Pacientes con enfermedad injerto contra huésped e infecciones asociadas al rechazo de trasplante / Patients with graft-versus-host disease and infections associated with transplant rejection

Introducción: durante muchos años las células madre hematopoyéticas han sido el tratamiento para muchos trastornos hematológicos, pero su eficacia está limitada por la enfermedad injerto contra huésped (EICH); una de las principales complicaciones del trasplante alogénico se encuentra asociado con morbilidad y mortalidad, por lo tanto, la prevención es importante para el éxito del trasplante alogénico. Objetivo: realizar una revisión acerca del reconocimiento clínico de una EICH para brindar el tratamiento correcto y evitar ciertas complicaciones, como infecciones que llevan al rechazo del injerto y ponen en riesgo la calidad de vida del paciente. En la mayoría de los casos las pruebas de laboratorio como biomarcadores y biopsias, son buenos predictores para procesos biológicos o patológicos que confirmen el diagnóstico y establezcan el estadio de la enfermedad. Metodología: se realizó una revisión bibliográfica en bases de datos, tales como Pubmed y ClinicalKey, con base en los siguientes términos MeSH: cirugía, mortalidad, patología, complicaciones, virología. Conclusión: la prevención y tratamiento de esta enfermedad predispone a infecciones y diferentes complicaciones que ponen en riesgo la vida del paciente.

Introduction: For many years hematopoietic stem cells have been the treatment for many hematological disorders, but their efficacy is limited by graft-versus-host disease (GVHD), one of the main complications of allogeneic transplantation associated with morbidity and mortality; therefore, prevention is important for the success of allogeneic transplantation. Objective: To review the clinical recognition of GVHD in order to provide the correct treatment and avoid certain complications, such as infections that lead to graft rejection and jeopardize the patient's quality of life. In most cases laboratory tests such as biomarkers and biopsies are good predictors of biological or pathological processes that confirm the diagnosis and establish the stage of the disease. Methodology: A bibliographic review was carried out in databases such as Pubmed and ClinicalKey based on the following MeSH terms: surgery, mortality, pathology, complications, virology. Conclusion: The prevention and treatment of this disease predisposes to infections and different complications that put the patient's life at risk.

New evidence for dietary fatty acids in the neutrophil traffic between the bone marrow and the peripheral blood.

Chronic administration of a high-fat diet in mice has been established to influence the generation and trafficking of immune cells such as neutrophils in the bone marrow, the dysregulation of which may contribute to a wide range of diseases. However, no studies have tested the hypothesis that a short-term, high-fat diet could early modulate the neutrophil release from bone marrow at fasting and at postprandial in response to a high-fat meal challenge, and that the predominant type of fatty acids in dietary fats could play a role in both context conditions. Based on these premises, we aimed to establish the effects of different fats [butter, enriched in saturated fatty acids (SFAs), olive oil, enriched in monounsaturated fatty acids (MUFAs), and olive oil supplemented with eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids] on neutrophil navigation from bone marrow to blood in mice. The analysis of cellular models for mechanistic understanding and of postprandial blood samples from healthy volunteers for translational purposes was assessed. The results revealed a powerful effect of dietary SFAs in promotion the neutrophil traffic from bone marrow to blood via the CXCL2-CXCR2 axis. Dietary SFAs, but not MUFAs or EPA and DHA, were also associated with increased neutrophil apoptosis and bone marrow inflammation. Similar dietary fatty-acid-induced postprandial neutrophilia was observed in otherwise healthy humans. Therefore, dietary MUFAs might preserve bone marrow health and proper migration of bone marrow neutrophils early in the course of high-fat diets even after the intake of high-fat meals.

CD4+ and CD8+ T-cell responses in bone marrow to fatty acids in high-fat diets.

