7-Nitroindazole reduces L-DOPA-induced dyskinesias in non-human Parkinsonian primate.

Nitric oxide (NO) plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). The objective of this study was to ascertain whether the NO synthase inhibitor, 7-nitroindazole (7-NI), is able to reduce L-DOPA-induced dyskinesias (LIDs) in a non-human primate model of PD chronically intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Six Parkinsonian macaques were treated daily with L-DOPA for 3-4 months until they developed LIDs. Three animals were then co-treated with a single dose of 7-NI administered 45 min before each L-DOPA treatment. Dyskinetic MPTP-treated monkeys showed a significant decrease in LIDs compared with their scores without 7-NI treatment (p < 0.05). The anti-Parkinsonian effect of L-DOPA was similar in all three monkeys with and without 7-NI co-treatment. This improvement was significant with respect to the intensity and duration of LIDs while the beneficial effect of L-DOPA treatment was maintained and could represent a promising therapy to improve the quality of life of PD patients.

Sensor Noise in LISA Pathfinder: In-Flight Performance of the Optical Test Mass Readout.

We report on the first subpicometer interferometer flown in space. It was part of ESA's Laser Interferometer Space Antenna (LISA) Pathfinder mission and performed the fundamental measurement of the positional and angular motion of two free-falling test masses. The interferometer worked immediately, stably, and reliably from switch on until the end of the mission with exceptionally low residual noise of 32.0_{-1.7}^{+2.4} fm/sqrt[Hz], significantly better than required. We present an upper limit for the sensor performance at millihertz frequencies and a model for the measured sensitivity above 200 mHz.

Analysis of the accuracy of actuation electronics in the laser interferometer space antenna pathfinder.

The Laser Interferometer Space Antenna Pathfinder (LPF) main observable, labeled Δg, is the differential force per unit mass acting on the two test masses under free fall conditions after the contribution of all non-gravitational forces has been compensated. At low frequencies, the differential force is compensated by an applied electrostatic actuation force, which then must be subtracted from the measured acceleration to obtain Δg. Any inaccuracy in the actuation force contaminates the residual acceleration. This study investigates the accuracy of the electrostatic actuation system and its impact on the LPF main observable. It is shown that the inaccuracy is mainly caused by the rounding errors in the waveform processing and also by the random error caused by the analog to digital converter random noise in the control loop. Both errors are one order of magnitude smaller than the resolution of the commanded voltages. We developed a simulator based on the LPF design to compute the close-to-reality actuation voltages and, consequently, the resulting actuation forces. The simulator is applied during post-processing the LPF data.

Delirium en los servicios de medicina interna: mucho por hacer / Delirium in internal medicine departments: much to do

No disponible

LISA Pathfinder Performance Confirmed in an Open-Loop Configuration: Results from the Free-Fall Actuation Mode.

We report on the results of the LISA Pathfinder (LPF) free-fall mode experiment, in which the control force needed to compensate the quasistatic differential force acting on two test masses is applied intermittently as a series of "impulse" forces lasting a few seconds and separated by roughly 350 s periods of true free fall. This represents an alternative to the normal LPF mode of operation in which this balancing force is applied continuously, with the advantage that the acceleration noise during free fall is measured in the absence of the actuation force, thus eliminating associated noise and force calibration errors. The differential acceleration noise measurement presented here with the free-fall mode agrees with noise measured with the continuous actuation scheme, representing an important and independent confirmation of the LPF result. An additional measurement with larger actuation forces also shows that the technique can be used to eliminate actuation noise when this is a dominant factor.

MCO: towards an ontology and unified vocabulary for a framework-based annotation of microbial growth conditions.

MOTIVATION: A major component in increasing our understanding of the biology of an organism is the mapping of its genotypic potential into its phenotypic expression profiles. This mapping is executed by the machinery of gene regulation, which is essentially studied by changes in growth conditions. Although many efforts have been made to systematize the annotation of experimental conditions in microbiology, the available annotations are not based on a consistent and controlled vocabulary, making difficult the identification of biologically meaningful comparisons of knowledge derived from different experiments or laboratories. RESULTS: We curated terms related to experimental conditions that affect gene expression in Escherichia coli K-12. Since this is the best-studied microorganism, the collected terms are the seed for the Microbial Conditions Ontology (MCO), a controlled and structured vocabulary that can be expanded to annotate microbial conditions in general. Moreover, we developed an annotation framework to describe experimental conditions, providing the foundation to identify regulatory networks that operate under particular conditions. AVAILABILITY AND IMPLEMENTATION: As far as we know, MCO is the first ontology for growth conditions of any bacterial organism, and it is available at http://regulondb.ccg.unam.mx and https://github.com/microbial-conditions-ontology. Furthermore, we will disseminate MCO throughout the Open Biological and Biomedical Ontology (OBO) Foundry in order to set a standard for the annotation of gene expression data. This will enable comparison of data from diverse data sources. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Leiomiosarcomas de grandes vasos en las extremidades inferiores / Leiomyosarcomas affecting main vessels in the lower extremities

