S-Nitrosylation in endothelial cells contributes to tumor cell adhesion and extravasation during breast cancer metastasis.

BACKGROUND: Nitric oxide is produced by different nitric oxide synthases isoforms. NO activates two signaling pathways, one dependent on soluble guanylate cyclase and protein kinase G, and other where NO post-translationally modifies proteins through S-nitrosylation, which is the modification induced by NO in free-thiol cysteines in proteins to form S-nitrosothiols. High levels of NO have been detected in blood of breast cancer patients and increased NOS activity has been detected in invasive breast tumors compared to benign or normal breast tissue, suggesting a positive correlation between NO biosynthesis, degree of malignancy and metastasis. During metastasis, the endothelium plays a key role allowing the adhesion of tumor cells, which is the first step in the extravasation process leading to metastasis. This step shares similarities with leukocyte adhesion to the endothelium, and it is plausible that it may also share some regulatory elements. The vascular cell adhesion molecule-1 (VCAM-1) expressed on the endothelial cell surface promotes interactions between the endothelium and tumor cells, as well as leukocytes. Data show that breast tumor cells adhere to areas in the vasculature where NO production is increased, however, the mechanisms involved are unknown. RESULTS: We report that the stimulation of endothelial cells with interleukin-8, and conditioned medium from breast tumor cells activates the S-nitrosylation pathway in the endothelium to induce leukocyte adhesion and tumor cell extravasation by a mechanism that involves an increased VCAM-1 cell surface expression in endothelial cells. We identified VCAM-1 as an S-nitrosylation target during this process. The inhibition of NO signaling and S-nitrosylation blocked the transmigration of tumor cells through endothelial monolayers. Using an in vivo model, the number of lung metastases was inhibited in the presence of the S-nitrosylation inhibitor N-acetylcysteine (NAC), which was correlated with lower levels of S-nitrosylated VCAM-1 in the metastases. CONCLUSIONS: S-Nitrosylation in the endothelium activates pathways that enhance VCAM-1 surface localization to promote binding of leukocytes and extravasation of tumor cells leading to metastasis. NAC is positioned as an important tool that might be tested as a co-therapy against breast cancer metastasis.

Association of SNPs in dopamine and serotonin pathway genes and their interacting genes with temperament traits in Charolais cows.

Cattle temperament is a complex trait, and molecular studies aimed at defining this trait are scarce. We used an interaction networks approach to identify new genes (interacting genes) and to estimate their effects and those of 19 dopamine- and serotonin-related genes on the temperament traits of Charolais cattle. The genes proopiomelanocortin (POMC), neuropeptide Y (NPY), solute carrier family 18, member 2 (SLC18A2) and FBJ murine osteosarcoma viral oncogene homologue (FOSFBJ) were identified as new candidates. Their potential to be associated with temperament was estimated according to their reported biological activities, which included interactions with neural activity, receptor function, targeting or synthesis of neurotransmitters and association with behaviour. Pen score (PS) and exit velocity (EV) measures were determined from 412 Charolais cows to calculate their temperament score (TS). Based on the TS, calm (n = 55; TS, 1.09 ± 0.33) and temperamental (n = 58; TS, 2.27 ± 0.639) cows were selected and genotyped using a 248 single-nucleotide variation (SNV) panel. Of the 248 variations in the panel, only 151 were confirmed to be polymorphic (single-nucleotide polymorphisms; SNPs) in the tested population. Single-marker association analyses between genotypes and temperament measures (EV, PS and/or TS) indicated significant associations of six SNPs from four candidate genes. The markers rs109576799 and rs43696138, located in the DRD3 and HTR2A genes, respectively, were significantly associated with both EV and TS traits. Four markers, rs110365063 and rs137756569 from the POMC gene and rs110365063 and rs135155082 located in SLC18A2 and DRD2, respectively, were associated with PS. The variant rs110365063 located in bovine SLC18A2 causes a change in the amino acid sequence from Ala to Thr. Further studies are needed to confirm the association of genetic profile with cattle temperament; however, our study represents important progress in understanding the regulation of cattle temperament by different genes with divergent functions.

