•Lyapunov stability results for distributed order nonlinear time-varying systems.•Asymptotic stability Theorem which partially extends the fractional Lyapunov direct method.•New way to determine the ...stability of a distributed order system by analyzing the integer order derivative of an appropriate Lyapunov function.
In this article we present a generalization of the Lyapunov direct method for distributed order nonlinear time-varying systems. By extending recently introduced properties of the Caputo fractional derivative to the distributed order case, we provide various ways to determine the stability or asymptotic stability of certain systems. The fractional results that inspired this work are recovered if an appropriate distribution function is chosen. Some examples are given to validate the obtained results.
INTRODUCTIONIn the last 15 years, considerable improvements have been made in acute stroke care in Guipuzkoa, including the implementation of a centralised care model at Hospital Universitario ...Donostia (HUD), improved coordination between professionals, early detection campaigns, new treatments, a stroke unit, and specific rehabilitation. The aim of this work is to describe the results of a reference hospital (HUD) in a centralised care model.MATERIAL AND METHODSWe performed a retrospective observational study of a sample of patients discharged between August and December 2015 from the HUD with a diagnosis of acute stroke (ICD-9-CM codes 430-436, except 433.10). We review patients' baseline characteristics, acute-phase care, and functional outcomes and mortality at discharge and at one year.RESULTS AND DISCUSSIONWe identified 536 patients, with a mean age of 73.6 years and a high comorbidity rate. Ischaemic stroke accounted for 64.8% of patients, followed by haemorrhagic stroke (20%) and transient ischaemic attack (14.8%). A total of 53% of patients were attended in <6 hours, with code stroke being activated in 37.1%; 52.2% of patients were admitted to the stroke unit. Intravenous therapy was administered to 8.3% of patients with ischaemic stroke, and 9.5% underwent mechanical thrombectomy. Surgery was performed in 12.1% patients with haemorrhagic stroke. Rehabilitation was started at hospital in 56% of patients, and 39.6% continued with this treatment at discharge. Mortality was 13.8% at discharge and 25.9% at one year (ischaemic stroke, 25.3%; haemorrhagic stroke, 47.5%); these figures are lower than those previously reported in Guipuzkoa. At one year, 62.5% of patients had a Barthel Index score of 95-100, and 50% a modified Rankin Scale score of 0-2.CONCLUSIONSAfter the strategic changes implemented in acute stroke care in Guipuzkoa, including the centralisation of the acute stroke care model, mortality rates at discharge and at one year are lower in 2015 than the previously reported rates, with similar rates of independence. These results are consistent with those published by other Spanish and European centres.
Garlic essential oil contains a variety of fat soluble organosulfur compounds with antibacterial activity. Nevertheless, only recent studies have evaluated garlic oil and its constituents as ...modulators of ruminal processes. The present study was undertaken to evaluate the potential of diallyl disulfide (DDS) and propyl propane thiosulfinate (PTS) to modulate rumen biohydrogenation in vitro. Six continuous-culture fermenters, inoculated with rumen fluid from goats, were used in two replicated incubation runs of 12 days each. Two fermenters per run received either a control diet (without additive) or the same diet with 80μl/L of DDS or 200μl/L of PTS daily. At the end of each incubation run, samples of fermenter contents were taken for fatty acid analysis. The DDS addition resulted in lower (P=0.012) total saturated fatty acids (SFA) and higher monounsaturated fatty acids (MUFA; P=0.001) and polyunsaturated fatty acids (PUFA; P=0.018) contents as compared to the control. Increases in trans-10, cis-12 CLA (P=0.065), trans-10 18:1 (P<0.001) and vaccenic acid (VA; trans-11-18:1) (P=0.009) were also observed. Similar results were found for PTS addition, although significant differences with the control group were detected only for PUFA and trans-10 18:1 amounts. Additionally, 1mL of the fermenter contents was incubated in vitro with 0.167g/L of linoleic acid (cis-9, cis-12 18:2; LA) for 0, 1, 3, 6, 9 and 24h. Vaccenic acid and trans-10 18:1 accumulated to higher concentrations (P=0.054 at 9h and P=0.021 at 3h, respectively) when LA was incubated with the fermenter contents treated with DDS and PTS. Garlic derived compounds did not affect the amount of total bacteria (P=0.936) or abundances of Butyrivibrio proteoclasticus (P=0.693); although PTS increased the abundance of Butyrivibrio fibrisolvens (P=0.001), in comparison to the control and DDS treatments. Differences in the Butyrivibrio group structure were observed from the cluster analysis, which showed segregation for fermenters with garlic derived compounds from those without additives. It was concluded that adding DDS and PTS to the diet of fermenters modified the fatty acid of rumen contents, with potential health benefits of ruminant products. These changes in biohydrogenation appeared to be related to shifts within the Butyrivibrio bacterial community. In vivo studies are now required to confirm the potential of these compounds.
