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Biosorption is an alternative procedure to remove metal ions from aqueous media using agricultural waste. In this work, the adsorption capacity and removal efficiency of agave bagasse (AB) toward Pb(II), Cd(II), and Zn(II) were analyzed. Parameters such as equilibrium pH, particle size, AB dosage, time, and initial metal ion concentration were discussed. The results showed that pH 5.5, 0.4 g (<250 μm), and only 15 min of contact assured conditions for maximum adsorption capacity. The kinetic studies were fitted to the pseudo-second-order model, whereas the isotherms showed good agreement with the Langmuir model. AB has a higher affinity for Pb(II) over Cd(II) and Zn(II), and the maximum adsorption capacities were 93.14, 28.50, and 24.66 mg g -1 , respectively. The results of the characterization evidenced two adsorption mechanisms. Scanning electron microscopy and X-ray diffraction displayed adsorption via the ion exchange mechanism by releasing Ca(II). The 13 C cross-polarization mode with magic-angle spinning nuclear magnetic resonance analysis demonstrated a complexation mechanism by cellulose, hemicellulose, and lignin groups with Pb(II) and Cd(II), whereas the complexation is mainly observed by cellulose groups for Zn(II). AB is a good alternative for the removal of metals without prior thermal or chemical treatment, with rapid kinetics, suitable adsorption capacity, and high removal efficiency contributing to waste management., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Pulses are a staple food cultivated since ancient times, which play an important role in the human diet. From a nutritional point of view, pulses are very interesting foods as they are rich in proteins, carbohydrates and dietary fibre. Dietary antioxidants are a complex mixture of hydrophilic and lipophilic compounds usually present in foods of plant origin, including pulses. In the present study, the phytochemical composition of selected pulses (common beans, fava beans, lentils, chickpeas, peas and lupins) has been reviewed in terms of their content of antioxidant compounds. The content of hydrosoluble antioxidants (organic acids, phenolic compounds), liposoluble antioxidants (tocopherols, carotenoids) and other compounds which exert antioxidant properties, such as dietary fibre and minerals (zinc, selenium), has been studied, reporting that pulses are an interesting source of these compounds, which have important health benefits, including a preventing role in cardiovascular diseases, anticarcinogenic or neuroprotective properties. It is important to take into account that pulses are not usually consumed raw, but they must be processed before consumption in order to improve their nutritional quality and their palatability, therefore, the effect of different technological and heat treatments (germination, cooking, boiling, extrusion) on the antioxidant compounds present in pulses has been also reviewed. In this regard, it has been observed that as a consequence of processing, the content of phytochemicals with antioxidant properties is usually decreased, but processed pulses maintain relevant amounts of these compounds, preserving their beneficial health effect., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The nutritional values, the identification of individual phenolic compounds as well as the functional properties (in vitro acetylcholinesterase (AChE) and pancreatic lipase inhibition) of Tunisian Feijoa sellowiana (O.Berg) leaves were determined by high-performance liquid chromatography coupled with diode array and mass spectrometry detector. Feijoa Sellowiana  leaves Extract (FSLE) were evaluated in the present work. Macronutrient components (proteins, carbohydrates, dietary fiber, lipids, and ashes) of FSLE as well as their fatty acids and mineral content were determined. The individual phenolic composition was characterized by the presence of flavonols (mostly quercetin glycosides), flavan-3-ols (procyanidins and catechins), and phenolic acid derivatives. To understand the possible inhibition mechanism exerted by the extract components, enzyme kinetic studies using derived Lineweaver-Burk (LB) plots and Michaelis-Menten were performed. The obtained results evidenced that FSLE exhibited important AChE inhibitory effect, behaving as a noncompetitive inhibitor. Furthermore, the leaves' extract inhibited irreversibly the pancreatic lipase, with maximum inhibition (70%) achieved at 1 mg/ml. PRACTICAL APPLICATIONS: In many countries of the world, Feijoa Sellowiana leaves are used as an alternative to tea drinks and as a folkloric medicine. Moreover, it is well known that the phytochemical compounds are a practical alternative for the prevention of many chronic diseases such as Alzheimer's and obesity. For this reason, the present study aimed to evaluate the nutritional, individual phenolic compounds, and functional properties of Feijoa Sellowiana leaves to valorize them as a food and pharmaceutical bioactive human source., (© 2019 Wiley Periodicals, Inc.)