Utilización de la ventilación no invasiva en la insuficiencia respiratoria aguda. Estudio multicéntrico en unidades de cuidados intensivos / Use of non-invasive ventilation in acute respiratory failure. Multicenter study in intensive care units

Objetivo. Estudiar el uso de la ventilación no invasiva (VNI) en la insuficiencia respiratoria aguda, en las unidades de cuidados intensivos (UCI) de España. Métodos. Se realizó una encuesta a 254 UCI. Al final de ésta se invitó a participar en un estudio multicéntrico retrospectivo, y proporcionar información detallada sobre pacientes ventilados. Resultados. Contestaron 123 UCI; 119 utilizaban la VNI, de manera muy variable. En la enfermedad pulmonar obstructiva crónica (EPOC), la VNI fue de primera elección en el 89% de las unidades; en el edema agudo de pulmón (EAP), el 79%; en la insuficiencia respiratoria tras la extubación, el 53%; en la neumonía, el 53%, y en el síndrome de distrés respiratorio agudo (SDRA), el 17%. Su utilización en la EPOC fue ocasional o nula en el 11% de las unidades, y en el EAP, en el 21%. 18 hospitales enviaron información de 432 pacientes ventilados, de los que 232 (54%) recibieron VNI como primera elección. La neumonía o el SDRA fueron factores independientes en relación con el fracaso de la VNI (odds ratio ajustada [ORa] = 5,71; intervalo de confianza [IC] del 95%, 1,83-17,8; p = 0,003). La admisión en una unidad que ventilara de forma no invasiva a más de 50 pacientes/año (ORa = 0,22; IC del 95%, 0,07-0,63; p = 0,005) y una mayor razón PaO2/FIO2 tras una hora de ventilación (ORa = 0,98 por punto; IC del 95%, 0,97-0,99; p < 0,001) fueron factores protectores. Conclusiones. La VNI es ampliamente utilizada en las UCI de España, pero es posible que siga estando infrautilizada en la EPOC y el EAP. El diagnóstico de neumonía o SDRA fue un factor independiente en relación con el fracaso. Ventilar a más de 50 pacientes/año y una mayor PaO2/FIO2 tras una hora fueron factores protectores(AU)

Objectives. Study the use of non-invasive ventilation (NIV) in patients with acute respiratory failure in intensive care units (ICUs) in Spain. Methods. A questionnaire was sent to 254 ICUs, after which, they were invited to participate in a multicenter, retrospective study, providing detailed information on ventilated patients. Results. Answers were received from 123 hospitals. Of these, 119 used NIV, although its use varied greatly. NIV is the treatment of choice in 89% of the units for chronic obstructive pulmonary disease (COPD), in 79% for acute pulmonary edema (APE), in 53% for postextubation failure, in 53% for pneumonia 53%, and in 17% for acute respiratory distress syndrome (ARDS). It was used occasionally in COPD in 11% of the units, and in 21% of the units for APE. Eighteen hospitals provided additional information on 432 ventilated patients, 232 (54%) of whom received NIV as first line therapy. Presence of pneumonia or acute respiratory distress syndrome (ARDS) was an independent predictive factor of NIV failure (ORa = 5.71; CI 95%, 1.83-17.8; p = 0.003). Admission in a unit with experience in NIV in > 50 patients/year (ORa = 0.22; CI 95%, 0.07-0.63; p = 0.005) and a higher PaO2/FiO2 ratio after one hour of ventilation (ORa = 0.98 per point; CI 95%, 0.97-0.99; p < 0.001) were protector factors. Conclusions. In Spain, NIV is widely used but it may continue to be underused in COPD and APE. The diagnosis of pneumonia or ARDS was an independent predictive risk factor. Admission in an ICU with NIV in more than 50 patients/year also have higher PaO2/FiO2 ratio after one hour of ventilation were predictive factors of success(AU)

Phase II study of arsenic trioxide and ascorbic acid for relapsed or refractory lymphoid malignancies: a Wisconsin Oncology Network study.

