Arbitration between controlled and impulsive choices.

The impulse to act for immediate reward often conflicts with more deliberate evaluations that support long-term benefit. The neural architecture that negotiates this conflict remains unclear. One account proposes a single neural circuit that evaluates both immediate and delayed outcomes, while another outlines separate impulsive and patient systems that compete for behavioral control. Here we designed a task in which a complex payout structure divorces the immediate value of acting from the overall long-term value, within the same outcome modality. Using model-based fMRI in humans, we demonstrate separate neural representations of immediate and long-term values, with the former tracked in the anterior caudate (AC) and the latter in the ventromedial prefrontal cortex (vmPFC). Crucially, when subjects' choices were compatible with long-run consequences, value signals in AC were down-weighted and those in vmPFC were enhanced, while the opposite occurred when choice was impulsive. Thus, our data implicate a trade-off in value representation between AC and vmPFC as underlying controlled versus impulsive choice.

Dopamine, Salience, and Response Set Shifting in Prefrontal Cortex.

Dopamine is implicated in multiple functions, including motor execution, action learning for hedonically salient outcomes, maintenance, and switching of behavioral response set. Here, we used a novel within-subject psychopharmacological and combined functional neuroimaging paradigm, investigating the interaction between hedonic salience, dopamine, and response set shifting, distinct from effects on action learning or motor execution. We asked whether behavioral performance in response set shifting depends on the hedonic salience of reversal cues, by presenting these as null (neutral) or salient (monetary loss) outcomes. We observed marked effects of reversal cue salience on set-switching, with more efficient reversals following salient loss outcomes. L-Dopa degraded this discrimination, leading to inappropriate perseveration. Generic activation in thalamus, insula, and striatum preceded response set switches, with an opposite pattern in ventromedial prefrontal cortex (vmPFC). However, the behavioral effect of hedonic salience was reflected in differential vmPFC deactivation following salient relative to null reversal cues. l-Dopa reversed this pattern in vmPFC, suggesting that its behavioral effects are due to disruption of the stability and switching of firing patterns in prefrontal cortex. Our findings provide a potential neurobiological explanation for paradoxical phenomena, including maintenance of behavioral set despite negative outcomes, seen in impulse control disorders in Parkinson's disease.

[Hirschsprung's disease and medullary carcinoma of the thyroids: two diseases in a monogenetic disorder]. / La enfermedad de Hirschsprung y el carcinoma medular de tiroides: dos enfermedades en una alteración monogénica.

INTRODUCTION: The most common gene involved in Hirschsprung's disease (HD) is protooncogene RET. More than 100 mutations of this gene have been described associated with HD. The mutations that change a cysteine with another aminoacid (mainly in exons 10 and 11) give a risk of familial medullary thyroid carcinoma (FTMC) and MEN 2A. These mutations are found in 5% of patients with HD and have an autosomal dominant inheritance. The FTMC is aggressive and the prophylactic thyroidectomy is the best treatment. We present our results in screening for RET protooncogene mutations associated with TMC in patients with HD. PATIENTS AND METHODS: We have treated 40 patients with HD in the last 15 years. We have classified the patients into two groups: A) high risk of RET protooncogene mutation associated with FTMC (family history of HD, long-segment and/or associated syndromes) and B) low risk (rectosigmoid involvement). We have identified the exons 7, 8, 9, 10, 11, 13, 14 and 15 of the RET protooncogene in 12 of 15 children from group A and 6 from 25 from group B. RESULTS: We have found the p.Cys620Ser mutation (exon 10) in a girl from group A (long-segment). In the family study, we have found the same mutation in her mother, her oncle and her cousin. CONCLUSION: The comprehensive management of children with HD requires screening for RET protooncogene mutations associated with FTMC. In the first-degree relatives of children with a mutation risk, screening is required.

