Decoding clinical and molecular pathways of liver dysfunction in Psoriatic Arthritis: Impact of cumulative methotrexate doses.

BACKGROUND: The occurrence of liver abnormalities in Psoriatic Arthritis (PsA) has gained significant recognition. Identifying key factors at the clinical and molecular level can help to detect high-risk patients for non-alcoholic fatty liver disease in PsA. OBJECTIVES: to investigate the influence of PsA and cumulative doses of methotrexate on liver function through comprehensive in vivo and in vitro investigations. METHODS: A cross-sectional study involving 387 subjects was conducted, 200 patients with PsA, 87 NAFLD-non-PsA patients, and 100 healthy donors (HDs), age and sex-matched. Additionally, a retrospective longitudinal study was carried out, including 83 PsA patients since initiation with methotrexate. Detailed clinical, and laboratory parameters along with liver disease risk were analyzed. In vitro, experiments with hepatocyte cell line (HEPG2) were conducted. RESULTS: PsA patients present increased liver disease risk associated with the presence of cardiometabolic comorbidities, inflammatory markers, onychopathy, and psoriasis. The treatment with PsA serum on hepatocytes encompassed inflammatory, fibrotic, cell stress, and apoptotic processes. At the molecular level, methotrexate impacts liver biology, although the cumulative doses did not affect those alterations, causing any potential damage to liver function at the clinical level. Finally, anti-PDE-4 or anti-JAK decreased the inflammatory profile induced by PsA serum on hepatocytes. CONCLUSION: 1)This study identifies the complex link between liver disease risk, comorbidities, and disease-specific features in PsA patients. 2)Methotrexate dose in PsA patients had no significant effect on liver parameters, confirmed by hepatocyte in vitro studies. 3)Anti-PDE-4 and anti-JAK therapies show promise in reducing PsA serum-induced hepatocyte activation, potentially aiding liver complication management.

External multicentre validation of pseudomyxoma peritonei PSOGI-Ki67 classification.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignant disease. Adding of the Ki67 proliferation index to the PSOGI PMP classification provided two different subcategories of the extensive HG-PMP group (HG-PMP ≤15% and HG-PMP >15%) with different survival in a previous unicentric study. This study aims to carry out an external and multicentre validation of this new proposed classification. METHOD: It was a prospective analysis of samples from a historical and international cohort of patients. A representative area with higher cellular density was used to determine the Ki67%. The Ki67 proliferation index (%) was determined in all the HG-PMP patients. A Cox proportional hazard models and multivariable COX models were used. The Kaplan-Meier method and the two-tailed log-rank test were used to analyse the effect of different PSOGI-Ki67 categories on OS and DFS. Its predictive accuracy was analysed using Harrel's C-index and the ROC curve. The calibration was performed using the calibration plots matching. RESULTS: After exclusions, 349 patients were available for analysis. The 5-years OS were 86% for LG-PMP, 59% for HG-PMP≤15, 38% for HG-PMP>15 and 42% for SRC-PMP (p = 0.0001). The 5-years DFS were 49% for LG-PMP, 35% for HG-PMP≤15, 16% for HG-PMP>15 and 18% SRC-PMP (p = 0.0001). The discrimination capability of PSOGI-Ki67 was validated. CONCLUSION: the PSOGI-Ki67 classification discriminates and predicts the OS and DFS in patients with PMP dividing the HG-PMP category into two well-defined sub-categories. The Ki67 proliferation index should be incorporated routinely in the pathology report for these patients.

Dysregulation of the miRNome unveils a crosstalk between obesity and prostate cancer: miR-107 asa personalized diagnostic and therapeutic tool.