Arsenic trioxide (As(2)O(3)) has established clinical activity in acute promyelocytic leukaemia and has pre-clinical data suggesting activity in lymphoid malignancies. Cell death from As(2)O(3) may be the result of oxidative stress. Agents which deplete intracellular glutathione, such as ascorbic acid (AA), may potentiate arsenic-mediated apoptosis. This multi-institution phase II study investigated a novel dosing schedule of As(2)O(3) and AA in patients with relapsed or refractory lymphoid malignancies. Patients received As(2)O(3) 0.25 mg/kg iv and AA 1000 mg iv for five consecutive days during the first week of each cycle followed by twice weekly infusions during weeks 2-6. Cycles were repeated every 8 weeks. The primary end point was objective response. In a subset of patients, sequential levels of intracellular glutathione and measures of Bcl-2 and Bax gene expression were evaluated in peripheral blood mononuclear cells during treatment. Seventeen patients were enrolled between March 2002 and February 2004. The median age was 71, and the majority of enrolled patients had non-Hodgkin's lymphoma (12/17). Sixteen patients were evaluable, and one patient with mantle cell lymphoma achieved an unconfirmed complete response after five cycles of therapy for an overall response rate of 6%. The trial, which had been designed as a two-stage study, was closed after the first stage analysis due to lack of activity. Haematologic toxicities were the most commonly reported events in this heavily pre-treated population, and comprised the majority of grade 3 and 4 toxicities. Intracellular depletion of glutathione was not consistently observed during treatment. As(2)O(3) and AA in this novel dosing strategy was generally well tolerated but had limited activity in patients with relapsed and refractory lymphoid malignancies.

[Investigation in early intervention]. / Investigación en atención temprana.

OBJECTIVE: Point out the importance of the research in early intervention (EI), its limitations, and peculiarities. DEVELOPMENT: After defender the importance of research in this applied field, its problems in EI are analysed from different perspectives. The idiosyncrasy of the intervention goals perfectly explain the concurrence of ethical and methodological limitations, which affect to the possible research designs. The diversity of possible needs of EI in the children lead to a great variability and heterogeneousity in the attended population and a great dispersion in the research purposes in this field. Centred in the interest by to improve the quality of the offered services, the actual situation of the research on the efficacy of the intervention in EI lead to reclaim insistently the development of multidimensional approaches. Evaluation of the intervention results, for example, must not exclusively centred in child developmental acquisitions, or at least not only in the classic aspects of motor, cognitive, language, etc.; quite the contrary, it must be take into account new areas and competencies, related both to the child and to his/her family. The evaluation of results or goals of the intervention must be only one dimensions more, which must be faced simultaneously to the evaluation of the characteristics of the child and his/her family and the characteristics of the programs itself. CONCLUSIONS: The accumulated experience after eight years of service of a Research Department in a Childhood Developmental and Early Intervention Centre permit point out that this type of initiatives are valid to promote the research in the EI field.