La enfermedad de Hirschsprung y el carcinoma medular de tiroides: dos enfermedades en una alteración monogénica / Hirschsprung’s disease and medullary carcinoma of the thyroids: Two diseases in a monogenetic disorder

Introducción. Las mutaciones del protooncogén RET son las más frecuentes en la enfermedad de Hirschsprung (EH). Hay descritas más de 100 mutaciones de este gen asociadas a EH, pero aquellas en que el error reemplaza una cisteína por otro aminoácido (principalmente en exones 10 y 11) presentan riesgo de MEN 2A y carcinoma medular de tiroides familiar (CMTF). Estas mutaciones de riesgo se hallan en un 5% de los pacientes con EH y presentan una herencia autosómica dominante. El CMTF tiene un comportamiento agresivo y la tiroidectomía profiláctica es el mejor tratamiento. Presentamos nuestros resultados en el cribado de las mutaciones del gen RET asociado a CMT en pacientes afectos de EH. Pacientes y método. Se han tratado en nuestro hospital 40 pacientes con EH en los últimos 15 años. Hemos clasificado a los pacientes en dos grupos: A) alto riesgo de mutación del gen RET asociada a CMTF (antecedentes familiares de EH, segmento largo y/o síndromes asociados) y B) bajo riesgo (afectación rectosigmo idea exclusiva).Se han determinado los exones 7, 8, 9, 10, 11, 13, 14 y 15 del protooncogén RET en 12/15 niños del grupo A y en 6/25 del grupo B. Resultados. Una niña del grupo A presenta la mutación p.Cys620Ser (exón 10). En el estudio familiar se ha encontrado esta misma mutación en la madre, el tío materno y una de sus hijas. Conclusiones. El manejo integral de los niños con EH exige el despistaje de mutaciones del gen RET asociadas a CMTF. En los familiares de primer grado de los niños con una mutación de riesgo, el cribado es obligatorio (AU)

Introduction. The most common gene involved in Hirschsprung’s disease (HD) is protooncogene RET. More than 100 mutations of this gene have been described associated with HD. The mutations that change a cysteine with another aminoacid (mainly in exons 10 and 11) give a risk of familial medullary thyroid carcinoma (FTMC) and MEN 2A. These mutations are found in 5% of patients with HD and have an autosomal dominant inheritance. The FTMC is aggressive and the prophylactic thyroidectomy is the best treatment. We present our results in screening for RET protooncogene mutations associated with TMC in patients with HD. Patients and methods. We have treated 40 patients with HD in the last 15 years. We have classifi ed the patients into two groups: A) high risk of RET protooncogene mutation associated with FTMC (family history of HD, long-segment and/or associated syndromes) and B) low risk (rectosigmoid involvement).We have identified the exons 7, 8, 9, 10, 11, 13, 14 and 15 of the RET protooncogene in 12 of 15 children from group A and 6 from 25 from group B. Results. We have found the p.Cys620Ser mutation (exon 10) in a girl from group A (long-segment). In the family study, we have found the same mutation in her mother, her oncle and her cousin. Conclusion. The comprehensive management of children with HD requires screening for RET protooncogene mutations associated with FTMC. In the fi rst-degree relatives of children with a mutation risk, screening is required (AU)

Dissociable roles of mGlu5 and dopamine receptors in the rewarding and sensitizing properties of morphine and cocaine.

RATIONALE: Drugs of abuse are initially used because of their rewarding properties. As a result of repeated drug exposure, sensitization to certain behavioral effects of drugs occurs, which may facilitate the development of addiction. Recent studies have implicated the metabotropic glutamate receptor 5 (mGlu5 receptor) in drug reward, but its role in sensitization is unclear. Stimulation of dopamine receptors plays an important role in drug reward, but not in the sensitizing properties of cocaine and morphine. OBJECTIVE: This study aims to evaluate the role of mGlu5 and dopamine receptors in the development of cocaine- and morphine-induced conditioned place preference (CPP) and psychomotor sensitization. MATERIALS AND METHODS: Rats were treated with the mGlu5 receptor antagonist MTEP (0, 1, 3, and 10 mg/kg, i.p.) or the dopamine receptor antagonist α-flupenthixol (0, 0.125, 0.25, and 0.5 mg/kg, i.p.) during place conditioning with either morphine (3 mg/kg, s.c.) or cocaine (15 mg/kg, i.p.). Furthermore, MTEP (1 mg/kg, i.p.) or α-flupenthixol (0.5 mg/kg, i.p.) was co-administered during cocaine (30 mg/kg, i.p.) or morphine (3.0 mg/kg, s.c.) pretreatment and psychomotor sensitization was tested 3 weeks post-treatment. RESULTS: MTEP attenuated the development of morphine- but not cocaine-induced CPP. In contrast, MTEP suppressed the development of cocaine- but not morphine-induced psychomotor sensitization. α-Flupenthixol blocked the development of both cocaine- and morphine-induced CPP but did not affect the development of sensitization to either drug. CONCLUSION: Dopamine receptor stimulation mediates cocaine and morphine reward but not sensitization. In contrast, the role of mGlu5 receptors in reward and sensitization is drug-specific.

