B_Muskiz_Muñatones] Documentación geométrica de la muralla interior del Castillo de Muñatones (Muskiz, Bizkaia)

[ES] Este proyecto corresponde a una continuación del que documenta la torre central y que se realizó en 2005. Dicho trabajo puede consultarse también es este repositorio: