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The human vasculature is essential in organs and tissues for the transport of nutrients, metabolic waste products, and the maintenance of homeostasis. The integration of vessels in in vitro organs-on-chip may, therefore, improve the similarity to the native organ microenvironment, ensuring proper physiological functions and reducing the gap between experimental research and clinical outcomes. This gap is particularly evident in drug testing and the use of vascularized models may provide more realistic insights into human responses to drugs in the pre-clinical phases of the drug development pipeline. In this context, different vascularized liver models have been developed to recapitulate the architecture of the hepatic sinusoid, exploiting either porous membranes or bioprinting techniques. In this work, we developed a method to generate perfusable vascular channels with a circular cross section within organs-on-chip without any interposing material between the parenchyma and the surrounding environment. Through this technique, vascularized liver sinusoid-on-chip systems with and without the inclusion of the space of Disse were designed and developed. The recapitulation of the Disse layer, therefore, a gap between hepatocytes and endothelial cells physiologically present in the native liver milieu, seems to enhance hepatic functionality (e.g., albumin production) compared to when hepatocytes are in close contact with endothelial cells. These findings pave the way to numerous further uses of microfluidic technologies coupled with vascularized tissue models (e.g., immune system perfusion) as well as the integration within multiorgan-on-chip settings.
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Antarctica has been affected directly and indirectly by human pressure for more than two centuries and recently plastic pollution has been recognized as a further potential threat for its unique biodiversity. Global long-range transport as well as local input from anthropogenic activities are potential sources of plastic pollution in both terrestrial and marine Antarctic territories. The present study evaluated the presence of microplastics in specimens of the Antarctic whelk Neobuccinum eatoni, a key species in benthic communities of the Ross Sea, one of the largest marine protected areas worldwide. To this aim, a thermo-oxidative extraction method was applied for microplastic isolation and quantification, and polymer identification was performed by manual µ-FTIR spectroscopy. Textile (semi-)synthetic or composite microfibers (length range: 0.8-5.7 mm) were found in 27.3% of whelk specimens, suggesting a low risk of bioaccumulation along Antarctic benthic food webs in the Ross Sea. Their polymer composition (of polyethylene terephthalate and cellulose-polyamide composites) matched those of outdoor technical clothing in use by the personnel of the Italian "Mario Zucchelli" station near Terra Nova Bay in the Ross Sea. Such findings indicate that sewage from base stations may act as potential local sources of textile microplastic fibers in this remote environment. More in-depth monitoring studies aiming at defining the extent of microplastic contamination related to such sources in Antarctica are encouraged.
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Microplásticos , Plásticos , Humanos , Bahías , Monitoreo del Ambiente/métodos , Regiones Antárticas , TextilesRESUMEN
OBJECTIVE: To appraise the highest evidence on hip morphology as a risk factor for developing hip osteoarthritis (OA). DESIGN: We searched for studies evaluating the association between radiological hip morphology parameters and the prevalence, incidence or progression of hip OA (based on different radiographic and clinical criteria) in the MEDLINE, EMBASE, Web of Science, Scopus, Cochrane Library and PEDro databases from inception until June 2020. Prospective and cross-sectional studies were separately evaluated. Data are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: We included 9 prospective and 21 cross-sectional studies in the meta-analysis, and evaluated 42,831 hips from 25,898 individuals (mean age: 59 years). Prospective studies showed that, compared with control hips, hips with cam morphology (alpha angle >60°; OR = 2.52, 95% CI: 1.83 to 3.46, P < 0.001) or hip dysplasia (lateral center-edge angle (LCEA) <25°; OR = 2.38, 95% CI: 1.84 to 3.07, P < 0.001), but not hips with pincer morphology (LCEA >39°; OR = 1.08, 95% CI: 0.57 to 2.07, P = 0.810), were more likely to develop hip OA than hips without these morphologies. Cross-sectional studies showed a greater prevalence of pincer morphology (LCEA >39°, OR = 3.71, 95% CI: 2.98 to 4.61, P < 0.001) and acetabular retroversion (crossover sign; OR = 2.65, 95% CI: 1.17 to 6.03, P = 0.020) in hips with OA than in control hips. CONCLUSION: Cam morphology and hip dysplasia were consistently associated with the development of hip OA. Pincer morphology was associated with hip OA in cross-sectional but not in prospective studies. The heterogeneous quantification of pincer morphology on radiographs limits a clear conclusion on its association with hip OA.
