Transcriptional profiling of whole blood identifies a unique 5-gene signature for myelofibrosis and imminent myelofibrosis transformation.

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Hans Carl Hasselbalch

Full Text Available Identifying a distinct gene signature for myelofibrosis may yield novel information of the genes, which are responsible for progression of essential thrombocythemia and polycythemia vera towards myelofibrosis. We aimed at identifying a simple gene signature - composed of a few genes - which were selectively and highly deregulated in myelofibrosis patients. Gene expression microarray studies have been performed on whole blood from 69 patients with myeloproliferative neoplasms. Amongst the top-20 of the most upregulated genes in PMF compared to controls, we identified 5 genes (DEFA4, ELA2, OLFM4, CTSG, and AZU1, which were highly significantly deregulated in PMF only. None of these genes were significantly regulated in ET and PV patients. However, hierarchical cluster analysis showed that these genes were also highly expressed in a subset of patients with ET (n = 1 and PV (n = 4 transforming towards myelofibrosis and/or being featured by an aggressive phenotype. We have identified a simple 5-gene signature, which is uniquely and highly significantly deregulated in patients in transitional stages of ET and PV towards myelofibrosis and in patients with PMF only. Some of these genes are considered to be responsible for the derangement of bone marrow stroma in myelofibrosis. Accordingly, this gene-signature may reflect key processes in the pathogenesis and pathophysiology of myelofibrosis development.

Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis

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Barbui, T; Thiele, J; Vannucchi, A M; Tefferi, A

2015-01-01

The 2001/2008 World Health Organization (WHO)-based diagnostic criteria for polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) were recently revised to accomodate new information on disease-specific mutations and underscore distinguishing morphologic features. In this context, it seems to be reasonable to compare first major diagnostic criteria of the former WHO classifications for myeloproliferative neoplasm (MPN) and then to focus on details that have been discussed and will be proposed for the upcoming revision of diagnostic guidelines. In PV, a characteristic bone marrow (BM) morphology was added as one of three major diagnostic criteria, which allowed lowering of the hemoglobin/hematocrit threshold for diagnosis, which is another major criterion, to 16.5 g/dl/49% in men and 16 g/dl/48% in women. The presence of a JAK2 mutation remains the third major diagnostic criterion in PV. Subnormal serum erythropoietin level is now the only minor criterion in PV and is used to capture JAK2-unmutated cases. In ET and PMF, mutations that are considered to confirm clonality and specific diagnosis now include CALR, in addition to JAK2 and MPL. Also in the 2015 discussed revision, overtly fibrotic PMF is clearly distinguished from early/prefibrotic PMF and each PMF variant now includes a separate list of diagnostic criteria. The main rationale for these changes was to enhance the distinction between so-called masked PV and JAK2-mutated ET and between ET and prefibrotic early PMF. The proposed changes also underscore the complementary role, as well as limitations of mutation analysis in morphologic diagnosis. On the other hand, discovery of new biological markers may probably be expected in the future to enhance discrimination of the different MPN subtypes in accordance with the histological BM patterns and corresponding clinical features

MODALITY OF TREATMENT IN ESSENTIAL THROMBOCYTHEMIA

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Lana Macukanovic-Golubovic

2008-10-01

Full Text Available Essential thrombocytosis (ET is clonal chronic myeloproliferative disorder which originates from abnormality of a multipotent hematopoietic stem cell.It is characterized by an increased platelet count, megakaryocytic hyperplasia and by hemorrhagic or thrombotic tendency. Symptoms and signs may include weakness, headaches, paresthesias, bleeding, splenomegaly, and digital ischemia. ET patients showed equal or slightly shorter survival than age- and sex-matched healthy population. Major causes of death were thrombotic and hemorrhagic complications or malignant progression due to both the natural history of the disease and, possibly, the use of chemotherapeutic agents.Diagnostic criteria for essential thrombocythemia were proposed in 2005 by the PVSG and demand diagnosis of exclusion.Myelosuppressive therapy to lower the platelet count usually consists of hydroxyurea, interferon alpha or anagrelide. Hydroxyurea is the most commonly used treatment, because of its efficacy, low cost and rare acute toxicity. Interferon alpha is a biological response modifier. It is not known to be teratogenic and does not cross the placenta, and is often the treatment of choice during pregnancy. Anagrelid suppresses bone marrow megakaryocytes by interfering with the maturation process and decreasing platelet production without affecting other blood cell lines. Low-dose aspirin may be used to control microvascular symptoms.Recommendations for management of patients with essential thrombocythemia were given by ASH. From a treatment standpoint, hydroxyurea is now confirmed to be the drug of choice for high-risk patients with essential thrombocythemia. Interferon alpha and anagrelide are reasonable second-line agents. Low-risk patients should receive low-dose aspirin alone. For the intermediate-risk patients, a consensus could not be reached on a recommendation for platelet-lowering treatment.

Essential thrombocythemia in a child: diagnostic and therapeutic dilemma.

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Asghar, Ramyar; Behzad, Elahi; Mohammad, Golsorkhtabar-Amiri

2005-11-01

We report an 11-year-old child with essential thrombocythemia ET, a very rare myeloproliferative disorder among children. Essential thrombocythemia can be complicated by life-threatening thrombosis with a risk of converting into acute leukemia. Cytoreductive therapy may reduce the risk of thromboembolic complications. We usually recommend cytoreductive treatment for asymptomatic adult patients with platelet counts of more than 1.5 million/micro liter, but treatment remains obscure in children. Herein, we report the results of child with ET, treated successfully with hydroxuea.