Investigación en atención temprana / Investigation in early intervention

Objetivo. Resaltar la importancia de la investigación en atención temprana (AT), sus limitaciones y peculiaridades. Desarrollo. Tras defender la importancia de la investigación en este campo aplicado, se aborda su problemática en AT desde distintas facetas. La idiosincrasia propia de los objetivos de intervención explica la concurrencia de limitaciones éticas y metodológicas que afectan a los posibles diseños de investigación. La diversidad de posibles necesidades de AT desemboca en una gran variabilidad y heterogeneidad en la población atendida y en una enorme dispersión en los intereses de la investigación. Centrándonos en la preocupación por la mejora de la calidad de la intervención y de los servicios ofertados, la situación actual de la investigación sobre la eficacia de la intervención en AT lleva a reclamar con insistencia el desarrollo de planteamientos multidimensionales. La evaluación de los resultados de la intervención, por ejemplo, no debe centrarse exclusivamente en las adquisiciones evolutivas del niño, o al menos no sólo en los clásicos aspectos motores, cognitivos, de lenguaje, etc., sino que debe tener en cuenta nuevas áreas y competencias, tanto relativas al niño como a su familia. La evaluación de resultados o metas de intervención debe ser sólo una dimensión más, que debe abordarse simultáneamente a la evaluación de las características del niño y su familia y de los propios programas. Conclusiones. La experiencia acumulada tras ocho años de funcionamiento de un departamento de investigación en un centro de desarrollo infantil y AT permite plantear que este tipo de iniciativas es válido para fomentar la investigación en el campo de la AT (AU)

Presencia de anticuerpos anti-Chlamydia pneumoniaeen procesos vasculares periféricos y neurológicos / The presence of anti-chlamydia pneumonia antibodies in peripheral vascular and neurological disorders

Objetivos. Analizar, retrospectivamente, la síntesis de anticuerpos frente a los antígenos MOMP y LPS de Chlamydia pneumoniae en pacientes con enfermedad oclusiva de las arterias periféricas (EOAP) y esclerosis múltiple (EM). Pacientes y métodos. Se estudiaron 190 muestras de suero procedentes de enfermos que se incluyeron en los siguientes grupos: grupo 1: 66 muestras de otros tantos enfermos con EOAP; grupo 2: 74 muestras de 31 pacientes con EM (20 remitente-recidivante y 11 secundariamente progresiva) seguidos en el tiempo, y grupo 3: 50 muestras de sujetos controles. En todas se determinaron, mediante ELISA, la IgG anti-MOMP y la IgG e IgA anti-LPS. La comparación de las variables continuas se realizó con la prueba U de Mann-Whitney. Las variables discretas se analizaron con la prueba de Fischer bilateral exacta. Para comparar la evolución de los anticuerpos en los enfermos con EM se utilizó la prueba de rangos con signo de Wilcoxon. Resultados. Los porcentajes de positividad, en los grupos 1 a 3, para la IgG anti-LPS fueron: 24,6 por ciento, 18,9 por ciento y 20,8 por ciento, respectivamente, sin que existieran diferencias entre enfermos y controles. Tampoco hubo diferencias para la IgA (29 por ciento, 29,7 por ciento y 25 por ciento, respectivamente). Sí se hallaron diferencias en la IgG anti-MOMP entre enfermos y controles (grupo 1: 80,3 por ciento, grupo 2: 37,8 por ciento y grupo 3: 33,3 por ciento). En los enfermos con EM, los resultados de la evolución de los anticuerpos no reflejaron una tendencia uniforme de las tasas de los diferentes anticuerpos. Conclusión. Se encontró una mayor tasa de IgG anti-MOMP en la EOAP y la EM; sin embargo, esto no ocurrió para la IgG e IgA anti-LPS (AU)

[Influence of the presence of hot flashes during menopause on the metabolism of nitric oxide. Effects of hormonal replacement treatment]. / Influencia de la presencia de sofocos durante la menopausia sobre el metabolismo del óxido nítrico. Efecto del tratamiento hormonal sustitutivo.