Sexual dysfunction in fibromyalgia patients.

OBJECTIVE: To investigate the prevalence of sexual dysfunction in female patients with fibromyalgia (FM), the impact of FM on sexual activity and the factors associated with sexual dysfunction in these patients. METHODS: Thirty-one consecutive women with FM were enrolled; two groups of 20 aged-matched healthy women and 26 patients with rheumatoid arthritis (RA) were used as controls. Demographic features were recorded in all patients. A cross-sectional analysis of pain (100-mm VAS scale), anxiety and depression (as determined by the STAI and Beck Depression Inventory scales, respectively) was performed. Sexual function was assessed by the Changes in Sexual Functioning Questionnaire (CSFQ). RESULTS: FM and RA patients showed a significantly higher rate of sexual dysfunction compared to healthy controls. Sexual dysfunction was more frequent among FM patients (97%) than in RA patients (84%) but without statistical differences. A univariate analysis showed that age (p=0.0002), marital (p=0.036) and work status (p=0.048), pain intensity (p=0.007), level of anxiety (p=0.002), level of depression (p=0.0005), were significantly associated with sexual dysfunction in FM. However, only the intensity of depression was associated with the sexual dysfunction in patients with FM in the multivariate analysis (p=0.012). CONCLUSIONS: Sexual function was very frequently and severely affected in patients with FM and this impairment appeared to be particularly associated with the degree of depression. The recognition of this dysfunction and its inclusion for the multidisciplinary management of FM may contribute to improve quality of life of these patients.

Regional adaptations in PSD-95, NGFI-A and secretogranin gene transcripts related to vulnerability to behavioral sensitization to amphetamine in the Roman rat strains.

Genetically selected for high or low two-way active avoidance, Roman high-avoidance (RHA) and Roman low-avoidance (RLA) rats differ in their central dopaminergic activity, sensation/novelty- and substance-seeking profiles. These animals are, therefore, well suited to identify anatomical and neurochemical concomitants of behavioral sensitization, a phenomenon linked to addictive liability. We submitted inbred RHA (RHA-I), inbred RLA (RLA-I) and Sprague-Dawley-OFA (SD-OFA) rats to a sensitization regimen with amphetamine and studied the behavioral response to an amphetamine challenge after a 2-week withdrawal period. The expression patterns of nerve growth factor inducible clone A (NGFI-A), secretogranin, post-synaptic density protein of 95 Kd (PSD-95), prodynorphin and proenkephalin mRNA were also analyzed using in situ hybridization, after the challenge with amphetamine. RHA-I rats showed stronger sensitization than SD-OFA rats. RLA-I rats did not show sensitization but were hyper-reactive to amphetamine. Expression of behavioral sensitization in RHA-I rats activated secretogranin and PSD-95 mRNA in the nucleus accumbens core. On the other hand, high induction of NGFI-A mRNA in the central amygdala was observed in RLA-I rats when they experienced amphetamine for the first time in the challenge. Our results reveal that 1) the acute locomotor response to amphetamine does not predict vulnerability to behavioral sensitization and 2) differences in vulnerability to sensitization may involve distinctive cellular adaptations at particular brain locations which may be related to addictive vulnerability.

Divergent anatomical pattern of D1 and D3 binding and dopamine- and cyclic AMP-regulated phosphoprotein of 32 kDa mRNA expression in the Roman rat strains: Implications for drug addiction.