Obesity is associated with disruptions in the adaptive immune system; however, dietary fatty acids in high-fat diets (HFDs) that induce obesity have consequences that are currently unclear regarding T-cell maintenance in bone marrow (BM). C57BL/6J mice were randomly assigned to isocaloric HFDs formulated with dietary fats rich in saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), or MUFAs supplemented with eicosapentaenoic and docosahexaenoic acids for 20 weeks, followed by an analysis of the immunophenotypic feature of lymphocytes (CD3+) T and their subsets CD4+ and CD8+ T cells in spleen and BM, identification of fatty acids in BM extracellular fluid and analysis of the correspondence between fatty acids with the frequency of T-cell subsets in BM. Splenic CD3+ T cells were reduced irrespective of HFDs. In BM, CD3+ T cells were reduced after HFD-SFAs, while CD4+ T cells were increased after HFDs enriched in MUFAs and CD8+ T cells were reduced irrespective of HFDs. In BM extracellular fluid, the content of palmitic and myristic acids increased after HFD-SFAs and that of oleic acid increased after HFDs enriched in MUFAs. There was a statistical correspondence between HFD-induced changes in fatty acids in BM extracellular fluid and HFD-induced changes in the frequency of CD3+ and CD4+ T cells in BM. These findings reveal an undervalued critical role for dietary fatty acids in the selective acquisition of T-cell subsets in BM, highlighting that oleic acid existing in the surroundings of T-cell niches during HFD-induced obesity could be instrumental in the maintenance of CD4+ T cells.

From Green Technology to Functional Olive Oils: Assessing the Best Combination of Olive Tree-Related Extracts with Complementary Bioactivities.

Our aim was to assess the combination of olive tree-related extracts with the most favorable profile of in vitro bioactive properties. We tested the antioxidant (increment of low-density lipoprotein resistance against oxidation), vasoactive (promotion of nitric oxide release and decrease of endothelin-1 production in human umbilical vein endothelial cells), anti-inflammatory (decrease of the endothelial production of vascular cell adhesion molecule-1), and antithrombotic (reduction of the endothelial release of plasminogen activator inhibitor-1) capacities of six phenolic extracts and three triterpenic acid solutions (Ps and Ts, respectively). We tested extracts alone and in combination, at nutritional (Ps: 0.05-0.5 µmol/L; Ts: 0.001-0.1 µmol/L) and nutraceutical doses (Ps: 1-10 µmol/L; Ts: 0.25-10 µmol/L). The combination of Ps rich in 3,4-dihydroxyphenylglycol (76%, P2), hydroxytyrosol (95%, P3), and oleuropein (70%, P4) (final nutritional concentration: 0.15 µmol/L; final nutraceutical concentration: 3 µmol/L) was the best in order to prepare functional products and nutraceuticals with cardioprotective properties, despite the fact that the isolated extract with the greatest in vitro properties was P5 (75% oleocanthal), suggesting a potential synergistic effect among different olive components.

Cardioprotective Effect of a Virgin Olive Oil Enriched with Bioactive Compounds in Spontaneously Hypertensive Rats.

Olive oil and its derivatives have been described to exert beneficial effects on hypertensive states and cardiovascular disease prevention. We studied the effects of chronic consumption of extra virgin olive oil (EVOO), enriched in bioactive compounds from olive fruit and leaves, on blood pressure, endothelial function, oxidative and inflammatory status, and circulating cholesterol levels, in spontaneously hypertensive rats (SHR). Thirty SHR were randomly assigned to three groups: a control untreated SHR group, an SHR group (1 mL/rat/day) of a control olive oil (17.6 mg/kg of phenolic compounds), and an SHR group (1 mL/rat/day) of the enriched EVOO (750 mg/kg of phenolic compounds) for eight weeks. Ten Wistar Kyoto rats (WKY) were included as healthy controls. Long-term administration of the enriched EVOO decreased systolic blood pressure and cardiac hypertrophy, and improved the ex vivo aortic endothelial dysfunction measured in SHR. Moreover, enriched oil supplementation reduced the plasma levels of Angiotensin II and total cholesterol, and the urinary levels of endothelin-1 and oxidative stress biomarkers, while pro-inflammatory cytokines were unaffected. In conclusion, sustained treatment with EVOO, enriched in bioactive compounds from the olive fruit and leaves, may be an effective tool for reducing blood pressure and cholesterol levels alone or in combination with pharmacological anti-hypertensive treatment.