Dietary fiber (DF) includes the remnants of the edible part of plants and analogous carbohydrates that are resistant to digestion and absorption in the human small intestine with complete or partial fermentation in the human large intestine. DF can be classified into two main groups according to its solubility, namely insoluble dietary fiber (IDF) that mainly consists on cell wall components, including cellulose, some hemicelluloses, lignin and resistant starch, and soluble dietary fiber (SDF) that consists of non-cellulosic polysaccharides as non-digestible oligosaccharides, arabinoxylans (AX), β-glucans, some hemicelluloses, pectins, gums, mucilages and inulin. The intake of DF is associated with health benefits. IDF can contribute to the normal function of the intestinal tract and it has an important role in the prevention of colonic diverticulosis and constipation. SDF is extensively fermented by gut microbiota and it is associated with carbohydrate and lipid metabolism, with important health benefits due to its hypocholesterolemic properties. Due to these nutritional and health properties, DF is widely used as functional ingredients in food industry, being whole grain cereals, pulses, fruits and vegetables the main sources of DF. Also some synthetic sources are employed, namely polydextrose, hydroxypropyl methylcellulose or cyclodextrins. The DF content of cereals varies depending on cultivars, their botanical components (pericarp, emdosperm and germ) and the processing conditions they have undergone (baking, extrusion, etc.). In cereal grains, AX are the predominant non-cellulose DF polysaccharides followed by cellulose and β-glucans, while in pseudocereals, pectins are quantitatively predominant., (© 2019 Elsevier Inc. All rights reserved.)

Innate lymphoid cells (ILCs) have been characterized as innate immune cells capable to modulate the immune response in the mucosae. Human ILCs have been rarely described in secondary lymphoid organs except in tonsils. Moreover, their function and phenotype in human secondary lymphoid organs during autoimmune diseases have never been studied. We took advantage of splenectomy as a treatment of immune thrombocytopenia (ITP) to describe and compare splenic ILC from 18 ITP patients to 11 controls. We first confirmed that ILC3 represented the most abundant ILC subset in human non-inflamed spleens, accounting for 90% of total ILC, and that they were mostly constituted of NKp44 - cells. On the contrary, proportions of ILC1 and ILC2 in spleens were lower than in blood. Splenic IL-2- and IFN-γ-producing ILC1 were increased in ITP. While the frequencies of total splenic ILC3 were similar in the two groups, splenic GM-CSF-producing ILC3 were increased in ITP. This is the first description of human ILC in a major secondary lymphoid organ during an autoimmune disease, ITP. We observed an expansion of splenic ILC1 that could participate to the Th1 skewing, while the increased production of GM-CSF by splenic ILC3 could stimulate splenic macrophages which play a key role in ITP pathophysiology., (Copyright © 2018. Published by Elsevier Ltd.)

The nutritional values and phytochemical composition of young shoots of wild Asparagus stipularis Forssk. from Tunisia were determined in this study. The antioxidant (tested by four different in vitro assays) and antiproliferative properties (against human tumour cell lines) of aqueous and hydroalcoholic extracts of the young shoots were also investigated. The obtained results indicated that the young shoots are a potential source of valuable nutrients and dietary fiber, and their hydroalcoholic extract showed marked antioxidant and antiproliferative activities in all tested assays. The major phenolic compound, characterized by using a high-performance liquid chromatograph coupled with diode-array and mass spectrometer detectors, in both extracts was diferuloyl glycerol. Our results reinforce the interest in recovering the traditional culinary uses of this wild plant, with potential functional properties, which can be included in the modern diet as an alternative to the variety of vegetables normally used.

Pulses are well known to be gluten-free functional foods that provide a rich source of nutritional and healthy compounds with antioxidant-promoting activity. In the present study, the bioactive compounds, dietary fibre, arabinoxylans, individual phenolic compounds and tocopherols, were evaluated in different lentil flours (raw and extruded at 140 and 160 °C) formulated with nutritional yeasts, along with the changes induced by the extrusion process. The total dietary fibre and arabinoxylan content significantly (p < 0.05) increased after the extrusion process while a significant decrease of all tocopherol isoforms was also observed. Catechin, caffeic, kaempferol and quercetin derivatives were identified in the raw and extruded lentil flours. The decreases of total phenolic and individual phenolic compounds were directly related to the extrusion temperature; total phenolics and catechin hexoside exhibited a larger decrease in the lentil flours formulated with higher content of nutritional yeast (12 and 16%). The antioxidant activity results, determined using different assays, reflected the important effect of extrusion processing and food ingredients.