BACKGROUND: To asses if the hot flushes during the menopause are associated to alterations in the metabolism of nitric oxide, total antioxidant activity and other biochemical parameters. To evaluate the effect of hormone replacement therapy (HRT) in the metabolism of nitric oxide, total antioxidant activity and biochemistry in menopausal women with and without hot flushes. PATIENTS AND METHODS: Experimental study. This study included 29 healthy menopausal women with hot flushes (12 with HRT) and 20 without them (6 with HRT), 45-55 years old, with duration of menopause ranging from 1 to 5 years. Control group included 14 fertile women. Determinations of estradiol, nitrite-nitrate, total antioxidant activity and basic analytic, were performed before previous and after 4-6 month of HRT therapy. RESULTS: Previously to HRT, hot flushes were associated to smaller level of total antioxidant activity (p < 0.05) in plasma, without differences in nitrite-nitrate concentrations. HRT was associated to increase in total antioxidant activity level and nitrite-nitrate concentrations (p < 0.05) in menopausal women, with and without hot flushes. CONCLUSIONS: Hot flushes during the menopause indicate a high level of oxidative stress and a higher cardiovascular risk. HRT decreased the oxidative stress level and increased the nitric oxide derivate metabolites in menopausal women with and without hot flushes.

Refractive errors in children with cerebral palsy, psychomotor retardation, and other non-cerebral palsy neuromotor disabilities.

The aim of this study was to analyse the refractive state of four different groups of children: those with spastic cerebral palsy (CP), aged between 7 and 81 months (N=50); psychomotor retardation, aged between 19 and 70 months (N=16); other neuromotor dysfunctions, aged between 12 and 75 months (N=37); and without psychomotor retardation, aged between 9 and 73 months (N=181). Refractive errors were determined using cycloplegic retinoscopy and non-cycloplegic retinoscopy (Mohindra's technique). We found higher percentages of hyperopia, tendency toward hyperopia, and other refractive anomalies in all the pathological groups of children than in the non-pathological control groups. Children from both the non-CP pathological control group and the group with psychomotor retardation had similar or even higher levels of hyperopia than children from the group with spastic CP. Our results in different age groups indicate a less effective normal emmetropization course in all the pathological groups of children studied. The correction of refractive errors is needed in these children before the end of the neural plasticity period.

Electrodermal orienting activity in children with Down syndrome.

The elicitation and habituation of electrodermal orienting responses to auditory stimuli of 19 children with Down syndrome and a control group, an age and sex-matched sample of children without mental retardation were compared. Stimuli were ten 2-second 80 dB, 1000 Hz tones followed by a test tone (80 dB, 500 Hz). Children with Down syndrome gave electrodermal orienting responses of a lower amplitude than did the children in the control group. Both groups showed habituation of their responses. No significant differences were found between groups in either skin conductance levels or frequency of nonspecific responses. Overall, children with Down syndrome showed electrodermal hyporesponsivity in their orienting responses to the stimuli.

Antihypertensive monotherapy and stress-induced changes in physiological activity.

The effects of two types of laboratory stressors, a structured interview and the cold pressor test, on blood pressure (BP) and heart rate (HR) were studied in normotensive individuals (n = 16), unmedicated hypertensive patients (n = 12), and medicated hypertensive patients (n = 46). Fifteen patients were in the bisoprolol group, 16 patients were in the enalapril group, and 15 patients were in the nitrendipine group. Concurrent physiologic measures, finger pulse volume (FPV), electrodermal activity, and respiratory frequency (RF), were also used to evaluate the level of stress reached by the subjects during and after the tasks. No significant differences were evident between the different treatments in BP and other physiologic responses to stressors. Patients receiving bisoprolol maintained lower HR and systolic BP values, but these differences were not related to the reaction to the stressors. No significant differences were noted in diastolic BP (DBP) between the different groups. The highest physiologic responses were obtained during the structured interview. Antihypertensive monotherapy does not attenuate cardiovascular reactions induced by acute stress in controlled laboratory conditions. In laboratory studies of the relationships between stress and hypertension, it is important that social stressors be used and that physiologic rather than cardiovascular measures of stress be recorded.

Responsiveness patterns and handedness differences in bilateral electrodermal asymmetry.