Phytochemical Study and Evaluation of the Cytotoxic Properties of Methanolic Extract from Baccharis obtusifolia.

Some species of the Baccharis genus have been shown to possess important biomedical properties, including cytotoxic activity. In this study, we examined the cytotoxic effect of methanol extract from Baccharis obtusifolia (Asteraceae) in cancer cell lines of prostate (PC-3), colon (RKO), astrocytoma (D-384), and breast (MCF-7). The methanolic extract displayed the largest substantial cytotoxic effect in lines of colon cancer (RKO) and cerebral astrocytoma (D-384). Chromatographic purification of the B. obtusifolia methanolic extract led to the isolation and identification of 5,4'-dihydroxy-7-methoxyflavone (1) and 5-hydroxy-7,4'-dimethoxyflavone (2) compounds of the flavonoid type.

Tyrosol and its metabolites as antioxidative and anti-inflammatory molecules in human endothelial cells.

Tyrosol (Tyr) is a phenolic compound found in virgin olive oil. After ingestion, Tyr undergoes extensive first pass intestinal/hepatic metabolism. However, knowledge about the biological effects of Tyr metabolites is scarce. We chemically synthesized Tyr glucuronate (Tyr-GLU) and sulphate (Tyr-SUL) metabolites and explored their properties against oxidative stress and inflammation in TNF-α-treated human umbilical vein endothelial cells (hECs). Tyr and Tyr-SUL prevented the rise of reactive oxygen species, the depletion of glutathione, and the down-regulation of glutathione peroxidase 1, glutamate-cysteine ligase catalytic subunit, and heme oxygenase-1 genes. Tyr-SUL and to a lower extent Tyr and Tyr-GLU prevented the phosphorylation of NF-κB signaling proteins. Tyr-GLU and Tyr-SUL also prevented the over-expression of adhesion molecules at gene, protein, and secretory levels, and the adhesion (Tyr-SUL > Tyr-GLU) of human monocytes to hECs. In vivo, Tyr, and most notably Tyr-SUL in a dose-dependent manner, ameliorated plantar and ear edemas in mice models of acute and chronic inflammation. This study demonstrates the antioxidant and/or anti-inflammatory properties of Tyr metabolites, with Tyr-SUL being the most effective.

Medicinal plants used as anthelmintics: Ethnomedical, pharmacological, and phytochemical studies.

Intestinal parasites delay mental and physical development in children. Infection with these parasites can result in complications during pregnancy and alter the health of newborns, which has long-term effects on educational attainment and economic productivity. The appearance of resistance against classical drug treatments generates interest in the development of new deworming alternatives. We think that research of new plants species may reveal potential antiparasitic compounds. This review is focused on the use of plants and secondary metabolites against intestinal parasites. We discuss the use of plants in traditional medicine and the use of plant secondary metabolites tried in in vitro and in vivo models when available.

Virgin Olive Oil and Hypertension.

The incidence of high blood pressure (BP) along with other cardiovascular (CV) risk factors on human health has been studied for many years. These studies have proven a link between unhealthy dietary habits and sedentary lifestyle with the onset of hypertension, which is a hallmark of CV and cerebrovascular diseases. The Mediterranean diet, declared by the UNESCO as an Intangible Cultural Heritage since 2013, is rich in vegetables, legumes, fruits and virgin olive oil. Thanks to its many beneficial effects, including those with regard to lowering BP, the Mediterranean diet may help people from modern countries to achieve a lower occurrence of CV disease. Data from human and animal studies have shown that the consumption of virgin olive oil shares most of the beneficial effects of the Mediterranean diet. Virgin olive oil is the only edible fat that can be consumed as a natural fruit product with no additives or preservatives, and contains a unique constellation of bioactive entities, namely oleic acid and minor constituents. In this review, we summarize what is known about the effects of virgin olive oil on hypertension.

Membrane composition and dynamics: a target of bioactive virgin olive oil constituents.