Summary
Background Familial melanoma, a cluster of several cases within a single family, accounts for approximately 10% of cases of melanoma. Hereditary melanoma is defined as two or more ...first‐degree relatives having melanoma. A member of a melanoma‐prone family has a 35–70‐fold increased relative risk of developing a melanoma. Genetic susceptibility is linked to the major susceptibility genes CDKN2A and CDK4, and the minor susceptibility gene MC1R.
Objectives To determine the clinical and genetic characteristics of cutaneous melanoma in melanoma‐prone families from Uruguay.
Methods We studied 13 individuals from six melanoma‐prone families living in Uruguay. Phenotype, familial and personal history were recorded. Molecular screening of CDKN2A and CDK4 was done by polymerase chain reaction–single strand conformational polymorphism analysis. The MC1R gene was sequenced.
Results Mutations in CDKN2A were detected in five of six families: c.−34G>T, p.G101W and p.E88X. A novel germline mutation p.E88X, associated with hereditary melanoma in two unrelated families, is described. We hypothesize that a founder effect occurred probably in the Mediterranean region. No mutations in CDK4 were detected. Six different MC1R variants, all previously reported, were present in Uruguayan families.
Conclusions The overall rate of deleterious CDKN2A mutations in our familial melanoma pedigrees, even though the sample size is small, was considerably higher (83%) than the often quoted range.
In the last 15 years, considerable improvements have been made in acute stroke care in Guipuzkoa, including the implementation of a centralised care model at Hospital Universitario Donostia (HUD), ...improved coordination between professionals, early detection campaigns, new treatments, a stroke unit, and specific rehabilitation. The aim of this work is to describe the results of a reference hospital (HUD) in a centralised care model.
We performed a retrospective observational study of a sample of patients discharged between August and December 2015 from the HUD with a diagnosis of acute stroke (ICD-9-CM codes 430-436, except 433.10). We review patients’ baseline characteristics, acute-phase care, and functional outcomes and mortality at discharge and at one year.
We identified 536 patients, with a mean age of 73.6 years and a high comorbidity rate. Ischaemic stroke accounted for 64.8% of patients, followed by haemorrhagic stroke (20%) and transient ischaemic attack (14.8%). A total of 53% of patients were attended in < 6 hours, with code stroke being activated in 37.1%; 52.2% of patients were admitted to the stroke unit. Intravenous therapy was administered to 8.3% of patients with ischaemic stroke, and 9.5% underwent mechanical thrombectomy. Surgery was performed in 12.1% patients with haemorrhagic stroke. Rehabilitation was started at hospital in 56% of patients, and 39.6% continued with this treatment at discharge. Mortality was 13.8% at discharge and 25.9% at one year (ischaemic stroke, 25.3%; haemorrhagic stroke, 47.5%); these figures are lower than those previously reported in Guipuzkoa. At one year, 62.5% of patients had a Barthel Index score of 95-100, and 50% a modified Rankin Scale score of 0-2.
After the strategic changes implemented in acute stroke care in Guipuzkoa, including the centralisation of the acute stroke care model, mortality rates at discharge and at one year are lower in 2015 than the previously reported rates, with similar rates of independence. These results are consistent with those published by other Spanish and European centres.
En los últimos 15 años se han introducido importantes mejoras en la atención de la enfermedad cerebrovascular aguda (ECVA) en Guipúzcoa que incluyen la implementación de un modelo centralizado en el Hospital Universitario Donostia (HUD), una mejor coordinación entre profesionales, campañas para su detección precoz, nuevos tratamientos, Unidad de Ictus y una rehabilitación específica. El objetivo de este trabajo es describir los resultados de un hospital de referencia (HUD) en un modelo de atención centralizado.
Estudio observacional retrospectivo de una muestra de pacientes dados de alta en el periodo de agosto-diciembre del año 2015 del HUD con diagnóstico de ECVA (CIE-9-MC-430-436 excepto 43310). Revisión de las características basales, atención en fase aguda, y resultados funcionales y de mortalidad al alta y al año.
Se incluyeron 536 pacientes cuya media de edad fue de 73,6 años y cuya comorbilidad era elevada. El ictus isquémico supuso el 64,8% de las altas, seguido de la ECVA hemorrágica (20%) y del accidente isquémico transitorio (AIT) (14,8%). Se atendió en < 6 h a un 53% de pacientes, activándose el “código ictus” en un 37,1%. Un 52,2% ingresaron en la Unidad de Ictus. Un 11,34% de los pacientes con ictus isquémico recibió terapia intravenosa y un 9,5% trombectomia mecánica. Un 12,1% de los pacientes con ECVA hemorrágica fue intervenido quirúrgicamente. El 56% inició rehabilitación en el hospital y un 39,6% la mantuvo al alta. La mortalidad al alta fue de un 13,8% y al año de un 25,9% (ictus isquémico: 25,3% y ECVA hemorrágica: 47,5%), menor a la descrita previamente en Guipúzcoa. Al año un 62,5% de pacientes tenían un Índice de Barthel (IB) 95-100, y un 50% una puntuación en escala de Rankin modificada (mRS) 0-2.