B cells are involved in immune thrombocytopenia (ITP) pathophysiology by producing antiplatelet auto-antibodies. However more than a half of ITP patients do not respond to B cell depletion induced by rituximab (RTX). The persistence of splenic T follicular helper cells (TFH) that we demonstrated to be expanded during ITP and to support B cell differentiation and antiplatelet antibody-production may participate to RTX inefficiency. Whereas it is well established that the survival of TFH depends on B cells in animal models, nothing is known in humans yet. To determine the effect of B cell depletion on human TFH, we quantified B cells and TFH in the spleen and in the blood from ITP patients treated or not with RTX. We showed that B cell depletion led to a dramatic decrease in splenic TFH and in CXCL13 and IL-21, two cytokines predominantly produced by TFH. The absolute count of circulating TFH and serum CXCL13 also decreased after RTX treatment, whatever the therapeutic response. Therefore, we showed that the maintenance of TFH required B cells and that TFH are not involved in the inefficiency of RTX in ITP., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

CD8(+) T cells participate in the pathogenesis of some vasculitides. However, little is known about their role in Giant Cell Arteritis (GCA). This study was conducted to investigate CD8(+) T cell involvement in the pathogenesis of GCA. Analyses were performed at diagnosis and after 3 months of glucocorticoid treatment in 34 GCA patients and 26 age-matched healthy volunteers. Percentages of CD8(+) T-cell subsets, spectratype analysis of the TCR Vβ families of CD8(+) T cells, levels of cytokines and chemokines and immunohistochemistry of temporal artery biopsies (TAB) were assessed. Among total CD8(+) T cells, percentages of circulating cytotoxic CD8 T lymphocytes (CTL, CD3(+)CD8(+)perforin(+)granzymeB(+)), Tc17 (CD3(+)CD8(+)IL-17(+)), CD63(+)CD8(+) T cells and levels of soluble granzymes A and B were higher in patients than in controls, whereas the percentage of Tc1 cells (CD3(+)CD8(+)IFN-γ(+)) was similar. Moreover, CD8(+) T cells displayed a restricted TCR repertoire in GCA patients. Percentages of circulating CTL, Tc17 and soluble levels of granzymes A and B decreased after treatment. CXCR3 expression on CD8(+) T cells and its serum ligands (CXCL9, -10, -11) were higher in patients. Analyses of TAB revealed high expression of CXCL9 and -10 associated with infiltration by CXCR3(+)CD8(+) T cells expressing granzyme B and TiA1. The intensity of the CD8 T-cell infiltrate in TAB was predictive of the severity of the disease. This study demonstrates the implication and the prognostic value of CD8(+) T-cells in GCA and suggests that CD8(+) T-cells are recruited within the vascular wall through an interaction between CXCR3 and its ligands., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Adoptive transfer of immunosuppressive cells has emerged as a promising strategy for the treatment of immune-mediated disorders. However, only a limited number of such cells can be isolated from in vivo specimens. Therefore efficient ex vivo differentiation and expansion procedures are critically needed to produce a clinically relevant amount of these suppressive cells., Objective: We sought to develop a novel, clinically relevant, and feasible approach to generate ex vivo a subpopulation of human suppressor cells of monocytic origin, referred to as human monocyte-derived suppressive cells (HuMoSCs), which can be used as an efficient therapeutic tool to treat inflammatory disorders., Methods: HuMoSCs were generated from human monocytes cultured for 7 days with GM-CSF and IL-6. The immune-regulatory properties of HuMoSCs were investigated in vitro and in vivo. The therapeutic efficacy of HuMoSCs was evaluated by using a graft-versus-host disease (GvHD) model of humanized mice (NOD/SCID/IL-2Rγc(-/-) [NSG] mice)., Results: CD33+ HuMoSCs are highly potent at inhibiting the proliferation and activation of autologous and allogeneic effector T lymphocytes in vitro and in vivo. The suppressive activity of these cells depends on signal transducer and activator of transcription 3 activation. Of therapeutic relevance, HuMoSCs induce long-lasting memory forkhead box protein 3-positive CD8+ regulatory T lymphocytes and significantly reduce GvHD induced with human PBMCs in NSG mice., Conclusion: Ex vivo-generated HuMoSCs inhibit effector T lymphocytes, promote the expansion of immunosuppressive forkhead box protein 3-positive CD8+ regulatory T cells, and can be used as an efficient therapeutic tool to prevent GvHD., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