The endogenous synthesis of lipids, which requires suitable dietary raw materials, is critical for the formation of membrane bilayers. In eukaryotic cells, phospholipids are the predominant membrane lipids and consist of hydrophobic acyl chains attached to a hydrophilic head group. The relative balance between saturated, monounsaturated, and polyunsaturated acyl chains is required for the organization and normal function of membranes. Virgin olive oil is the richest natural dietary source of the monounsaturated lipid oleic acid and is one of the key components of the healthy Mediterranean diet. Virgin olive oil also contains a unique constellation of many other lipophilic and amphipathic constituents whose health benefits are still being discovered. The focus of this review is the latest evidence regarding the impact of oleic acid and the minor constituents of virgin olive oil on the arrangement and behavior of lipid bilayers. We highlight the relevance of these interactions to the potential use of virgin olive oil in preserving the functional properties of membranes to maintain health and in modulating membrane functions that can be altered in several pathologies. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.

p38 MAPK protects human monocytes from postprandial triglyceride-rich lipoprotein-induced toxicity.

Postprandial triglyceride (TG)-rich lipoproteins (TRLs) transport dietary fatty acids through the circulatory system to satisfy the energy and structural needs of the tissues. However, fatty acids are also able to modulate gene expression and/or induce cell death. We investigated the underlying mechanism by which postprandial TRLs of different fatty acid compositions can induce cell death in human monocytes. Three types of dietary fat [refined olive oil (ROO), high-palmitic sunflower oil (HPSO), and butter] with progressively increasing SFA:MUFA ratios (0.18, 0.41, and 2.08, respectively) were used as a source of postprandial TRLs (TRL-ROO, TRL-HPSO, and TRL-BUTTER) from healthy men. The monocytic cell line THP-1 was used as a model for this study. We demonstrated that postprandial TRLs increased intracellular lipid accumulation (31-106%), reactive oxygen species production (268-349%), DNA damage (133-1467%), poly(ADP-ribose) polymerase 1 (800-1710%) and caspase-3 (696-1244%) activities, and phosphorylation of c-Jun NH2-terminal kinase (JNK) (54 kDa, 141-288%) and p38 (24-92%). These effects were significantly greater with TRL-BUTTER, and TRL-ROO did not induce DNA damage, DNA fragmentation, or p38 phosphorylation. In addition, blockade of p38, but not of JNK, significantly decreased intracellular lipid accumulation and increased cell death in postprandial TRL-treated cells. These results suggest that in human monocytes, p38 is involved in survival signaling pathways that protect against the lipid-mediated cytotoxicity induced by postprandial TRLs that are abundant in saturated fatty acids.

Gastrointestinal stromal tumors (GISTs): role of CD 117 and PDGFRA Golgi-like staining pattern in the recognition of mutational status.

AIMS: to determine whether potential correlations between CD117 and PDGFRA might serve as an indication for targeted therapies. MATERIAL AND METHODS: immunohistochemical expression of CD117 and PDGFRA was evaluated in 99 paraffin-embedded GISTs in conjunction with KIT and PDGFRA mutational status. RESULTS: CD117-positive staining was noted in 93 out of 99 cases. The predominant staining pattern was cytoplasmic, either with or without membrane accentuation; in 44.5% of cases, a clear Golgi-like pattern was evident. Correlations were found between KIT mutation and both CD117 expression (p = 0.006) and Golgi-like pattern (p = 0.026). Cytoplasmic PDGFRA-positive staining was detected in 87% of cases, both with and without membrane accentuation; in 8% cases an evident Golgi-like staining pattern was observed. A significant correlation was noted between PDGFRA mutations and Golgi-like staining pattern (p = 0.001). Moreover, 95% of PDGFRA-positive GISTs were also CD117-positive, suggesting that expression of the two markers is not mutually exclusive; most of these had mutations in KIT exon 11. PDGFRA-positive/CD117-negative tumors had mutations in PDGFRA, mainly in exon 18. PDGFRA-negative/CD117-negative staining was observed in 15% of cases, all of which displayed mutations in KIT exon 11. CD117-positive/PDGFRA-negative cases were characterized by mutations in KIT, mainly in exon 11. CONCLUSIONS: CD117 and PDGFRA staining are not exclusive, and the presence of a Golgi-like staining pattern for either, whilst not pathognomonic, is highly suggestive of KIT and PDGFRA mutated GISTs, respectively, and may be used with some reservations as an alternative indication for prescribing targeted therapies.