Tras las modificaciones estratégicas introducidas en la atención a la ECVA en Guipúzcoa, incluyendo la centralización del modelo de atención, la mortalidad al alta y anual en 2015 es menor a la descrita previamente, con tasas de autonomía similares. Estos resultados se encuentran en línea con los resultados publicados por parte de otros centros españoles y europeos.
Introduction: Dialysis fluid (DF), an essential element in hemodialysis (HD), is manufactured in situ by mixing three components: treated water, bicarbonate concentrate and acid concentrate. To avoid ...the precipitation of calcium and magnesium carbonate that is produced in DF by the addition of bicarbonate, it is necessary to add an acid. There are 2 acid concentrates that contain acetate (ADF) or citrate (CDF) as a stabilizer. Objective: To compare the acute effect of HD with CDF vs. ADF on the metabolism of calcium, phosphorus and magnesium, acid base balance, coagulation, inflammation and hemodynamic stability. Methods: Prospective, multicenter, randomized and crossed study, of 32 weeks duration, in patients in three-week HD, AK-200-Ultra-S or Artis monitor, 16 weeks with ADF SoftPac®, prepared with 3 mmol/L of acetate, and 16 weeks with CDF SelectBag Citrate®, with 1 mmol/L of citrate. Patients older than 18 years were included in HD for a minimum of 3 months by arteriovenous fistula. Epidemiological, dialysis, pre and postdialysis biochemistry, episodes of arterial hypotension, and coagulation scores were collected monthly during the 8 months of the study. Pre and post-dialysis analysis were extracted: venous blood gas, calcium (Ca), ionic calcium (Cai), phosphorus (P), magnesium (Mg) and parathyroid hormone (PTH) among others.ClinicalTrials.gov NCT03319680. Results: We included 56 patients, 47 (84%) men and 9 (16%) women, mean age: 65.3 (16.4) years, technique HD/HDF: 20 (35.7%)/36 (64.3%).We found differences (p < 0.05) when using the DF with citrate (C) versus acetate (A) in the postdialysis values of bicarbonate C: 26.9 (1.9) vs. A: 28.5 (3) mmol/L, Cai C: 1.1 (0.05) vs. A: 1.2 (0.08) mmol/L, Mg C: 1.8 (0.1) vs A: 1, 9 (0.2) mg/dL and PTH C: 255 (172) vs. 148 (149) pg/mL. We did not find any differences in any of the parameters measured before dialysis. Of the 4416 sessions performed, 2208 in each group, 311 sessions (14.1%) with ADF and 238 (10.8%) with CDF (p < 0.01), were complicated by arterial hypotension. The decrease in maximum blood volume measured by Hemoscan® biosensor was also lower −3.4 (7.7) vs −5.1 (8.2) although without statistical significance. Conclusion: Dialysis with citrate acutely produces less postdialysis alkalemia and significantly modifies Ca, Mg and PTH. CDF has a positive impact on hemodynamic tolerance. Resumen: Introducción: El líquido de diálisis (LD), elemento esencial en la hemodiálisis (HD), se fabrica in situ mezclando 3 componentes: agua tratada, concentrado de bicarbonato y concentrado ácido. Para evitar la precipitación de carbonato cálcico y magnésico que se produce en el LD por la adición de bicarbonato, es necesario añadir un ácido. Existen 2 concentrados ácidos según contengan acetato (LDA) o citrato (LDC) como estabilizante. Objetivo: Comparar el efecto agudo de la HD con LDC vs. LDA sobre el metabolismo del calcio, fosforo y magnesio, el equilibrio ácido base, la coagulación, inflamación y la estabilidad hemodinámica. Métodos: Estudio prospectivo, multicéntrico, aleatorizado y cruzado, de 32 semanas de duración, en pacientes en HD trisemanal, monitor AK-200-Ultra-S o Artis, 16 semanas con LDA SoftPac®, elaborado con 3 mmol/l de acetato, y 16 semanas con LDC SelectBag Citrate®, con 1 mmol/l de citrato. Se incluyeron pacientes mayores de 18 años en HD durante un mínimo de 3 meses mediante fístula arteriovenosa. Se recogieron datos epidemiológicos, de diálisis, bioquímica pre- y posdiálisis, episodios de hipotensión arterial, y scores de coagulación mensualmente durante los 8 meses de estudio. Se extrajeron pre- y posdiálisis: gasometría venosa, calcio (Ca), calcio iónico (Cai), fósforo (P), magnesio (Mg) y hormona paratiroidea (PTH), entre otros.ClinicalTrials.gov NCT03319680. Resultados: Se incluyeron 56 pacientes, 47 (84%) hombres y 9 (16%) mujeres de edad media: 65,3 (16,4) años, técnica HD/HDF: 20 (35,7%)/36 (64,3%).Encontramos diferencias (p < 0,05) cuando utilizamos el