Prostate-specific antigen (PSA) is the gold-standard marker to screen prostate cancer (PCa) nowadays. Unfortunately, its lack of specificity and sensitivity makes the identification of novel tools to diagnose PCa an urgent medical need. In this context, microRNAs (miRNAs) have emerged as potential sources of non-invasive diagnostic biomarkers in several pathologies. Therefore, this study was aimed at assessing for the first time the dysregulation of the whole plasma miRNome in PCa patients and its putative implication in PCa from a personalized perspective (i.e., obesity condition). Plasma miRNome from a discovery cohort (18 controls and 19 PCa patients) was determined using an Affymetrix-miRNA array, showing that the expression of 104 miRNAs was significantly altered, wherein six exhibited a significant receiver operating characteristic (ROC) curve to distinguish between control and PCa patients (area under the curve [AUC] = 1). Then, a systematic validation using an independent cohort (135 controls and 160 PCa patients) demonstrated that miR-107 was the most profoundly altered miRNA in PCa (AUC = 0.75). Moreover, miR-107 levels significantly outperformed the ability of PSA to distinguish between control and PCa patients and correlated with relevant clinical parameters (i.e., PSA). These differences were more pronounced when considering only obese patients (BMI > 30). Interestingly, miR-107 levels were reduced in PCa tissues versus non-tumor tissues (n = 84) and in PCa cell lines versus non-tumor cells. In vitro miR-107 overexpression altered key aggressiveness features in PCa cells (i.e., proliferation, migration, and tumorospheres formation) and modulated the expression of important genes involved in PCa pathophysiology (i.e., lipid metabolism [i.e., FASN] and splicing process). Altogether, miR-107 might represent a novel and useful personalized diagnostic and prognostic biomarker and a potential therapeutic tool in PCa, especially in obese patients.

Splicing factor SF3B1 is overexpressed and implicated in the aggressiveness and survival of hepatocellular carcinoma.

Splicing alterations represent an actionable cancer hallmark. Splicing factor 3B subunit 1 (SF3B1) is a crucial splicing factor that can be targeted pharmacologically (e.g. pladienolide-B). Here, we show that SF3B1 is overexpressed (RNA/protein) in hepatocellular carcinoma (HCC) in two retrospective (n = 154 and n = 172 samples) and in five in silico cohorts (n > 900 samples, including TCGA) and that its expression is associated with tumor aggressiveness, oncogenic splicing variants expression (KLF6-SV1, BCL-XL) and decreased overall survival. In vitro, SF3B1 silencing reduced cell viability, proliferation and migration and its pharmacological blockade with pladienolide-B inhibited proliferation, migration, and formation of tumorspheres and colonies in liver cancer cell lines (HepG2, Hep3B, SNU-387), whereas its effects on normal-like hepatocyte-derived THLE-2 proliferation were negligible. Pladienolide-B also reduced the in vivo growth and the expression of tumor-markers in Hep3B-induced xenograft tumors. Moreover, SF3B1 silencing and/or blockade markedly modulated the activation of key signaling pathways (PDK1, GSK3b, ERK, JNK, AMPK) and the expression of cancer-associated genes (CDK4, CD24) and oncogenic SVs (KLF6-SV1). Therefore, the genetic and/or pharmacological inhibition of SF3B1 may represent a promising novel therapeutic strategy worth to be explored through randomized controlled trials.

Current status of multidisciplinary care in psoriatic arthritis in Spain: NEXUS 2.0 project. / Estado actual de la atención multidisciplinar para pacientes con artritis psoriásica en España: proyecto NEXUS 2.0.

OBJECTIVE: 1) To analyze the implementation of multidisciplinary care models in psoriatic arthritis (PsA) patients, 2) To define minimum and excellent standards of care. METHODS: A survey was sent to clinicians who already performed multidisciplinary care or were in the process of undertaking it, asking: 1) Type of multidisciplinary care model implemented; 2) Degree, priority and feasibility of the implementation of quality standards in the structure, process and result for care. In 6 regional meetings the results of the survey were presented and discussed, and the ultimate priority of quality standards for care was defined. At a nominal meeting group, 11 experts (rheumatologists and dermatologists) analyzed the results of the survey and the regional meetings. With this information, they defined which standards of care are currently considered as minimum and which are excellent. RESULTS: The simultaneous and parallel models of multidisciplinary care are those most widely implemented, but the implementation of quality standards is highly variable. In terms of structure it ranges from 22% to 74%, in those related to process from 17% to 54% and in the results from 2% to 28%. Of the 25 original quality standards for care, 9 were considered only minimum, 4 were excellent and 12 defined criteria for minimum level and others for excellence. CONCLUSIONS: The definition of minimum and excellent quality standards for care will help achieve the goal of multidisciplinary care for patients with PAs, which is the best healthcare possible.

Diagnostic performance of imaging-guided core needle biopsy of the mesentery and peritoneum. / Rentabilidad diagnóstica de la biopsia con aguja gruesa guiada por técnicas de imagen del mesenterio y del peritoneo.

OBJECTIVE: To evaluate the diagnostic performance of imaging-guided core needle biopsy of nodules and diffuse infiltration of the omentum or of the peritoneum. MATERIAL AND METHODS: We retrospectively evaluated 57 patients who underwent core needle biopsy of the peritoneum or of the omentum between March 2014 and January 2017. We used computed tomography (CT) to plan the biopsy. Biopsies were guided by CT or ultrasonography (US). We classified the results as diagnostic (benign / malignant) or inconclusive (inadequate sample). We calculated the sensitivity, specificity, positive-predictive value, and negative predictive value. We analyzed whether the specimen was diagnostic depending on the imaging technique used (CT or US) and on the type of omental or peritoneal involvement from which the specimen was obtained (mass, nodule, or diffuse involvement). RESULTS: All (100%) the percutaneous biopsies were diagnostic. The sensitivity of the technique was 98.18% and the specificity was 100%. The positive predictive value was 100% and the negative predictive value was 50%. Both the specimens obtained under CT guidance (n=10) and those obtained under US guidance (n=47) were diagnostic. Likewise, biopsies of masses (n=24), of nodules (n=17), and even of diffuse infiltration (n=16) of the peritoneum or omentum enabled the histologic diagnosis. The rate of complications was 1.75% (one death). CONCLUSION: Percutaneous core needle biopsy has high sensitivity regardless of the imaging technique used to guide the technique (CT or US) and of the type of lesion biopsied (mass, nodule, diffuse infiltration). It is a useful technique with a very low rate of complications, although severe complications can occur.

Diversidad antigénica de las vacunas antiparotiditicas / Antigenic diversity of vaccines againts mumps

La parotiditis es una enfermedad infecciosa inmunoprevenible  causada por el virus de la parotiditis, miembro del género Rubulavirus, familia Paramyxoviridae, del cual se conocen 12 genotipos confirmados, designados como A-L y otro nuevo genotipo designado como M. Las vacunas anti-parotiditis por lo general,  se fabrican empleando virus vivo atenuado de alguno de estos genotipos y están  disponibles como monovalente (parotiditis) y trivalente (sarampión-rubéola-parotiditis). A pesar de los programas de vacunación implementados por muchos países, se han presentado brotes de parotiditis en forma epidémica en la cual se ha detectado co-circulación de genotipos entre poblaciones vacunadas. Entre las posibles explicaciones  están: el fracaso primario a la vacunación, pérdida de efectividad secundaria e infección por virus heterólogos. Como consecuencia la Organización Mundial de la Salud (OMS) ha recomendado estudios moleculares epidemiológicos, que incluya la genotipificación de cepas circulantes del virus de la parotiditis, como parte del programa de vigilancia. Esto permitirá una mayor información de la distribución de los genotipos en todo el mundo, contribuyendo a la vigilancia de la parotiditis y posiblemente en la reformulación de vacunas más eficaces. Esta revisión muestra la importancia que tiene la caracterización molecular  o genotipificación del virus de la parotiditis, con el propósito de comprender y explicar el comportamiento epidemiológico de esta enfermedad que ha sido ampliamente controlada por la aplicación sistemática de la vacuna a nivel mundial.