Objetivos: Evaluar los resultados de la resección en bloque y la reconstrucción vascular de leiomiosarcomas con afectación de vasos principales en las extremidades inferiores. Material y métodos: Desde enero de 1983 a diciembre 2016 se diagnosticaron 42 pacientes con leiomiosarcomas, de los que 6 afectaban a vasos principales de las extremidades inferiores (denominados vasculares). Se registraron retrospectivamente datos epidemiológicos, estudios de imagen, cirugía realizada, tratamientos adyuvantes, complicaciones, así como las recidivas y mortalidad. Resultados: Todos los pacientes fueron afectos de leiomiosarcomas de alto grado(II-III FNCLCC), con un diámetro mayor tumoral de 9,1cm de media (6-15) y un seguimiento medio de 23 meses (7-36). La edad media fue de 64 años (29-84). El primer síntoma fue una tumoración palpable en 4 de ellos. Los otros 2 casos comenzaron con fenómenos tromboembólicos. En 5 casos el origen fueron los vasos femorales, mientras que un caso fue a nivel poplíteo. A pesar de que todos los casos preservaban la extremidad, 3 (50%) presentaron diseminación pulmonar, 2 (33%) hepática y un caso presentó recidiva local. Dos casos fueron exitus al finalizar el estudio y hubo un caso de pérdida de seguimiento. Discusión y conclusiones: Los leiomiosarcomas vasculares son tumores altamente agresivos con baja tasa de supervivencia a los 5 años. En nuestro estudio, el 50% de los pacientes se mantienen en remisión completa con un seguimiento medio de 23 meses. Es frecuente que su inicio asocie la presencia de una masa tumoral con fenómenos trombóticos (33% de nuestros casos). La cirugía de resección tumoral habitualmente compromete las estructuras vasculares principales, hecho que implica una resección y técnicas reconstructivas vasculares para el salvamento de la extremidad

Objective: To evaluate the results of bloc resection and vascular reconstruction of leiomyosarcomas with involvement of main vessels in the lower extremities. Material and methods: From January 1983 to December 2016, 42 patients with leiomyosarcomas were diagnosed. Six of these leiomyosarcomas affected main vessels of the lower extremities (called vascular). Epidemiological data, imaging studies, surgery performed, adjuvant treatments, complications, as well as recurrences and mortality were retrospectively recorded. Results: All the patients were affected by high-grade leiomyosarcomas (II-III FNCLCC classification), with a larger tumour average diameter of 9.1cm(6-15) and a mean follow-up of 23 months (7-36). The average age was 64 years (29-84). The first symptom was a palpable tumour in 4 of them. The other 2 cases debuted with thromboembolic phenomena. In 5 cases the origin was the femoral vessels, while one case was at the popliteal level. Although all cases preserved the limb, in 3 cases (50%) they presented pulmonary dissemination,2 cases (33%) hepatic dissemination and one case had local recurrence. Two cases died at the end of the study and there was one case of loss to follow-up. Discussion and conclusions: Vascular leiomyosarcomas are highly aggressive tumours with a low survival rate at 5 years. In our study, 50% of the patients remain in complete remission with a mean follow-up of 23 months. Their onset frequently associates the presence of tumour mass with thrombotic phenomena (33% of our cases). Tumour resection surgery usually compromises the main vascular structures, which implies resection and vascular reconstructive techniques to salvage the limb

Leiomyosarcomas affecting main vessels in the lower extremities. / Leiomiosarcomas de grandes vasos en las extremidades inferiores.