T lymphocytes activated by dendritic cells (DC) which present tumor antigens play a key role in the antitumor immune response. However, in patients suffering from active cancer, DC are not efficient at initiating and supporting immune responses as they participate to T lymphocyte inhibition. DC in the tumor environment are functionally defective and exhibit a characteristic of immature phenotype, different to that of DC present in nonpathological conditions. The mechanistic bases underlying DC dysfunction in cancer responsible for the modulation of T-cell responses and tumor immune escape are still being investigated. Using two different mouse tumor models, we showed that tumor-infiltrating DC (TIDC) are constitutively immunosuppressive, exhibit a semimature phenotype, and impair responder T lymphocyte proliferation and activation by a mechanism involving CD39 ectoenzyme.

Antiplatelet-antibody-producing B cells play a key role in immune thrombocytopenia (ITP) pathogenesis; however, little is known about T-cell dysregulations that support B-cell differentiation. During the past decade, T follicular helper cells (TFHs) have been characterized as the main T-cell subset within secondary lymphoid organs that promotes B-cell differentiation leading to antibody class-switch recombination and secretion. Herein, we characterized TFHs within the spleen of 8 controls and 13 ITP patients. We show that human splenic TFHs are the main producers of interleukin (IL)-21, express CD40 ligand (CD154), and are located within the germinal center of secondary follicles. Compared with controls, splenic TFH frequency is higher in ITP patients and correlates with germinal center and plasma cell percentages that are also increased. In vitro, IL-21 stimulation combined with an anti-CD40 agonist antibody led to the differentiation of splenic B cells into plasma cells and to the secretion of antiplatelet antibodies in ITP patients. Overall, these results point out the involvement of TFH in ITP pathophysiology and the potential interest of IL-21 and CD40 as therapeutic targets in ITP., (© 2014 by The American Society of Hematology.)

Background: The forced expiratory volume at first second (FEV(1)) during spirometry reflects the severity of chronic obstructive pulmonary disease (COPD) and is known to be an important prognostic factor. It is uncertain whether the response to short-acting bronchodilators may predict long-term outcomes such as hospitalizations and mortality., Methods: We retrospectively studied a total of 1203 consecutive COPD patients without significant comorbidities during a mean (±SD) of 69 ± 39 months of follow-up. At baseline the subjects were classified as those with positive or negative bronchodilator test (BDT) and also in quartiles of absolute bronchodilator response to 400 μg of salbutamol. Hospital visits and mortality were the end points., Results: A positive bronchodilator test was observed in 332 (27.6%) of the patients. There were 73 (21.9%) deaths in patients with a positive BDT versus 253 (28.7%) in those with a negative BDT (p = 0.04). In adjusted Cox regression analysis a positive BDT was significantly associated with a prolonged time to first hospitalization. After stratifying the population by quartiles of response to BDT, a dose-response relationship was observed with the best outcomes in the quartile with highest level of airflow reversibility, even after controlling for age, sex, BMI, smoking status and baseline postbronchodilator FEV(1)., Conclusions: In a large population of well characterized COPD patients without significant comorbidities, those demonstrating higher levels of reversibility at baseline presented better long-term outcomes even after controlling for other known prognostic factors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The pathogenic role of B cells in immune thrombocytopenia (ITP) has justified the therapeutic use of anti-CD20 antibodies such as rituximab (RTX). However, 60% of ITP patients do not respond to RTX. To decipher the mechanisms implicated in the failure of RTX, and because the spleen plays a well-recognized role in ITP pathogenesis, 12 spleens from ITP patients who had been nonresponders to RTX therapy were compared with 11 spleens from RTX-untreated ITP patients and 9 controls. We here demonstrate that in RTX-nonresponder ITP patients, preferential Th1 and Tc1 T lymphocyte polarizations occur, associated with an increase in splenic effector memory CD8(+) T-cell frequency. Moreover, in the RTX- nonresponder patient group, the CD8(+) T-cell repertoire displays a restricted pattern. In the blood, the phenotype of CD8(+) T cells before and after RTX treatment is not modified in responders or nonresponders. Altogether, these results demonstrate for the first time an activation of splenic CD8(+) T cells in ITP patients who did not respond to RTX and suggest their involvement in platelet destruction in these patients.