Mumps is a vaccine-preventable infectious disease, caused by mumps virus, member of Rubulavirus genus, Paramyxoviridae family, has been classified into 12 confirmed genotypes, designated as A-L and one proposed genotype, M. Usually the anti-mumps vaccines are manufactured using attenuated live virus genotypes and any of these are available as monovalent (mumps) and trivalent (measles-mumps-rubella). Although vaccination programs implemented by many countries, there have been outbreaks of mumps in epidemic form, in which has been detected co-circulation of genotypes among vaccinated populations. Possible explanations are: the primary vaccination failure, loss of high effectiveness and heterologous virus infection. Because of this, the World Health Organization (WHO) has recommended molecular epidemiological studies, including genotyping of circulating strains of mumps virus as part of the monitoring program. This information will allow greater distribution of genotypes worldwide, contributing to monitoring and possibly mumps reformulating more effective vaccines. This review shows the importance of molecular characterization and genotyping of mumps virus, in order to understand and explain the epidemiological behavior of the disease has been largely controlled by the systematic application of the vaccine worldwide.

Polyphosphate binds to human von Willebrand factor in vivo and modulates its interaction with glycoprotein Ib.

BACKGROUND: Polyphosphate, a phosphate polymer released by activated platelets, has recently been described as a potent modulator of blood coagulation and fibrinolysis. In blood plasma, polyphosphate binds to and alters the biological functions of factor XII, fibrin(ogen), thrombin and factor VII activating protease. OBJECTIVES: The aim of the present study is to investigate whether polyphosphate also binds to von Willebrand factor (VWF) and alters some of its activities. METHODS/RESULTS: When studying patients with type 1 von Willebrand disease (VWD) and their healthy relatives, we discovered a significant correlation between von Willebrand factor (VWF) and platelet polyphosphate levels. We have also found polyphosphate in preparations of VWF isolated from normal platelets and plasma. Surface plasmon resonance and electrophoretic mobility assays indicated that polyphosphate interacts with VWF in a dose- and time-dependent manner. Treatment of normal plasma with active exopolyphosphatase decreased the VWF ristocetin cofactor (VWF:RCo) activity, a functional measure of VWF binding to platelet glycoprotein receptor Ib. VWF collagen binding and multimerization were unaltered after polyphosphate depletion. Moreover, addition of polyphosphate increased the deficient VWF:RCo activity presented by plasma from patients with type 1 VWD. CONCLUSIONS: Our results reveal that a new role is played by polyphosphate in hemostasis by its interaction with VWF, and suggest that this polymer may be effective in the treatment of some types of VWD.

Reducción de flora contaminante en alimentos mediante tratamiento con microondas / Flora of reduction in food contamination by treatment with microwave

La contaminación bacteriana de alimentos que se consumen en la calle servidas por expendedores ambulantes constituye una alternativa alimentaria para los trabajadores y estudiantes, pero a la vez es fuente de enfermedades trasmitidas por alimentos a los consumidores, para el estudio de la acción de hornos microondas sobre la contaminación de alimentos se tomaron setenta y siete (77) muestras de alimentos de la ciudad de Trujillo-Venezuela, colectadas en expendios (21 perros calientes, 32 empanadas y 24 arepas), tomadas en condiciones de asepsia se trasladaron en cadena de frío hasta el laboratorio para su estudio. De cada muestra se separaron dos partes, una para irradiarla con microondas durante un minuto para luego someterla al estudio bacteriológico y otra control sin el citado tratamiento. Se confirmó contaminación fecal en el 60% de las muestras examinadas, la exposición a microondas durante un minuto redujo en un 85,4% las cargas de bacterias coliformes. Los resultados demuestran la destrucción de bacterias en un 90% de perros calientes, 40% en empanadas y 66,6% de arepas que resultaron positivas. La acción del microondas sobre los alimentos resultó ser una técnica efectiva para reducir las cargas de bacterias contaminantes.

Food that is served by mobile stall and consumed on the street is a nutritional alternative for workers and students but, sometimes, the bacterial contamination of this “fast food” can be a diseasis transmitted by food to consumer. In this study of the effect of microwave ovens on the contamination of food, seventy-seven examples of “fast food” were collected from mobile stalls (twenty-one hot-dogs, thirty-two empanadas and twenty-for arepas). The sample were taken in aseptic conditions and transferred to the laboratory in cold storage. Each sample was divided into two parts. One part was irradiated with microwaves for one minute and the subjected to a bacteriological analysis. The other was not subjected to the radiation treatment. Fecal contamination was confirmed in 60% of the samples examined; the one minute exposure to microwaves reduced the levels of bacterial coliforms by 85.4%. The results revealed the destruction of bacteria in 90% of the hot-dogs, in 40% of the empanadas and in 66.6% of de arepas that were diagno-sed as positive. The effect of microwaves proved to be an effective technique in reducing the levels of bacterial conta-minants in food-stuffs.