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Articulación de la Cadera/anatomía & histología , Articulación de la Cadera/diagnóstico por imagen , Osteoartritis de la Cadera/epidemiología , Osteoartritis de la Cadera/etiología , Estudios Transversales , Progresión de la Enfermedad , Humanos , Incidencia , Prevalencia , Estudios Prospectivos , Radiografía , Factores de RiesgoRESUMEN
BACKGROUND: Complete atrioventricular block (AVB3) may be an urgent potentially lifethreatening situation. Our objective was to describe the routine management of AVB 3, with emphasis on the organizational aspects. METHODS: From September 2019 to November 2019, a prospective national survey including 28 questions was electronically sent to 100 physicians (Google Form). RESULTS: The answers were collected from 93 physicians (response rate 93%). Permanent pacemaker implantation during weekends and nights (after 8PM) is possible for 49% of the operators (<5 times a year), for 15% (>5 times a year), impossible for 36% of the operators. For AVB3 nonresponsive to isoproterenol occurring during the night, a temporary pacing lead (TPL) is implanted by: the on-site medical staff on-duty (27%), the on-call interventional cardiologist (21%), the on-call electrophysiologist (19%), a permanent pacemaker is implanted by the electrophysiologist (12%), the strategy is not standardized (15%). An externalized active fixation lead (AFL) for AVB3 has already been implanted by 50% of the operators. 80 (86%) have already observed a dislocation of the TPL, a cardiac perforation already occurred in 57 (61%), a groin hematoma in 35 (38%), and this technique was proscribed for 4% of the operators. CONCLUSION: Our survey shows important disparities in terms of management of AVB3 among the different centers. An externalized AFL with a reusable generator was used by half of the centers.
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Atención Posterior/organización & administración , Bloqueo Atrioventricular/terapia , Encuestas de Atención de la Salud , Marcapaso Artificial , Adulto , Atención Posterior/estadística & datos numéricos , Anciano , Argelia , Cardiotónicos/uso terapéutico , Resistencia a Medicamentos , Francia , Lesiones Cardíacas/epidemiología , Hematoma/epidemiología , Humanos , Isoproterenol/uso terapéutico , Malí , Persona de Mediana Edad , Mónaco , Marruecos , Marcapaso Artificial/efectos adversos , Estudios Prospectivos , Implantación de Prótesis/efectos adversos , Implantación de Prótesis/métodos , TúnezRESUMEN
BACKGROUND: Increased postural balance challenge is associated with more fluctuations in centre of pressure movement, indicating increased interference from the postural control system. The role of intrinsic foot muscles in balance control is relatively understudied and whether such control system interference occurs at the level of these muscles is unknown. RESEARCH QUESTION: Do fewer fluctuations in intrinsic foot muscle excitation occur in response to increased postural balance challenge? METHODS: Surface EMGs were recorded using a grid of 13 × 5 channels from the plantar surface of the foot of 17 participants, who completed three balance tasks: bipedal stance; single leg stance and bipedal tip-toe. Centre of pressure (CoP) movement was calculated from simultaneously recorded force plate signals. Fluctuations in CoP and EMGs for each task were quantified using a sample entropy based metric, Entropy Halflife (EnHL). Longer EnHL indicates fewer signal fluctuations. RESULTS: The shortest EMG EnHL, 9.27 ± 3.34 ms (median ± interquartile range), occurred during bipedal stance and the longest during bipedal tip-toe 15.46 ± 11.16 ms, with 18.80 ± 8.00 ms recorded for single leg stance. Differences were statistically significant between bipedal stance and both bipedal tip-toe (p < 0.001) and single leg stance (p < 0.001). CoP EnHL for both anterior-posterior and medial-lateral movements also differed significantly between tasks (p < 0.001, both cases). However, anterior-posterior CoP EnHL was longest for bipedal stance 259.84±230.22 ms and shortest for bipedal tip-toe 146.25±73.35 ms. Medial-lateral CoP EnHL was also longest during bipedal stance 215.73±187.58 ms, but shortest for single leg stance 113.48±83.01 ms. SIGNIFICANCE: Fewer fluctuations in intrinsic foot muscle excitation occur in response to increased postural balance challenge. Fluctuations in CoP movement during balance must be predominantly driven by excitation of muscles extrinsic to the foot. Intrinsic foot muscles therefore likely play a greater role in stabilisation of the foot than balance control during the postural tasks studied.