Objective: Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4+ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR)., Methods: A prospective study of the phenotype and the function of major CD4+ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew., Results: Compared with control subjects, patients with GCA and patients with PMR had a decreased frequency of Treg cells and Th1 cells, whereas the percentage of Th17 cells was significantly increased. Furthermore, an analysis of temporal artery biopsy specimens obtained from patients affected by GCA for whom biopsy results were positive demonstrated massive infiltration by Th17 and Th1 lymphocytes without any Treg cells. After glucocorticoid treatment, the percentages of circulating Th1 and Th17 cells decreased, whereas no change in the Treg cell frequency was observed. The frequency of CD161+CD4+ T cells, which are considered to be Th17 cell precursors, was similar in patients and control subjects. However, these cells highly infiltrated GCA temporal artery biopsy specimens, and their ability to produce interleukin-17 in vitro was significantly enhanced in patients with GCA and patients with PMR and was correlated with a decrease in the phosphorylated form of STAT-1., Conclusion: This study is the first to demonstrate that the frequency of Treg cells is decreased in patients with GCA and patients with PMR, and that CD161+CD4+ T lymphocytes, differentiated into Th1 cells and Th17 cells, are involved in the pathogenesis of GCA and PMR., (Copyright © 2012 by the American College of Rheumatology.)

Objective: From an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti-interleukin-6 (anti-IL-6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL-6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL-6 blockade on the balance between Th17 cells and Treg cells in patients with active RA., Methods: Patients with active RA for whom TCZ had been prescribed by a rheumatologist were enrolled in this study. Phenotypic analyses of T cell populations were performed, and the Disease Activity Score in 28 joints (DAS28) was assessed. Serum cytokine levels and other parameters of inflammation were measured before the first infusion and after the third infusion of TCZ (8 mg/kg)., Results: Compared to controls, levels of Th17 cells (CD4+IL-17+) were increased and Treg cells (CD4+CD25(high) FoxP3+) were decreased in the peripheral blood of patients with active RA. The suppressive function of circulating Treg cells was not impaired in patients with active RA. TCZ treatment induced a significant decrease in the DAS28 associated with a significant decrease in the percentage of Th17 cells (from a median of 0.9% to 0.45%; P = 0.009) and an increase in the percentage of Treg cells (from a median of 3.05% to 3.94%; P = 0.0039) in all patients., Conclusion: This study demonstrates for the first time that inhibition of IL-6 function by TCZ corrects the imbalance between Th17 cells and Treg cells in patients with RA., (Copyright © 2012 by the American College of Rheumatology.)

Immune thrombocytopenia (ITP) is an autoimmune disease with a complex pathogenesis. As in many B cell-related autoimmune diseases, rituximab (RTX) has been shown to increase platelet counts in some ITP patients. From an immunologic standpoint, the mode of action of RTX and the reasons underlying its limited efficacy have yet to be elucidated. Because splenectomy is a cornerstone treatment of ITP, the immune effect of RTX on this major secondary lymphoid organ was investigated in 18 spleens removed from ITP patients who were treated or not with RTX. Spleens from ITP individuals had follicular hyperplasia consistent with secondary follicles. RTX therapy resulted in complete B-cell depletion in the blood and a significant reduction in splenic B cells, but these patients did not achieve remission. Moreover, whereas the percentage of circulating regulatory T cells (Tregs) was similar to that in controls, splenic Tregs were reduced in ITP patients. Interestingly, the ratio of proinflammatory Th1 cells to suppressive Tregs was increased in the spleens of patients who failed RTX therapy. These results indicate that although B cells are involved in ITP pathogenesis, RTX-induced total B-cell depletion is not correlated with its therapeutic effects, which suggests additional immune-mediated mechanisms of action of this drug.