[69 years old male patient, with impairment of physical condition, hyperpigmentation, cutaneous lesion and a deficient response to treatment]. / Varón de 69 años con afectación del estado general, hiperpigmentación, lesión cutánea y respuesta deficiente al tratamiento.

We submit the case of a male patient, suffering from a tuberculous ethiology adrenal primary insufficiency, showing a dermal lesion, in which necrotizing granulomas were found, and from which bacterial culture growth yielded mycobacterium bovis. Given the clinical findings, and awaiting for the bacterial culture result, a triple treatment with tuberculostatics was started, but had to be discontinued because of hepatic toxicity. After culture of cutaneous biopsy yielded micobaterium tuberculosis, treatment with streptomycin, rifampicin and etambutol was restarted. Three weeks later, in spite of increasing hydrocortisone dose to 40 mg, adrenal insufficiency reappeared. Under the circumstances, we chose to continue rifampicin and double hydrocortisone dose. The case is of concern because of the concurrency of three nowadays infrequent disorders: tuberculous ethiology adrenal insufficiency, cutaneous tuberculosis due to mycobacterium bovis and primary adrenal insufficiency due to rifampicin treatment, the latter resolved after increasing hydrocortisone dose.

Clinical features of late onset psoriatic arthritis.

The aim of this work is to compare the clinical and radiological manifestations of patients presenting late onset psoriatic arthritis (PsA) with early onset PsA. An overall of 96 consecutive PsA patients were studied over an 8-month-period. Clinical, laboratory and radiographic signs were assessed. Of the 96 patients studied, 84 had their earliest symptoms before the age of 60 (Group I) and 12 after it (Group II). In Group II the mean age was 65.7 years (range 60-73), the sex ratio (male/female) was 9/3. All patients were HLA-B27 negative; the clinical forms observed were: polyarticular (6 patients; 50%), oligoarticular (4 patients; 33%) and spondyloarthropathy (SpA) (2 patients; 17%). Only two patients had asymmetric sacroiliitis and three had history of dactylitis episodes. In conclusion, we found distinct clinical manifestations in late onset PsA. Peripheral affection was found predominant. The male/female ratio was higher than other age groups.

Characterization of VIP receptor-effector system antagonists in rat and mouse peritoneal macrophages.

In the present study we show that the synthetic peptides [4-Cl-D-Phe6,Leu17]VIP and the growth hormone releasing factor (GRF) analog [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 inhibit in a competitive manner the specific [125I]VIP binding to both rat and mouse peritoneal macrophages. In rat peritoneal macrophages, the order of potency of the different peptides, as expressed by the IC50 values was: VIP (IC50 = 1.90 +/- 0.16 nM) > [4-Cl-D-Phe6,Leu17]VIP (IC50 = 125.8 +/- 13.2 nM) > [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 (IC50 = 354.8 +/- 21.2 nM). In mouse peritoneal macrophages a similar pattern of potency was observed: VIP (IC50 = 1.58 +/- 0.12 nM) > [4-Cl-D-Phe6,Leu17]VIP (IC50 = 110.8 +/- 10.7 nM) > [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 (IC50 = 251 +/- 19.2 nM). The behavior as VIP receptor antagonists of both [4-Cl-D-Phe6,Leu17]VIP and [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2 in rat and mouse peritoneal macrophages was confirmed by: (a) the shift to the right of VIP dose-stimulated cyclic AMP production curves in the presence of the two antagonists; (b) the agreement between the order of efficacy of the two peptides in competition experiments with the corresponding inhibition of cyclic AMP production; (c) the inefficiency of the two antagonists on the stimulation of cyclic AMP production by the beta-adrenoceptor agonist isoproterenol, which indicates the specificity of the interaction; (d) the synergic effect of VIP on isoproterenol-stimulated cyclic AMP production was completely abolished by [4-Cl-D-Phe6,Leu17]VIP or [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2, suggesting that both antagonists acted via specific VIP receptors. Moreover, propranolol, a beta-adrenoceptor antagonist, did not affect the VIP-stimulated cyclic AMP production and the antagonist role of [4-Cl-D-Phe6,Leu17]VIP or [Ac-Tyr1,D-Phe2]GRF-(1-29)-NH2; (e) in cross-linking experiments, the intensity of the labeling of the [125I]VIP/receptor complexes was significantly lower with the antagonists than in the control experimental situation in both mouse and rat peritoneal macrophage membranes.