Gastrointestinal stromal tumors: morphological, immunohistochemical and molecular changes associated with kinase inhibitor therapy.

Recurrent or metastatic GISTs are currently treated with kinase inhibitors since they achieves disease control in 70-85% of patients but this response depend on KIT and PDGFRA gene mutation status. We review the morfological and molecular findings associated to kinase inhibitors administration in GISTs based on the literature on Medline and authors' own experience. The initial response to kinase inhibitors (imatinib mesylate, Gleevec, Novartis) usually is partial and depend on the mutational KIT or PDGFRA state. Amongst patients wih KIT mutations, the best results are achived in those harboring exon 11 (85%) and exon 9 (45%) mutations. GISTs harboring PDGFRA gene mutations generally respond favorably except those involving the Asp842Val mutation. In the absence of KIT/PDGFRA gene mutations, partial response or disease stabilization is reported in 23% and 50% of patients, respectively, and disease progression in 19%. Histological examination of tumors displaying an initial response to imatinib reveals a highly-variable reduction in the number of tumor cells, a decline in the proliferative index, myxohyaline or sclerohyaline stroma, and a varying degree of bleeding and edema, necrosis and cystification. 72% of patients with initial good response to imatinib, display metastases or new nodule growth within an existing clinically-quiescent tumor after 12-36 months of treatment. This secondary resistance is characterized by a number of well-defined morphological and molecular changes. Histologically, the new growths display increased mitotic activity, pleomorphism, an epithelioid or mixed phenotype and persistent KIT expression although more rarely, dedifferentiation and loss of KIT expression (Fig. 4), as well as trans-differentiation into a rhabdomyosarcoma or epithelial phenotype has been reported. Molecularly, 46-67% of patients present additional KIT mutations, generally in the kinase domain (exons 13, 14 and 17) but also in the ATP-binding domain (exons 15,16) of the same allele. Secondary PDGFRA mutations are very rare. Secondary mutations have not been observed in GISTs not harboring KIT/PDGFRA mutations, or in tumors displaying an unusual morphology or loss of CD117 expression. A number of studies highlight the presence of different resistance mutations within different new tumor nodules, as well as the simultaneous development of distinct resistant tumor subclones within a single lesion (acquired polyclonal resistance). Secondary mutation in genes other than KIT/PDGFRA has only been reported in BRAF (Val600Glu).

The flavonol isorhamnetin exhibits cytotoxic effects on human colon cancer cells.

The aim of this study was to determine whether isorhamnetin, an immediate 3'-O-methylated metabolite of quercetin, affects proliferation, cell death, and the cell cycle of human colon carcinoma (HCT-116) cells. Isorhamnetin was found to be a potent antiproliferative agent in a dose- and time-dependent manner, with an IC50 of 72 µM after 48 h of incubation as estimated by MTT assay. Flow cytometry and fluorescence microscopy analysis showed that isorhamnetin exerted a stimulatory effect on apoptosis and necrosis. Isorhamnetin also increased the number of cells in G2/M phase. Serum deprivation appeared to potentiate the effects of isorhamnetin on cell death and facilitated cell cycle progression to G0/G1 phase. These results suggest that isorhamnetin might mediate inhibition of HCT-116 cell growth through the perturbation of cell cycle progression and are consistent with the notion that G2/M checkpoints could be a conserved target for flavonoids in human colon cancer cells, leading to apoptotic and necrotic death. These antiproliferative, apoptotic, necrotic, and cell cycle effects suggest that isorhamnetin may have clinically significant therapeutic and chemopreventive capabilities. To our knowledge, this is the first report of the effect of isorhamnetin on human colon cancer cells.

[Assessment of dietary habits related to iodine intake and iodine concentration and thyroid dysfunction in a non-preselected population in Spain (the Thyrobus Project)]. / Evaluación de los hábitos alimentarios relacionados con la ingesta de yodo, el estado nutricional de yodo y disfunción tiroidea en cuatro poblaciones no seleccionadas (proyecto Tirobus).