Autoradiography analysis of D1, D2 and D3 dopamine receptors and in situ hybridization analysis of mRNA for dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32) were performed in brains of naïve Roman high avoidance (RHA) and Roman low avoidance (RLA) inbred rats. These strains, genetically selected for high (RHA) or extremely low (RLA) active avoidance acquisition in the two-way shuttle box, differ in indices of dopaminergic activity along with sensation/novelty and substance-seeking behavioral profiles. The present study shows no differences in D2 receptor binding between the two strains. In contrast, the D1 and D3 receptor binding in the nucleus accumbens was higher in RHA-I rats, whereas RLA-I rats show higher D3 binding in the Calleja islands. Together with previous evidence showing behavioral and presynaptic differences related to the dopamine system, the present results suggest a higher dopaminergic tone at the nucleus accumbens shell in RHA-I rats. Besides, the comparison of the expression pattern of DARPP-32 mRNA with that of dopamine receptor binding revealed a mismatch in some amygdala nuclei. In some cortical structures (prelimbic and cingulate cortices, the dentate gyrus) as well as in the central amygdala, RHA-I rats showed higher DARPP-32 mRNA expression than RLA-I rats. Hence, RHA-I and RLA-I rats may be a useful tool to identify dopamine-related mechanisms that predispose to drug and alcohol dependence.

Cosmogenic neutrinos and signals of TeV gravity in air showers and neutrino telescopes.

The existence of extra dimensions allows the possibility that the fundamental scale of gravity is at the TeV. If that is the case, gravity could dominate the interactions of ultrahigh energy cosmic rays. In particular, the production of microscopic black holes by cosmogenic neutrinos has been estimated in a number of papers. We consider here gravity-mediated interactions at larger distances, where they can be calculated in the eikonal approximation. We show that for the expected flux of cosmogenic neutrinos these elastic processes give a stronger signal than black hole production in neutrino telescopes. Taking the bounds on the higher-dimensional Planck mass M(D) (D=4 + n) from current air shower experiments, for n=2(6) elastic collisions could produce up to 118 (34) events per year at IceCube. On the other hand, the absence of any signal would imply a bound of M(D) > or approximately 5 TeV.

Perfil del paciente polimedicado en Atención Primaria e intervención para disminuirla polimedicación de ansiolíticos / Profile of the polymedicated patient in Primary Health Care and intervention aimed at reducing anxiolytic polymedication

Introducción: La polimedicación en pacientes crónicos en Atención Primaria es un problema grave por sus múltiples interacciones y contraindicaciones. Objetivos: Describir la población crónica polimedicada y realizar una intervención de mejora en el grupo de medicamentos más prescrito. Métodos: Primera fase: estudio descriptivo, transversal sobre el perfil de los pacientes polimedicados de 5 Centros de Atención Primaria (CAP). Segunda fase: intervención de mejora del uso de benzodiazepinas (BDZ) en uno de los CAP a través de una sesión informativa junto a la entrega a cada médico del resultado de una revisión de los Carnets de Largo Tratamiento (CLT) con polimedicación ansiolítica. Variables: Sexo, edad, número de medicamentos por CLT, medicamentos de eficacia dudosa, grupos farmacológicos más prescritos, número de benzodiazepinas por CLT, benzodiazepina más prescrita y porcentaje de reducción del número de BDZ. Resultados: El 19,66 por ciento de pacientes crónicos están polimedicados con una media de 7,80 medicamentos por CLT; 59,52 por ciento son mujeres con una media de edad de 70,40 años. El porcentaje de medicamentos de eficacia dudosa es bajo y el grupo farmacológico más prescrito en los polimedicados es el de los ansiolíticos. Tras la intervención el número de BDZ totales disminuyó un 2,3 por ciento, aunque no se encontraron diferencias estadísticamente significativas (chi cuadrado 0,26; p=0,88). Conclusiones: Existe una elevada proporción de pacientes polimedicados en Atención Primaria. La intervención de mejora en el consumo de BDZ demuestra que resulta difícil disminuir su uso, debido seguramente a las complicaciones de su retirada. Debe promoverse el uso racional de BDZ antes de instaurar un tratamiento (AU)

Introduction: Polimedication in cronic patients in primary care is an important problems for their frequent interactions and connterindications. Objectives: To describe the polimedicated cronic population and to make and intervention in order to improve this situation within the group of the most prescribed medicines. Methods: First fuse: descriptive transversal study on the polimedicate patients profile in 5 primary care centers (CAP). Second Fase: intervention to improve the use of benzodiacepines (BDZ) in one of the CAP though on informative session and to delivering the results of a review of the long treatment cards (CLT) with ansiolitic polimedication. Variables: Sex, age, number of drug for CH: drugeduce its use, drugs with questionable efficacy, most prescribed pharmacological groups, number of BDZ per CLT, most prescribed (BDZ). Results: 19.66% of the cronic patients were polimedicated with a mean of 7.80 drugs per CTL; 59.52% were women with a mean age of 70.4% the percentage of questionable efficacy of drugs prescribed was low and the most prescribed pharmacological group in polimedicated patients were ansiolitics. After the intervention the total number of BZP was reduced in a 2.3% without statistical significant differences (X 0,26; P=0.88). Conclusions: There are a high proportion of polimedicated patients in primary a care. The intervention to improve BDZ use shows that is dificult to reduced its use, probably because the complications for discontinuing. The rational use of BZD should be promoted before to start a treatment (AU)

Arginine 121 is a crucial residue for the specific cytotoxic activity of the ribotoxin alpha-sarcin.