Santolindiacetylene, a polyacetylene derivative isolated from the essential oil of Santolina canescens.

The yield, composition, and some pharmacological activities (hepatoprotective and antioxidant) of the essential oil of Santolina canescens aerial parts have been investigated. The essential oil qualitative data were determined by gc and gc-ms. The main component, santolindiacetylene [1], was isolated and characterized by spectral methods, and the structure assigned as 1-(2'-naphthyl)hexa-2,4-diyne. The protective activities of the essential oil and its main component [1] were evaluated against carbon tetrachloride-induced hepatotoxicity in a rat model. In both cases a significant hepatoprotective effect was observed, as evident from the strong decrease of elevated GPT serum levels caused by carbon tetrachloride-induced hepatic damage.

Expression of VIP receptors in mouse peritoneal macrophages: functional and molecular characterization.

Receptors for VIP in mouse peritoneal macrophages (MPM) were examined using [125I]labeled VIP as ligand. The receptor binding was rapid, reversible, saturable, specific, and dependent on time, pH, temperature and cell concentration. At 15 degrees C, the stoichiometric data suggested the presence of two classes of VIP receptors with Kd values of 1.05 +/- 0.2 and 66.4 +/- 11.0 nM and binding capacities of 19.2 +/- 2.8 and 706.6 +/- 172.0 fmol VIP/10(6) cells. The interaction showed a high degree of specificity, as suggested by competition experiments with various peptides structurally related to VIP as follows: VIP > helodermin > rGRF > PHI >> secretin. Glucagon, pancreastatin, somatostatin, insulin, and octapeptide of cholecystokinin (CCK 26-33) were ineffective at concentrations as high as 1 microM. VIP was a potent and efficient stimulator of cyclic AMP production in MPM. The stimulation was observed at a concentration as low as 0.01 nM VIP. Half-maximal stimulation (ED50) was observed at 1.0 +/- 0.2 nM VIP, and maximal stimulation (three-fold above basal levels) was obtained between 0.1-1 microM. The cyclic AMP system of mouse peritoneal macrophages showed a high specificity for VIP. The order of potency observed in inducing cyclic AMP production was VIP > helodermin > rGRF > PHI >> secretin. Glucagon, insulin, pancreastatin, somatostatin and octapeptide of cholecystokinin did not modify cyclic AMP levels at concentrations as high as 1 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Gas exchange and water balance of a mistletoe species and its mangrove hosts.

The gas exchange and water relations of the hemiparasite Pthirusa maritima and two its mangrove host species, Conocarpus erectus and Coccoloba uvifera, were studied in an intertidal zone of the Venezuelan coast. Carbon uptake and transpiration, leaf osmotic and total water potential, as well as nutrient content in the xylem sap and leaves of mistletoes and hosts were followed through the dry and wet season. In addition, carbon isotope ratios of leaf tissue were measured to further evaluate water use efficiency. Under similar light and humidity conditions, mistletoes had higher transpiration rates, lower leaf water potentials, and lower water use efficiencies than their hosts. Potassium content was much higher in mistletoes than in host leaves, but mineral nutrient content in the xylem sap of mistletoes was relatively low. The resistance of the liquid pathway from the soil to the leaf surface of mistletoes was larger than the total liquid flow resistance of host plants. Differences in the daily cycles of osmotic potential of the xylem sap also indicate the existence of a high resistance pathway along the vascular connection between the parasite pathway along the vascular connection between the parasite and its host. P. maritima mistletoes adjust to the different physiological characteristics of the host species which it parasitizes, thus ensuring an adequate water and carbon balance.