Known for years as professional APCs, dendritic cells (DCs) are also endowed with tumoricidal activity. This dual role of DC as killers and messengers may have important implications for tumor immunotherapy. However, the tumoricidal activity of DCs has mainly been investigated in animal models. Cancer cells inhibit antitumor immune responses using numerous mechanisms, including the induction of immunosuppressive/ tolerogenic DCs that have lost their ability to present Ags in an immunogenic manner. In this study, we evaluated the possibility of generating tumor killer DCs from patients with advanced-stage cancers. We demonstrate that human monocyte-derived DCs are endowed with significant cytotoxic activity against tumor cells following activation with LPS. The mechanism of DC-mediated tumor cell killing primarily involves peroxynitrites. This observed cytotoxic activity is restricted to immature DCs. Additionally, after killing, these cytotoxic DCs are able to activate tumor Ag-specific T cells. These observations may open important new perspectives for the use of autologous cytotoxic DCs in cancer immunotherapy strategies.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder that occurs in elderly patients. One of the main diagnostic criteria is the accumulation of heterogeneous monocytes in the peripheral blood. We further explored this cellular heterogeneity and observed that part of the leukemic clone in the peripheral blood was made of immature dysplastic granulocytes with a CD14(-)/CD24(+) phenotype. The proteome profile of these cells is dramatically distinct from that of CD14(+)/CD24(-) monocytes from CMML patients or healthy donors. More specifically, CD14(-)/CD24(+) CMML cells synthesize and secrete large amounts of alpha-defensin 1-3 (HNP1-3). Recombinant HNPs inhibit macrophage colony-stimulating factor (M-CSF)-driven differentiation of human peripheral blood monocytes into macrophages. Using transwell, antibody-mediated depletion, suramin inhibition of purinergic receptors, and competitive experiments with uridine diphosphate (UDP)/uridine triphosphate (UTP), we demonstrate that HNP1-3 secreted by CD14(-)/CD24(+) cells inhibit M-CSF-induced differentiation of CD14(+)/CD24(-) cells at least in part through P2Y6, a receptor involved in macrophage differentiation. Altogether, these observations suggest that a population of immature dysplastic granulocytes contributes to the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the differentiation capabilities of monocytes.

Background: Acquired somatic deletions and loss-of-function mutations in one or several codons of the TET2 (Ten-Eleven Translocation-2) gene were recently identified in hematopoietic cells from patients with myeloid malignancies, including myeloproliferative disorders and myelodys-plastic syndromes. The present study was designed to determine the prevalence of TET2 gene alterations in chronic myelomonocytic leukemias., Design and Methods: Blood and bone marrow cells were collected from 88 patients with chronic phase chronic myelomonocytic leukemia and from 14 with acute transformation of a previously identified disease. Polymerase chain reaction analysis and direct sequencing were used to sequence exons 3 to 11 of the TET2 gene. Annotated single nucleotide polymorphisms were excluded. Survival curves were constructed by the Kaplan-Meier method., Results: We detected TET2 mutations in 44 of 88 (50%) patients with chronic myelomonocytic leukemia, which suggests that TET2 gene mutations are especially frequent in this myeloid disease. A TET2 gene alteration was identified in 18 of the 43 patients studied at diagnosis and was associated with a trend to a lower overall survival rate; confining the analysis to the 29 patients with chronic myelomonocytic leukemia-1, according to the WHO classification, the difference in overall survival between patients with or without TET2 gene mutations became statistically significant., Conclusions: TET2 gene alterations are more frequent in chronic myelomonocytic leukemia than in other subgroups of hematopoietic diseases studied so far and could negatively affect the patients' outcome. The striking association between TET2 gene alterations and monocytosis, already observed in patients with systemic mastocytosis, could indicate a negative role of TET2 in the control of monocytic lineage determination.

The differentiation of human peripheral blood monocytes into resident macrophages is driven by colony-stimulating factor-1 (CSF-1), which upon interaction with CSF-1 receptor (CSF-1R) induces within minutes the phosphorylation of its cytoplasmic tyrosine residues and the activation of multiple signaling complexes. Caspase-8 and -3 are activated at day 2 to 3 and contribute to macrophage differentiation, for example, through cleavage of nucleophosmin. Here, we show that the phosphatidylinositol-3 kinase and the downstream serine/threonine kinase AKT connect CSF-1R activation to caspase-8 cleavage. Most importantly, we demonstrate that successive waves of AKT activation with increasing amplitude and duration are required to provoke the formation of the caspase-8-activating molecular platform. CSF-1 and its receptor are both required for oscillations in AKT activation to occur, and expression of a constitutively active AKT mutant prevents the macrophage differentiation process. The extracellular receptor kinase 1/2 pathway is activated with a coordinated oscillatory kinetics in a CSF-1R-dependent manner but plays an accessory role in caspase activation and nucleophosmin cleavage. Altogether, CSF-1 stimulation activates a molecular clock that involves phosphatidylinositol-3 kinase and AKT to promote caspase activation. This oscillatory signaling pathway, which is coordinated with extracellular receptor kinase 1/2 oscillatory activation, involves CSF-1 and CSF-1R and controls the terminal differentiation of macrophages.