Alpha-sarcin, a cyclizing ribonuclease secreted by the mould Aspergillus giganteus, is one of the best characterized members of a family of fungal ribotoxins. This protein induces apoptosis in tumour cells due to its highly specific activity on ribosomes. Fungal ribotoxins display a three-dimensional protein fold similar to those of a larger group of microbial noncytotoxic RNases, represented by RNases T1 and U2. This similarity involves the three catalytic residues and also the Arg121 residue, whose counterpart in RNase T1, Arg77, is located in the vicinity of the substrate phosphate moiety although its potential functional role is not known. In this work, Arg121 of alpha-sarcin has been replaced by Gln or Lys. These two mutations do not modify the conformation of the protein but abolish the ribosome-inactivating activity of alpha-sarcin. In addition, the loss of the positive charge at that position produces dramatic changes on the interaction of alpha-sarcin with phospholipid membranes. It is concluded that Arg121 is a crucial residue for the characteristic cytotoxicity of alpha-sarcin and presumably of the other fungal ribotoxins.

TeV strings and the neutrino-nucleon cross section at ultrahigh energies.

In scenarios with the fundamental unification scale at the TeV one expects string excitations of the standard model fields at accessible energies. We study the neutrino-nucleon cross section in these models. We show that duality of the scattering amplitude forces the existence of a tower of massive leptoquarks that mediate the process in the s channel. Using the narrow-width approximation we find a sum rule for the production rate of resonances with different spin at each mass level. We show that these contributions can increase substantially the standard model neutrino-nucleon cross section, although they seem insufficient to explain the cosmic ray events above the Greisen-Zatsepin-Kuz'min cutoff energy.

The solubility of the ribotoxin alpha-sarcin, produced as a recombinant protein in Escherichia coli, is increased in the presence of thioredoxin.

The yield of purified recombinant alpha-sarcin increases approximately three- to fourfold when this toxin is co-expressed in Escherichia coli with thioredoxin. This increased production is attributed to the existence, in the presence of thioredoxin, of a reducing environment which allows rearrangement of incorrect disulphide bonds to produce the soluble native conformation. The protein thus produced retains the structural, spectroscopic and enzymatic features of the natural fungal alpha-sarcin.

New black blood pulse sequence for studies of the heart.

The black blood concept is based on the signal void principle of the sequences in Spin Echo, SE or FSE, which are very useful for studying the mediastinum and heart. In this setting, new sequences are continuously introduced to eliminate the artifacts caused by breathing and heart movements. One such sequence is the Double-IR preparation Black Blood FSE. We report our experience in 97 patients, using this new pulse sequence to evaluate cardiac pathology, and establish comparisons with the conventional Spin Echo sequences. The study comprises mediastinal disease and aorta and heart explorations. We consider this new Double-IR preparation FSE sequence to be an excellent choice for evaluating chest, mediastinal and cardiac images. The sequence offers improved spatial resolution of both the vessels and other chest structures with respect to conventional Spin Echo imaging. With the exception of patients presenting severe heart problems, or in the presence of intense bradycardia, the required 16 cycles in apnea are well tolerated. The purpose of the present study is to present our initial results with this new pulse sequence as applied to cardiac pathology, in comparison with conventional Spin Echo imaging.

Laryngeal involvement in pediatric neurofibromatosis: a case report and review of the literature.

A case of neurofibroma of the larynx occurring in generalized neurofibromatosis (von Recklinghausen's disease) is presented, and the previously reported pediatric cases are reviewed. Laryngeal involvement in neurofibromatosis is rare and the predominant signs and symptoms include dyspnea, stridor, loss or change of voice and dysphagia. Problems posed related to diagnosis, management and course of this infrequent laryngeal localization are discussed.