OBJECTIVE: To evaluate the results of bloc resection and vascular reconstruction of leiomyosarcomas with involvement of main vessels in the lower extremities. MATERIAL AND METHODS: From January 1983 to December 2016, 42 patients with leiomyosarcomas were diagnosed. Six of these leiomyosarcomas affected main vessels of the lower extremities (called vascular). Epidemiological data, imaging studies, surgery performed, adjuvant treatments, complications, as well as recurrences and mortality were retrospectively recorded. RESULTS: All the patients were affected by high-grade leiomyosarcomas (ii-iii FNCLCC classification), with a larger tumour average diameter of 9.1cm(6-15) and a mean follow-up of 23 months (7-36). The average age was 64 years (29-84). The first symptom was a palpable tumour in 4 of them. The other 2 cases debuted with thromboembolic phenomena. In 5 cases the origin was the femoral vessels, while one case was at the popliteal level. Although all cases preserved the limb, in 3 cases (50%) they presented pulmonary dissemination,2 cases (33%) hepatic dissemination and one case had local recurrence. Two cases died at the end of the study and there was one case of loss to follow-up. DISCUSSION AND CONCLUSIONS: Vascular leiomyosarcomas are highly aggressive tumours with a low survival rate at 5 years. In our study, 50% of the patients remain in complete remission with a mean follow-up of 23 months. Their onset frequently associates the presence of tumour mass with thrombotic phenomena (33% of our cases). Tumour resection surgery usually compromises the main vascular structures, which implies resection and vascular reconstructive techniques to salvage the limb.

Beyond the Required LISA Free-Fall Performance: New LISA Pathfinder Results down to 20 µHz.

In the months since the publication of the first results, the noise performance of LISA Pathfinder has improved because of reduced Brownian noise due to the continued decrease in pressure around the test masses, from a better correction of noninertial effects, and from a better calibration of the electrostatic force actuation. In addition, the availability of numerous long noise measurement runs, during which no perturbation is purposely applied to the test masses, has allowed the measurement of noise with good statistics down to 20 µHz. The Letter presents the measured differential acceleration noise figure, which is at (1.74±0.05) fm s^{-2}/sqrt[Hz] above 2 mHz and (6±1)×10 fm s^{-2}/sqrt[Hz] at 20 µHz, and discusses the physical sources for the measured noise. This performance provides an experimental benchmark demonstrating the ability to realize the low-frequency science potential of the LISA mission, recently selected by the European Space Agency.

Charge-Induced Force Noise on Free-Falling Test Masses: Results from LISA Pathfinder.

We report on electrostatic measurements made on board the European Space Agency mission LISA Pathfinder. Detailed measurements of the charge-induced electrostatic forces exerted on free-falling test masses (TMs) inside the capacitive gravitational reference sensor are the first made in a relevant environment for a space-based gravitational wave detector. Employing a combination of charge control and electric-field compensation, we show that the level of charge-induced acceleration noise on a single TM can be maintained at a level close to 1.0 fm s^{-2} Hz^{-1/2} across the 0.1-100 mHz frequency band that is crucial to an observatory such as the Laser Interferometer Space Antenna (LISA). Using dedicated measurements that detect these effects in the differential acceleration between the two test masses, we resolve the stochastic nature of the TM charge buildup due to interplanetary cosmic rays and the TM charge-to-force coupling through stray electric fields in the sensor. All our measurements are in good agreement with predictions based on a relatively simple electrostatic model of the LISA Pathfinder instrument.

Validation of PROFUND prognostic index over a four-year follow-up period.

BACKGROUND/OBJECTIVES: The PROFUND index stratifies accurately the 12-month mortality risk of polypathological patients (PPs), but its fitness over a longer follow-up period remains unknown. We aimed to explore the calibration and discrimination power of PROFUND index over 4-years, in order to assess its follow-up interval generalizability. DESIGN: Multicenter prospective cohort-study. SETTING: 33 Spanish hospitals. PARTICIPANTS: PPs included after hospital discharge, outpatient clinics, or home hospitalization. MEASUREMENTS: Mortality over a 4-year follow-up period. METHODS: PROFUND index calibration was assessed by risk-quartiles predicted/observed mortality (Hosmer-Lemeshow goodness-of-fit test), and its discrimination power by ROC curves. RESULTS: A total of 768 patients were included (630 [82%] of them completed the 4-year follow-up). Global mortality rate was 63.5%. When assessing individual patient scores, mortality was 52% in the lowest risk group (0-2 points in PROFUND score); 73.5% in the low-intermediate risk group (3-6 points), 85% in the intermediate-high group (7-10 points); and 92% in the highest risk group (≥11 points). Accuracy testing of the PROFUND index showed good calibration (P=.8 in the Hosmer-Lemeshow goodness-of-fit test), and also a good discrimination power (AUC=0.71 [0.67-0.77] in ROC curve). CONCLUSIONS: The PROFUND index maintained its accuracy in predicting mortality of polypathological patients over a 4-year follow-up period. This index may be of potential usefulness in deciding the most appropriate health-care interventions in populations with multimorbidity.