Aims: The aim of our study was to assess the spontaneous outcome of acute myocarditis associated with severe cardiac dysfunction in children, as well as to compare these features with those occurring in adult patients., Methods: Fifty patients consecutively diagnosed of acute myocarditis during the last 7 years in our hospital were studied; 15 patients were children younger than 14 years, and 35 were adults. Immunosuppressive therapy was not used in any patient., Results: Mean age was 2 +/- 3 years in children, ranging from 2 months to 12 years. One patient required temporary pacing for a third-degree atrioventricular block, while the remaining 14 children had severe congestive heart failure, with a left ventricular ejection fraction of 30 +/- 12% (16 to 44%). After a mean follow-up of 21 +/- 26 months, only 3 children died, at 1, 4 and 10 months after the initial diagnosis. Death was sudden in all 3 patients. Left ventricular ejection fraction rose to 45 +/- 14% at 1 month after diagnosis, and to 58 +/- 15% at the end of follow-up. Unfavorable evolution (death or evolution to chronic dilated cardiomyopathy, with a left ventricular ejection fraction < 45%) occurred in 6 children (40%) at 1 month after diagnosis and in only 4 (25%) at the end of follow-up. The 9 children with 1-month favorable outcome were alive and had an ejection fraction > 45% at long-term, while only 2 of the 6 children with 1-month unfavorable outcome were alive and had an ejection fraction > 45% at long-term. Only the 3 children who died had an ejection fraction < 30% at 1-month. Favorable outcome was more frequent in children that in adult patients with acute myocarditis (75% versus 46%)., Conclusions: The outcome of acute myocarditis with severe cardiac dysfunction was favorable in a majority of pediatric patients; this favorable evolution was less frequent in adults. Patients in whom left ventricular ejection fraction did not increase at short-term had a higher risk of death, and they should probably be considered for heart transplantation.

To assess the incidence of a specific etiology and the role of methods for specific etiologic diagnosis in patients with primary acute pericarditis, we studied 100 patients with primary acute pericarditis consecutively admitted to our hospital between 1991 and 1993. A general diagnostic protocol was performed in all patients, whereas only pericardiocentesis was performed in patients with clinical cardiac tamponade or an unfavorable course with anti-inflammatory drugs. Surgical drainage and pericardial biopsy was performed in patients with tamponade relapse. A specific etiology was discovered in 22 patients (22%) (neoplasms in 7, tuberculosis in 4, other infections in 3, collagen diseases in 3, thyroid disorders in 4, and dissecting aortic aneurysm in 1). The general diagnostic protocol led to a specific diagnosis in 15 patients (68% of all patients with specific acute pericarditis) and pericardiocentesis in the other 7 patients (32%). The role of a diagnostic protocol, therapeutic pericardiocentesis, and diagnostic pericardiocentesis was similar and complementary. Pericardial biopsy results were negative in the 5 patients in whom it was performed. Cardiac tamponade and an unfavorable clinical outcome were significantly (p < 0.001) associated with the finding of a specific etiology; when both features were combined, sensitivity was 86% and specificity 85%, positive predictive value 63% and negative predictive value 96%. We conclude that the specific etiology in patients with primary acute pericarditis is about 20% to 25%, and that about 90% of these specific cases can be discovered by using the described systematic diagnostic protocol only in patients with an unfavorable outcome (cardiac tamponade or poor clinical course).

Introduction and Objectives: Sudden death is not uncommon in patients with severe congestive heart failure. The aim of our study was to assess the incidence, mechanisms and clinical predictors of sudden death in a large series of patients with severe congestive heart failure evaluated for heart transplantation., Methods: With this aim we have reviewed our experience on 240 consecutive patients with severe heart failure studied in our hospital from May 1986 to June 1992. Heart failure was due to ischemic heart disease in 35% of patients and idiopathic dilated cardiomyopathy in 65%. Age was 47 +/- 12 years, left ventricular ejection fraction was 20 +/- 6%, and symptom class was IV in 88% of patients and III in 12%., Results: Sixty-eight of the 240 patients (28%) died without transplantation. Death was sudden in 21 patients (31% of deaths, and 9% of all patients), due to heart failure in 41 (68%), and due to malignancy (ampuloma) in 1 (1%). Mechanism of sudden death could be identified in 12 cases: ventricular tachycardia/fibrillation in 8 and bradycardia/electromechanical dissociation in 4. On multivariate analysis (stepwise logistic regression), a lower tolerated captopril dosage (p = 0.004), a lower systolic blood pressure (p = 0.079) and a history of a ventricular tachycardia/fibrillation (p = 0.073) were independent predictors of sudden death., Conclusions: It seems possible to identify, between patients with severe heart failure, a subgroup of patients at higher risk for sudden death by means of such simple clinical parameters.