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Pie/fisiología , Músculo Esquelético/fisiología , Equilibrio Postural/fisiología , Adulto , Electromiografía , Entropía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Movimiento/fisiología , PresiónRESUMEN
This paper provides a first insight of the potential of the ß- Radio Guided Surgery (ß--RGS) in a complex surgical environment like the abdomen, where multiple sources of background concur to the signal at the tumor site. This case is well reproduced by ex-vivo samples of 90Y-marked Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP NET) in the bowel. These specimens indeed include at least three wide independent sources of background associated to three anatomical districts (mesentery, intestine, mucose). The study is based on the analysis of 37 lesions found on 5 samples belonging to 5 different patients. We show that the use of electrons, a short range particle, instead of γ particles, allows to limit counts read on a lesion to the sum of the tumor signal plus the background generated by the sole hosting district.The background on adjacent districts in the same specimen/patient is found to differ up to a factor 4, showing how the specificity and sensitivity of the ß--RGS technique can be fully exploited only upon a correct measurement of the contributing background. This locality has been used to set a site-specific cut-off algorithm to discriminate tumor and healthy tissue with a specificity of 100% and a sensitivity, on this test data sample, close to 100%. Factors influencing the sensitivity are also discussed. One of the specimens set allowed us evaluate the volume of the lesions, thus concluding that the probe was able to detect lesions as small as 0.04â¯mL in that particular case.
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Partículas beta/uso terapéutico , Tumores Neuroendocrinos/cirugía , Cirugía Asistida por Computador/métodos , Algoritmos , HumanosRESUMEN
The transverse emittance of the electron beam is a fundamental parameter in linac-based x-ray free-electron lasers (FELs). We present results of emittance measurements carried out at SwissFEL, a compact x-ray FEL facility at the Paul Scherrer Institute in Switzerland, including a description of the novel high-resolution measurement techniques and the optimization procedure. We obtained slice emittance values at the undulator entrance down to 200 nm for an electron beam with a charge of 200 pC and an rms duration of 30-40 fs. Furthermore, we achieved slice emittances as low as 100 nm for 10 pC beams with few fs duration. These values set new standards for electron linear accelerators. The quality, verification, and control of our electron beams allowed us to generate high-power FEL radiation for a wavelength as short as 0.1 nm using an electron beam with an energy of only 6 GeV. The emittance values demonstrated at SwissFEL would allow producing hard x-ray FEL pulses with even lower-energy beams, thus paving the way for even more compact and cost-effective FEL facilities.
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PURPOSE: The lack of inter-method agreement can produce inconsistent results in neuroimaging studies. We evaluated the intra-method repeatability and the inter-method reproducibility of two widely-used automatic segmentation methods for brain MRI: the FreeSurfer (FS) and the Statistical Parametric Mapping (SPM) software packages. METHODS: We segmented the gray matter (GM), the white matter (WM) and subcortical structures in test-retest MRI data of healthy volunteers from Kirby-21 and OASIS datasets. We used Pearson's correlation (r), Bland-Altman plot and Dice index to study intra-method repeatability and inter-method reproducibility. In order to test whether different processing methods affect the results of a neuroimaging-based group study, we carried out a statistical comparison between male and female volume measures. RESULTS: A high correlation was found between test-retest volume measures for both SPM (r in the 0.98-0.99 range) and FS (r in the 0.95-0.99 range). A non-null bias between test-retest FS volumes was detected for GM and WM in the OASIS dataset. The inter-method reproducibility analysis measured volume correlation values in the 0.72-0.98 range and the overlap between the segmented structures assessed by the Dice index was in the 0.76-0.83 range. SPM systematically provided significantly greater GM volumes and lower WM and subcortical volumes with respect to FS. In the male vs. female brain volume comparisons, inconsistencies arose for the OASIS dataset, where the gender-related differences appear subtler with respect to the Kirby dataset. CONCLUSIONS: The inter-method reproducibility should be evaluated before interpreting the results of neuroimaging studies.
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Encéfalo/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética , Programas Informáticos , Femenino , Humanos , MasculinoRESUMEN
Short wavelength free-electron lasers (FELs), providing pulses of ultrahigh photon intensity, have revolutionized spectroscopy on ionic targets. Their exceptional photon flux enables multiple photon absorptions within a single femtosecond pulse, which in turn allows for deep insights into the photoionization process itself as well as into evolving ionic states of a target. Here we employ ultraintense pulses from the FEL FERMI to spectroscopically investigate the sequential emission of electrons from gaseous, atomic argon in the neutral as well as the ionic ground state. A pronounced forward-backward symmetry breaking of the angularly resolved emission patterns with respect to the light propagation direction is experimentally observed and theoretically explained for the region of the Cooper minimum, where the asymmetry of electron emission is strongly enhanced. These findings aim to originate a better understanding of the fundamentals of photon momentum transfer in ionic matter.