The aim of the present study was to examine the relationship between subjects' handedness and electrodermal asymmetry when subjects were divided according to their electrodermal Responsiveness Patterns, obtained during a stimulus-free period. Skin conductance was bilaterally recorded in a sample of 48 subjects (24 dextrals and 24 sinistrals) during the performance of two tasks (watching a film and listening to neutral tones). Subjects were divided into four groups of 12 subjects each (dextral right-hand responders, dextral left-hand responders, sinistral right-hand responders and sinistral left-hand responders). No differences were found between dextral and sinistral subjects. Orientation of electrodermal asymmetry in each Responsiveness Patterns remained constant throughout the two conditions: right-hand responders showed higher electrodermal activity on their right hand, while left-hand responders showed higher electrodermal activity on their left hand. In addition, left-hand responders showed a slower habituation rate on their left hand than on their right hand, whereas right-hand responders showed no significant differences between hands.

Sex differences and bilateral electrodermal activity: a replication.

The present study was aimed at replicating the results of a previous work on sex differences and electrodermal asymmetry from our laboratory (Román, et al. 1987). Skin conductance was bilaterally recorded in a sample of 44 dextral volunteers (22 males and 22 females) during a stimulus-free period, and the performance of two tasks (verbal and spatial). Subjects were grouped into two groups of right-hand and left-hand dominance in their electrodermal responses (EDRs) in accordance with their laterality coefficient scores at rest. During the tasks subjects appeared clearly differentiated by their lateralization in the magnitude and frequency of EDRs independently of gender: right-hand responders showed higher electrodermal activity on their right hand, while left-hand responders showed higher electrodermal activity on their left hand. Sex differences were not observed within each responsiveness pattern. The orientation of phasic electrodermal changes remained constant throughout the different conditions.

Sex differences and the asymmetry of specific and non-specific electrodermal responses.

Phasic electrodermal conductance responses were bilaterally recorded from 30 subjects (15 males and 15 females). After a 5-min adaptation period subjects were presented with two series of ten 80-dB tones each, with a 4-min rest period between the two series. Data from sinistrals, ambidextrous, and from subjects with familial sinistrality were excluded from statistical analysis. Males displayed more asymmetry between hands both in their non-specific and specific responses, with larger skin conductance responses on the left hand. Females showed a less marked asymmetry, with larger skin conductance responses on the right hand. Similar results were found in skin conductance levels. It was concluded that sex differences are an important variable in the study of electrodermal asymmetry.

Sex differences, activation level, and bilateral electrodermal activity.

The effects of the activation level and subject's sex on bilateral skin conductance measures were studied. Thirty right-handed subjects (15 males and 15 females) were exposed to three types of stimulus conditions: rest-period, verbal task and spatial task. Results showed that no relationship was observed between EDA asymmetry and the increase in the activation level induced by the verbal and the spatial tasks. Males showed both higher SCRs and greater frequency of responses on the left than on the right hand. The direction of electrodermal asymmetry remained constant regardless of the stimulus conditions. It was concluded that sex differences are important in the study of EDA asymmetry and that this asymmetry appeared to depend on peripheral variations.

Three-year experience with NORPLANT subdermal contraception.

NORPLANTTM (Laboratorios Gutfol, S.A., Mexico City, Mexico) subdermal implants containing levonorgestrel were accepted by 816 women in a two-phase study initiated in 1975 and augmented in 1978. Through 3 years of first-segment use, acceptors experienced five pregnancies, a cumulative net rate of 0.7 per 100, and a gross pregnancy rate of 1.1 per 100. First-segment continuation at 3 years was at the rate of 44.6 per 100, an annual average of 76 per 100. NORPLANT users experienced irregular menstruation, with high interindividual variation, but with normal average numbers of bleeding days and of bleeding episodes. Hemoglobin levels increased moderately during implant use. The incidence of systolic blood pressure readings above 145 mm Hg or diastolic readings above 95 mm Hg was similar to that observed among users of the TCu 200 intrauterine device enrolled under the same selection criteria in the same clinics between the two phases of the NORPLANT study. Comparative data on pregnancy and other rates are also given for these intrauterine device acceptors.