High neutrophil to lymphocyte ratio measured before starting ipilimumab treatment is associated with reduced overall survival in patients with melanoma.

BACKGROUND: There is an unmet need to identify markers predictive of response to ipilimumab in patients with melanoma because the number of responders to ipilimumab is low and its cost is very high. An increase in absolute lymphocyte count (ALC) or low neutrophil/lymphocyte ratio (NLR) just before the third infusion has been reported to be associated with better overall survival (OS). OBJECTIVES: Our aim was to determine whether NLR measured before the first infusion was associated with OS. PATIENTS AND METHODS: Data were collected on a consecutive series of 58 patients treated with ipilimumab in four hospitals, including 51 at stage M1c and four at stage M1b. The influences of the NLR and other factors such as lactate dehydrogenase (LDH), performance status, ALC, absolute neutrophil count (ANC) and corticosteroids on survival were studied. We also assessed this association with NLR categorized as a binary variable. The cut-off value for the NLR was determined with time-dependent receiver operating characteristic (ROC) analysis. Univariate and multivariate analyses were performed using Cox regression models. RESULTS: High NLR (≥) 4, high ANC LDH levels (>2), performance status ≥2, symptomatic brain metastases, and corticosteroids before week 1 were associated with poorer survival on univariate analysis. Using multivariate analysis, a significant association between high NLR (continuous variable) and poorer survival was demonstrated and remained significant after adjustment on potential confounders [hazard ratio (HR) = 1·21, 95% confidence interval (CI) 1·07-1·36]. NLR ≥4 was an independent prognostic factor (HR = 2·2, 95% CI 1·01-4·78). Intake of corticosteroids before week 1 was not an independent prognostic factor (HR = 1·28, 95% CI 0·54-3·06). CONCLUSIONS: High NLR (≥4) before initiating ipilimumab treatment in patients with metastatic melanoma is an independent prognostic indicator of poor survival.

Application of stages of change model to adolescents' physical activity in relation to psychological variables.

AIM: This study investigated the stages of change in physical activity in relation to psychological variables: self-efficacy, physical self-concept and barriers to physical activity, as well as gender. Furthermore, cluster profiles were created based on psychological variables to be compared with stages of change groups. METHODS: Data were obtained from a representative sample of adolescents (N.=1618, 14.46±1.28 years) from Aragon region (Spain). The different strata were selected according to the geographical region, environment, type of school, age and gender RESULTS: Males (75.5%) and very active adolescents (96.9% participant boys and 93.5% participants girls) were more prevalent in the action and maintenance groups. We found significant differences in psychosocial variables by stages of change and gender, showing higher scores in active groups for physical self-concept (effects of gender and stages of change: F(1, 1618)=313.82 P<0.001, η²=0.230) and self-efficacy (F(1, 1618)=324.34 P<0.001, η²=0.236), and lower scores in passive groups for intrapersonal (F(1, 1618)=179.73 P<0.001, η²=0.146) and extrapersonal barriers (F(1, 1618)=189.42 P<0.001, η²=0.153). Psychological cluster profiles created with these variables showed significant relationships with stages of change groups (χ²(1)=162,76, P<0.001; Pearson R=0.359 P<0.001). CONCLUSION: The findings of the research suggest the importance of the study, showing strong determinants of PA, physical self-concept, self-efficacy and perceived barriers, in relation to the intention to change behaviour, not only stage of change model variables. Furthermore, the study can be relevant to designing more effective health promotion programmes in the adolescent population.

Do epoch lengths affect adolescents' compliance with physical activity guidelines?