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BACKGROUND: Leukoaraiosis (LA) is a common radiological finding in elderly, frequently associated with several clinical disorders, including unexplained dizziness. The pathogenesis of LA is multifactorial, with a dysfunction of cerebral microcirculation resulting in chronic hypoperfusion and tissue loss, with oxidative stress involved in this cascade. OBJECTIVE: The aim of this study was to analyse some oxidative stress biomarkers in a cohort of LA patients. METHOD: Fifty-five consecutive patients (33 males, median age 75 years) with LA were recruited. In a subgroup of 33 patients with LA and unexplained dizziness, we have then performed an open study to evaluate if 60-day supplementation with a polyphenol compound may modify these biomarkers and influence quality of life, analysed with the Dizziness Handicap Inventory (DHI) scale. RESULTS: At baseline, blood oxidative stress parameters values were outside normal ranges and compared to matched healthy controls. After the two months supplementation, we observed a significant decrement of advanced oxidation protein products values and a significant improvement of DHI. CONCLUSION: Oxidative stress biomarkers may be useful to detect redox imbalance in LA and to provide non-invasive tools to monitor disease status and response to therapy.
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Trastornos Cerebrovasculares , Suplementos Dietéticos , Mareo , Leucoaraiosis , Estrés Oxidativo/efectos de los fármacos , Polifenoles/administración & dosificación , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Trastornos Cerebrovasculares/tratamiento farmacológico , Trastornos Cerebrovasculares/metabolismo , Trastornos Cerebrovasculares/patología , Mareo/tratamiento farmacológico , Mareo/metabolismo , Mareo/patología , Femenino , Humanos , Leucoaraiosis/tratamiento farmacológico , Leucoaraiosis/metabolismo , Leucoaraiosis/patología , Masculino , Persona de Mediana EdadRESUMEN
A selection of historical textile fragments from the Venetian art dealer Moisè Michelangelo Guggenheim collection, ranging from XV to XVIII century, has been investigated by means of non-invasive techniques in order to reveal the coloring materials. Imaging was preliminarily used to visually investigate the selected artwork fragments in order to investigate their structure and conservation conditions; Fiber Optics Reflectance Spectroscopy (FORS) allowed recognizing the main natural dyestuffs, such as indigotin and anthraquinones-based compounds, except the yellow ones, difficultly identifiable when using this non-invasive technique. Collected spectroscopic data have been also elaborated by using a clustering algorithm that permitted to group collected spectra on the basis of similar properties and evidencing their inflection point wavelength as the most influencing feature.
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Intrinsic foot muscles (IFM) are a crucial component within the human foot. Investigating their functioning can help understand healthy and pathological behaviour of foot and ankle, fundamental for everyday activities. Recording muscle activation from IFM has been attempted with invasive techniques, mainly investigating single muscles. Here we present a novel methodology, to investigate the feasibility of recording physiological surface EMG (sEMG) non-invasively and quantify patterns of activation across the whole plantar region of the foot. sEMG were recorded with a 13â¯×â¯5 array from the sole of the foot (nâ¯=â¯25) during two-foot stance, two-foot tiptoe and anterior/posterior sways. Physiological features of sEMG were analysed. During anterior/posterior epochs within the sway task, sEMG patterns were analysed in terms of signal amplitude (intensity) and structure (Sample Entropy) distribution, by evaluating the centre of gravity (CoG) of each topographical map. Results suggest signals are physiological and not affected by loading. Both amplitude and sample entropy CoG coordinates were grouped in one region and overlapped, suggesting that the region with highest amplitude corresponds with the most predictable signal. Therefore, both spatial and temporal features of IFM activation may be recorded non-invasively, providing opportunity for more detailed investigation of IFM function in healthy and patient populations.