Introduction and Aims: Brain death causes myocardial impairment by some mechanisms not yet well understood. The aim of this work was to assess the echocardiographic features found in these patients and their implication in donor selection for heart transplantation., Methods: With this aim, we have studied 38 consecutive patients with brain death assessed as possible donors for heart transplant in our hospital in the last 3 years. Age was 23 +/- 13 years; 77% were male. No history of cardiac disease was present in any patient. An adequate transthoracic echocardiogram was obtained in 74% of patients; transesophageal view was used in the remaining 26%., Results: Echocardiogram was strictly normal in only 14 patients (37%). Mild valvular alterations were found in 5 patients (13%); a dilated aortic root in 1 (3%); moderate concentric left ventricular hypertrophy in 5 (14%); mild pericardial effusion in 1 (3%); mild septal hypokinesia with normal left ventricular ejection fraction in 4 (10%); abnormal left ventricular diastolic function in 7 (18%); and diffuse hypokinesia with ejection fraction less than 60% in 14 (37%). In 7 patients (18%) ejection fraction was lower than 40% (one of them was cocaine-addict). Mean ejection fraction was 59 +/- 15% (23 to 83%). Only 2 of the 19 (10%) donor hearts implanted in our hospital showed early dysfunction after transplant, but no relation to pretransplant ejection fraction was found. Ejection fraction increased from 62% pretransplant to 73% at one week after transplant in the other 17 cases., Conclusions: Brain death commonly causes alterations of left ventricular function, and this impairment is severe in almost 20% of cases. These echocardiographic features must be known when selection of donors for heart transplantation is concerned.

Introduction and Aims: Although uncommonly, infective endocarditis in non-addict patients may involve people without predisponente heart disease. The aim of our study was to assess the clinical and prognostic features of this type of endocarditis and to compare them with those of the more common type of endocarditis with underlying lesion., Methods: With this aim, we have reviewed 71 consecutive cases of non-addict infective endocarditis diagnosed in our hospital in the last 7 years; there was no preexisting cardiac lesion in 9 patients (13% of all endocarditis and 21% of native valve endocarditis), while underlying heart disease, including mitral valve prolapse, was present in the remaining 62 patients., Results: Mean age was significantly lower in 9 patients without preexistent lesion (28 +/- 18 versus 46 +/- 17 years, p < 0.01), while there was no differences for gender. Infection involved the aortic valve in 56%, the tricuspid or pulmonary valve in 33% and the mitral valve in only 11% of the patients without underlying cardiopathy (for 44%, 4% and 49%, respectively, in patients with cardiopathy). Staphylococcus aureus caused 67% of cases in patients without cardiopathy and only 9% in those with cardiopathy. Surgery was required in a similar proportion by both groups of patients (55% and 56%), although mortality was more than twice higher in patients with prior cardiac lesions (25% versus 11%)., Conclusions: A significant proportion of non-addict infective endocarditis involves patients without predisponente heart disease. These cases have some differential features (younger age, aortic and right heart valves involvement, S. aureus as the main causative agent and lower mortality) in comparison to those of endocarditis in patients with underlying cardiopathy.

We report a case of a patient with an aortic prosthetic valve who had Q fever endocarditis, glomerulonephritis and rapidly progressive renal failure. He was seen in 1987 and successfully treated by heart valve surgery and a one-year course of doxycycline. Five years later, the patient had another episode of Q fever endocarditis, involving the native mitral valve, complicated with acute renal failure and severe mitral regurgitation that required hemodialysis and mitral valve replacement. The outcome was again successful. This case report raises the question of whether Q fever endocarditis can be eradicated, and also the required duration of antibiotic therapy for this disease.

Q fever (Coxiella burnetii) is an uncommon cause of culture-negative infective endocarditis. Four cases of Q fever endocarditis diagnosed at our hospital in the last 7 years are reported (8% of all infective endocarditis). Infection involved a prosthetic heart valve in 3 cases (15% of all prosthetic valve endocarditis), and one patient with single ventricle and pulmonary stenosis in the remaining case. Important complications developed in all cases, and 3 patients underwent cardiac surgery. Mortality was 50%. Some diagnostic and therapeutical aspects of this disease are discussed.