AIM: This study examined the effect of different epoch lengths (from 3 to 60 s) on (a) moderate to vigorous physical activity (MVPA), (b) 10 minutes bouts of MVPA and (c) compliance with World Health Organization (WHO) guidelines, as measured with an ActiGraph accelerometer. METHODS: A sample of 401 adolescents (14.48±0.69 years) wore a GT3X accelerometer to measure physical activity (PA) for 7 consecutive days. Data, originally collected in 1-s epoch(s), were then reintegrated into epochs of 3-, 5-, 10-, 15-, 30-, 45- and 60-s. RESULTS: The results showed a significant epoch effect (P=0.000) for time spent in MVPA, 10-min bouts of MVPA and the extent of compliance with guidelines percentage of compliance of guidelines. Bland-Altman analysis showed good agreement between 5- and 10-, 5- and 15-, and 10- and 15-s data, both for MVPA and 10-min bouts of MVPA. CONCLUSION: Epidemiological studies should take into account the sampling interval to offer accurate conclusions with regard to levels of MVPA and the extent to which adolescents comply with guidelines. Shorter epochs, such as 5-, 10- or 15-s are proposed for comparative studies carried out with adolescents in this area.

Cardiac adverse effects of naloxone-precipitated morphine withdrawal on right ventricle: role of corticotropin-releasing factor (CRF) 1 receptor.

Opioid addiction is associated with cardiovascular disease. However, mechanisms linking opioid addiction and cardiovascular disease remain unclear. This study investigated the role of corticotropin-releasing factor (CRF) 1 receptor in mediating somatic signs and the behavioural states produced during withdrawal from morphine dependence. Furthermore, it studied the efficacy of CRF1 receptor antagonist, CP-154,526 to prevent the cardiac sympathetic activity induced by morphine withdrawal. In addition, tyrosine hydroxylase (TH) phosphorylation pathways were evaluated. Like stress, morphine withdrawal induced an increase in the hypothalamic-pituitary-adrenal (HPA) axis activity and an enhancement of noradrenaline (NA) turnover. Pre-treatment with CRF1 receptor antagonist significantly reduced morphine withdrawal-induced increases in plasma adrenocorticotropic hormone (ACTH) levels, NA turnover and TH phosphorylation at Ser31 in the right ventricle. In addition, CP-154,526 reduced the phosphorylation of extracellular signal-regulated kinase (ERK) after naloxone-precipitated morphine withdrawal. In addition, CP-154,526 attenuated the increases in body weight loss during morphine treatment and suppressed some of morphine withdrawal signs. Altogether, these results support the idea that cardiac sympathetic pathways are activated in response to naloxone-precipitated morphine withdrawal suggesting that treatment with a CRF1 receptor antagonist before morphine withdrawal would prevent the development of stress-induced behavioural and autonomic dysfunction in opioid addicts.

[A rare side effect of mesotherapy: Nicolau syndrome]. / Un effet indésirable rare de la mésothérapie : la dermite de Nicolau.

BACKGROUND: Nicolau's livedoid dermatitis is associated with drug-induced embolism in the cutaneous arterial bed, generally as a result of accidental intra-arterial injection. Herein, we report a case that is somewhat surprising because of its late onset following mesotherapy injections. CASE REPORT: A 53-year-old man, with a history solely of tendinopathy for which he underwent mesotherapy sessions, consulted for livedoid lesions of the front of the knee with central necrosis. History-taking revealed a final course of mesotherapy three weeks earlier for patellar tendinitis below the left kneecap; intradermal injection of procaine and piroxicam had been unusually and intensely painful. The remainder of the clinical examination revealed additional livedoid lesions on the outside of the left ankle as well as purpuric lesions on the pads of the toes on the left foot. Laboratory tests revealed nothing of note. Skin biopsies of the livedoid circumference of the lesion showed arteriolar emboli of an amorphous material within the dermis obliterating the arteriolar lumen. The clinical appearance of skin lesions after mesotherapy led us to a diagnosis of Nicolau livedoid dermatitis. DISCUSSION: Nicolau dermatitis is a rare skin complication described as occurring mainly as a result of intramuscular injections. The reported case is special because it comprises Nicolau dermatitis arising out of a session of mesotherapy employing an intradermal injection. However, there are only very few cases in which subcutaneous injections have induced Nicolau dermatitis. The pathophysiology is not well known, but several mechanisms are involved: arterial ischaemia by vasospasm or thrombosis. In this case, the semiotic appearance of the lesions and histological analysis militate in favour of accidental injection of a skin product into an arteriole, resulting in obliteration of the latter. Mesotherapy can induce Nicolau dermatitis.