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Electromiografía/métodos , Pie/fisiología , Músculo Esquelético/fisiología , Adulto , Tobillo/fisiología , Articulación del Tobillo/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
In linac-driven free-electron lasers, colliders, and energy recovery linacs, a common way to compress the electron bunch to kiloampere level is based upon the implementation of a magnetic dispersive element that converts particle energy deviation into a path-length difference. Nonlinearities of such a process are usually compensated by enabling a high harmonic rf structure properly tuned in amplitude and phase. This approach is however not straightforward, e.g., in C-band and X-band linacs. In this Letter we demonstrate that the longitudinal self-induced field excited by the electron beam itself is able to linearize the compression process without any use of high harmonic rf structure. The method is implemented at the FERMI linac, with the resulting high quality beam used to drive the seeded free-electron laser during user experiments.
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Single-photon laser-enabled Auger decay (spLEAD) is predicted theoretically [B. Cooper and V. Averbukh, Phys. Rev. Lett. 111, 083004 (2013)PRLTAO0031-900710.1103/PhysRevLett.111.083004] and here we report its first experimental observation in neon. Using coherent, bichromatic free-electron laser pulses, we detect the process and coherently control the angular distribution of the emitted electrons by varying the phase difference between the two laser fields. Since spLEAD is highly sensitive to electron correlation, this is a promising method for probing both correlation and ultrafast hole migration in more complex systems.
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Spontaneous dissection of cervical arteries (sCAD) is a major cause of ischemic stroke in young patients, with an incidence varying from 1.7 to 3/100,000/year for extracranial internal carotid artery (ICAD) and 1 to 1.9/100,000/year for extracranial vertebral artery (VAD). Reliable epidemiological data on stroke incidence related to sCAD are scarce in Italy. This study aims to evaluate the incidence, clinical features, and outcome of cerebrovascular events related to sCAD and spontaneous intracranial arteries dissections (sIAD) in the city of Pisa (Italy). We retrospectively analyzed consecutive patients admitted between December 1997 and June 2015 with a diagnosis of stroke, TIA, or Bernard-Horner syndrome due to acute cervical or intracranial artery dissection. Considering that our hospital collects presumptively all patients hospitalized with sCAD coming from the referral geographical area, data may provide a good approximation to real incidence of sCAD in our population. Clinical and radiological features, acute treatment and outcome were collected. Seventy-seven cases were included (mean age 48.1±10.4 years, range 23-77,72.7% males), 66 residents in the district of Pisa. Crude incidence rate of cerebrovascular events due to intra or extracranial dissection was 1.88/100,000/year. The incidence of ICAD was 0.80/100,000/year and 0.43/100,000/year for VAD. Stroke occurred in 76.6% of patients. VAD was more prone to cause ischemic stroke and present with cervical pain or focal signs (p < 0.01) than ICAD group, which had older age at onset. sIAD were more frequent in the posterior circle (p = 0.01) and more associated with ischemic lesions. A good outcome (mRS 0-2) was observed in 79% of patients. This is the first epidemiological attempt to investigate impact of sCAD and sIAD in Italy.
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Disección Aórtica/epidemiología , Trastornos Cerebrovasculares/epidemiología , Adulto , Edad de Inicio , Anciano , Disección Aórtica/terapia , Trastornos Cerebrovasculares/terapia , Vértebras Cervicales , Ciudades , Femenino , Humanos , Incidencia , Italia/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: COPD is one of the leading causes of morbidity and mortality. Pharmacotherapy improves quality of life and reduces exacerbations although low adherence with prescribed treatments may represent a barrier to optimal disease management. The first objective of this paper is to report the distribution of COPD patients according to GOLD categories, in a sample of patients from a cohort study in an area of the Latium region in Italy. The second objective is to evaluate the agreement between the distributions of severity obtained from the HCPs and the experts included in the study board (Board). METHODS: COPD patients were given a card to collect demographic and clinical data at baseline. Information in those cards was independently evaluated by HCPs and Board to include each patient into one of the four GOLD categories. RESULTS: In a sample of 187 stable COPD patients, 59% male, mean age 70 year, the distribution of GOLD categories according to the Board was: 6% A, 34% B, 2% C, and 58% D. A discrepancy in GOLD classification was observed between the study board and field-based HCPs, regarding more than 50% of the patients, with a clear trend to underestimate the frequency of patients in D level (21%) and to overestimate the frequency in C level (21%). CONCLUSIONS: These results describe for the first time the distribution of COPD patients in an Italian cohort according to the GOLD categories, with the highest frequencies in levels B and D. The misclassification from HCPs may impact the therapeutic approach and the clinical outcomes.