LD con citrato (C) frente a acetato (A) en los valores posdiálisis de bicarbonato C: 26,9 (1,9) vs. A: 28,5 (3) mmol/l, Cai C: 1,1 (0,05) vs A: 1,2 (0,08) mmol/l, Mg C. 1,8 (0,1) vs A: 1,9 (0,2) mg/dl y PTH C: 255 (172) vs. 148 (149) pg/ml. No encontramos diferencias en ninguno de los parámetros medidos prediálisis. Se registraron menos episodios de hipotensión arterial durante las sesiones con el LDC; de las 4.416 sesiones de HD, 2.208 en cada grupo, cursaron con hipotensión 311 sesiones (14,1%) con LDA y 238 (10,8%) con LDC (p < 0,01). También fue menor la caída de volumen sanguíneo máximo medido por biosensor Hemoscan® −3,4(7,7) vs. −5,1 (8,2), aunque sin significación estadística. Conclusión: La diálisis con citrato produce de forma aguda menor alcalemia posdiálisis y modifica de forma significativa el Ca, el Mg y la PTH. El LDC tiene un impacto positivo sobre la tolerancia hemodinámica. Keywords: Hemodialysis, Bicarbonate, Acetate, Citrate, Calcium, Magnesium, Arterial hypotension, Palabras clave: Hemodiálisis, Bicarbonato, Acetato, Citrato, Calcio, Magnesio, Hipotensión arterial
Fibropolycystic liver disease is characterized by hyperproliferation of the biliary epithelium and the formation of multiple dilated cysts, a process associated with unfolded protein response (UPR). ...In the present study, we aimed to understand the mechanisms of cyst formation and UPR activation in hepatocytic c-Jun N-terminal kinase 1/2 (
) knockout mice. Floxed JNK1/2 (
) and
animals were sacrificed at different time points during progression of liver disease. Histological examination of specimens evidenced the presence of collagen fiber deposition, increased α-smooth muscle actin (αSMA), infiltration of CD45, CD11b and F4/80 cells and proinflammatory cytokines (
,
) and liver injury (e.g., ALT, apoptosis and Ki67-positive cells) in
compared with
livers from 32 weeks of age. This was associated with activation of effectors of the UPR, including BiP/GRP78, CHOP and spliced XBP1. Tunicamycin (TM) challenge strongly induced ER stress and fibrosis in
animals compared with
littermates. Finally, thioacetamide (TAA) administration to
mice induced UPR activation, peribiliary fibrosis, liver injury and markers of biliary proliferation and cholangiocarcinoma (CCA). Orthoallografts of DEN/CCl
-treated
liver tissue triggered malignant CCA. Altogether, these results suggest that activation of the UPR in conjunction with fibrogenesis might trigger hepatic cystogenesis and early stages of CCA.
Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and ...cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.
Abstract
We present new maps of the Milky Way disk showing the distribution of metallicity (Fe/H),
α
-element abundances (Mg/Fe), and stellar age, using a sample of 66,496 red giant stars from the ...final data release (DR17) of the Apache Point Observatory Galactic Evolution Experiment survey. We measure radial and vertical gradients, quantify the distribution functions for age and metallicity, and explore chemical clock relations across the Milky Way for the low-
α
disk, high-
α
disk, and total population independently. The low-
α
disk exhibits a negative radial metallicity gradient of −0.06 ± 0.001 dex kpc
−1
, which flattens with distance from the midplane. The high-
α
disk shows a flat radial gradient in metallicity and age across nearly all locations of the disk. The age and metallicity distribution functions shift from negatively skewed in the inner Galaxy to positively skewed at large radius. Significant bimodality in the Mg/Fe–Fe/H plane and in the Mg/Fe–age relation persist across the entire disk. The age estimates have typical uncertainties of ∼0.15 in log(age) and may be subject to additional systematic errors, which impose limitations on conclusions drawn from this sample. Nevertheless, these results act as critical constraints on galactic evolution models, constraining which physical processes played a dominant role in the formation of the Milky Way disk. We discuss how radial migration predicts many of the observed trends near the solar neighborhood and in the outer disk, but an additional more dramatic evolution history, such as the multi-infall model or a merger event, is needed to explain the chemical and age bimodality elsewhere in the Galaxy.
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