INTRODUCTION: Most of the studies on urinary iodine levels in Spain in the last decade have reported a significant improvement. A survey was undertaken together with an information campaign on the thyroid gland, the importance of iodine intake and hypothyroidism in four Spanish cities. The goals of the survey were to obtain information on consumption of iodine-containing foods, to measure urinary iodine levels and to evaluate the prevalence of thyroid dysfunction. MATERIALS AND METHODS: A non-preselected population attending the information campaign centers located in Barcelona, La Coruña, Malaga and Madrid was studied. A questionnaire on fish, milk and iodized salt consumption was administered. Urinary iodine levels (Pino's method) and thyrotropin (TSH) concentrations (Whatman 903® dry paper method) were measured. RESULTS: A total of 872 questionnaires were completed (Madrid 40%; La Coruña 27%; Malaga 19%; and Barcelona 14%). The mean age was 51 years (SD 16); 81% were women. A total of 60.6% of interviewees reported they consumed iodized salt, 90.8% reported daily milk intake and 29.3% reported fish consumption ≥3 times per week. The mean urinary iodine concentration was 143.2 µg/L. The prevalence of high TSH levels (>4 mUI/L) was 1.3% and that of low TSH levels (<0.4 mUI/mL) was 1.2%. CONCLUSIONS: According to the World Health Organization criteria, the median urinary iodine concentration, both overall or by city, is indicative of optimal iodine intake. In addition to iodized salt intake, consumption of products such as milk and fish has probably contributed to these positive results. The prevalences of undiagnosed hyperthyroidism and hypothyroidism detected in this study were similar to those found in other studies.

3,4-Dihydroxyphenylglycol (DHPG): an important phenolic compound present in natural table olives.

The presence of 3,4-dihydroxyphenylglycol (DHPG) was studied in 32 samples and 10 different cultivars of natural table olives, using an accurate method to avoid wrong quantification. Hydroxytyrosol (HT), tyrosol, and verbascoside were also quantified, as these four compounds comprise the majority of the chromatographic profile. Analyses were carried out by HPLC-DAD-UV after extraction of all phenolics, and hydroxytyrosol was the major component in nearly all samples. High levels of DHPG (up to 368 mg/kg of dry weight) were found in the pulp of natural black olives independent of cultivar and processing method, similar to its concentration in the brine in almost all of the samples. The presented data for this antioxidant indicate that natural table olives are a rich source of DHPG and hydroxytyrosol, compounds with interesting nutritional and antioxidant properties.

Antioxidant activity of ethanolic extracts from several asparagus cultivars.

Three different methods (antiradical activity, inhibition of primary oxidation, and ferric reducing power) have been used to evaluate the antioxidant activity of eight different asparagus cultivars and byproducts: white and green asparagus from Alcalá del Río (Guadalquivir Valley, Seville) and American hybrids, native spears, and their byproducts from Huétor-Tájar (Vega de Granada). The correlation between antioxidant activity and total phenol content was studied. Six standards were also tested to validate the modified methods for antioxidant activity determination. Results obtained for antiradical capacity and reducing power were very similar, and a high correlation with phenols was found (R > or = 0.9 for both tests). Sample origin was an important factor, spears from Huétor-Tájar having higher values (ARC between 7 and 10 and P(R) of 0.25-0.33) than those from Alcalá del Río (ARC 0.6-2 and P(R) of 0.05-0.07). Significant differences were found between spears with the same origin, suggesting that genetics are another factor to take into account. Asparagus inhibits lipid primary oxidation, but no correlation between the inhibition percentage and phenols was observed. Asparagus origin was the only factor that led to significant differences: samples from Huétor-Tájar had higher values (POIC between 18 and 32) than those from Alcalá del Río (POIC of 5-9). Byproducts from the canning industry at Huétor-Tájar were also assayed for antioxidant activity; the results obtained suggested that byproducts could be considered as an excellent source of natural antioxidants.