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OBJECTIVES: to validate the MSRA questionnaire proposed as prescreening tool for sarcopenia, in a population of community-dwelling elderly subjects. DESIGN: observational study. SETTING: community dwelling elderly subjects. PARTICIPANTS: 274 community dwelling elderly subjects, 177 women and 97 men, aged 66-78 years. MEASUREMENTS: Based on EWGSOP diagnostic criteria subjects were classified as sarcopenic and non-sarcopenic. The Mini Sarcopenia Risk Assessment (MSRA) questionnaire, is composed of seven questions and investigates anamnestic and nutritional characteristics related to risk of sarcopenia onset (age, protein and dairy products consumption, number of meals per day, physical activity level, number of hospitalizations and weight loss in the last year). RESULTS: 33.5% of the study population, were classified as sarcopenic. With the 7-item MSRA score, subjects with a score of 30 or less, had a 4-fold greater risk of being sarcopenic than subjects with a score higher than 30 (OR:4.20;95% CI:2.26-8.06); area under the ROC curve was 0.786 (95% CI:0.725-0.847). In a logistic regression, considering as dependent variable the probability of being sarcopenic, and as independent variables the 7 items of the questionnaire, two items (number of meals and milk and dairy products consumption) showed non-significant diagnostic power. A 5-item score was then derived and the area under the ROC curve was 0.789 (95% IC:0.728-0.851). Taking into account the cost of false positive and false negative costs and the prevalence of sarcopenia, the "optimal" threshold of the original MSRA score (based on 7 items) is 30, with a sensitivity of 0.804 and a specificity of 0.505, while the "optimal" threshold of the MSRA score based on 5 items, is 45, with a sensitivity of 0.804 and a specificity of 0.604. CONCLUSION: this preliminary study shows that the MSRA questionnaire is predictive of sarcopenia and can be suggested as prescreening instrument to detect this condition. The use of a short form of the MSRA questionnaire improves the capacity to identify sarcopenic subjects.
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Ejercicio Físico/fisiología , Fuerza Muscular/fisiología , Medición de Riesgo/métodos , Sarcopenia/diagnóstico , Encuestas y Cuestionarios , Anciano , Femenino , Humanos , Modelos Logísticos , Masculino , Prevalencia , Curva ROCRESUMEN
The hitherto unexplored two-photon doubly excited states [Ne^{*}(2p^{-1}3s)]_{2} were experimentally identified using the seeded, fully coherent, intense extreme ultraviolet free-electron laser FERMI. These states undergo ultrafast interatomic Coulombic decay (ICD), which predominantly produces singly ionized dimers. In order to obtain the rate of ICD, the resulting yield of Ne_{2}^{+} ions was recorded as a function of delay between the extreme ultraviolet pump and UV probe laser pulses. The extracted lifetimes of the long-lived doubly excited states, 390(-130/+450) fs, and of the short-lived ones, less than 150 fs, are in good agreement with ab initio quantum mechanical calculations.
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Parkinson's disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration.
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Ácido 3,4-Dihidroxifenilacético/análogos & derivados , Multimerización de Proteína/efectos de los fármacos , Vesículas Sinápticas/efectos de los fármacos , Vesículas Sinápticas/metabolismo , alfa-Sinucleína/metabolismo , Ácido 3,4-Dihidroxifenilacético/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Línea Celular , Membrana Celular/metabolismo , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/ultraestructura , Permeabilidad , Agregado de Proteínas , Agregación Patológica de Proteínas , Unión Proteica , Espectrometría de Masas en Tándem , alfa-Sinucleína/químicaRESUMEN
We report the case of an 82-year-old man presenting with ventricular fibrillation (VF) occurring acutely after atrioventricular node (AVN) ablation. This patient had severe valvular cardiomyopathy, chronic atrial fibrillation (AF), and underwent prior to the AVN ablation a biventricular implantable cardiac defibrillator positioning. The VF was successfully cardioverted with one external electrical shock. What makes this presentation original is that the pre-ablation spontaneous heart rate in AF was slow (84 bpm), and that VF occurred after ablation despite a minimal heart rate drop of only 14 bpm. VF is the most feared complication of AVN ablation, but it had previously only been described in case of acute heart rate drop after ablation of at least 30 bpm (and more frequently>50 bpm). This case report highlights the fact that VF may occur after AVN ablation regardless of the heart rate drop, rendering temporary fast ventricular pacing mandatory whatever the pre-ablation heart rate.