Treatment and management of myelofibrosis in the era of JAK inhibitors

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Keohane C

2013-08-01

Full Text Available Clodagh Keohane, Deepti H Radia, Claire N HarrisonDepartment of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UKAbstract: Myelofibrosis (MF can present as a primary disorder or evolve from polycythemia vera (PV or essential thrombocythemia (ET to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT, the use of cytoreductive agents (ie, hydroxyurea, splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs, androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment.Keywords: myelofibrosis, ruxolitinib, JAK inhibitor

Assessment of rotation thromboelastometry parameters in patients with essential thrombocythemia at diagnosis and after hydroxyurea therapy.

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Treliński, Jacek; Okońska, Marta; Robak, Marta; Chojnowski, Krzysztof

2016-03-01

Patients with essential thrombocythemia suffer from thrombotic complications that are the main source of mortality. Due to its complex pathogenesis, no existing single laboratory method is able to identify the patients at highest risk for developing thrombosis. Twenty patients with essential thrombocythemia at diagnosis, 15 healthy volunteers and 20 patients treated with hydroxyurea were compared with regard to certain rotation thromboelastometry parameters. Clotting time (CT), clot formation time (CFT), α-angle, and maximum clot firmness (MCF) were assessed by using the INTEM, EXTEM, FIBTEM, and NATEM tests. Patients with essential thrombocythemia at diagnosis demonstrated significantly higher mean platelet count and markedly lower mean red blood count than controls. CT and CFT readings were found to be markedly lower in essential thrombocythemia patients at diagnosis than in the control group according to the EXTEM test. Patients at diagnosis had markedly lower CT values (EXTEM, FIBTEM) than patients on hydroxyurea therapy. Alpha angle values were markedly higher in essential thrombocythemia patients at diagnosis than in controls, according to the EXTEM, FIBTEM and NATEM tests. MCF readings were significantly higher in essential thrombocythemia patients at diagnosis than in controls according to EXTEM, INTEM, FIBTEM, and NATEM tests. Patients on hydroxyurea therapy had markedly lower MCF values according to EXTEM test than patients at diagnosis. Patients with essential thrombocythemia demonstrate a prothrombotic state at the time of diagnosis, which is reflected in changes by certain rotation thromboelastometry parameters. The hydroxyurea therapy induces downregulation of the prothrombotic features seen in essential thrombocythemia patients at diagnosis.

Whole blood transcriptional profiling reveals deregulation of oxidative and antioxidative defence genes in myelofibrosis and related neoplasms. Potential implications of downregulation of Nrf2 for genomic instability and disease progression

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Hasselbalch, Hans Carl; Thomassen, Mads; Riley, Caroline Hasselbalch

2014-01-01

The Philadelphia-negative chronic myeloproliferative neoplasms - essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) (MPNs) - have recently been shown to be associated with chronic inflammation, oxidative stress and accumulation of reactive oxygen species (ROS). Using...

Treatment and management of myelofibrosis in the era of JAK inhibitors.

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Keohane, Clodagh; Radia, Deepti H; Harrison, Claire N

2013-01-01

Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment.

Generation of human iPSCs from an essential thrombocythemia patient carrying a V501L mutation in the MPL gene.

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Liu, Senquan; Ye, Zhaohui; Gao, Yongxing; He, Chaoxia; Williams, Donna W; Moliterno, Alison; Spivak, Jerry; Huang, He; Cheng, Linzhao

2017-01-01

Activating point mutations in the MPL gene encoding the thrombopoietin receptor are found in 3%-10% of essential thrombocythemia (ET) and myelofibrosis patients. Here, we report the derivation of induced pluripotent stem cells (iPSCs) from an ET patient with a heterozygous MPL V501L mutation. Peripheral blood CD34 + progenitor cells were reprogrammed by transient plasmid expression of OCT4, SOX2, KLF4, c-MYC plus BCL2L1 (BCL-xL) genes. The derived line M494 carries a MPL V501L mutation, displays typical iPSC morphology and characteristics, are pluripotent and karyotypically normal. Upon differentiation, the iPSCs are able to differentiate into cells derived from three germ layers. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Optimal therapy for polycythemia vera and essential thrombocythemia

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Silver, Richard T; Hasselbalch, Hans K

2016-01-01

Objectives: To determine the value of recombinant interferon-alfa (rIFNα) in the treatment of polycythemia vera (PV) and essential thrombocythemia (ET) based on its biological activities and phase 2 clinical studies, pending completion of phase 3 trials; to determine importance of the Internet...

A Rare Presentation of Extramedullary Hematopoiesis in Post-polycythemic Myelofibrosis

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Konca Degertekin, Ceyla; Özkurt, Zübeyde Nur; Akyürek, Nalan; Yağcı, Münci

2012-01-01

Polycythemia vera is a clonal proliferative disorder of the bone marrow that could possibly evolve into myelofibrosis in its natural course. Progression to myelofibrosis is usually a late stage complication and presents clinically with refractory cytopenias and extramedullary hematopoiesis (EMH). EMH can occur in any tissue during the course of post-polycythemic myelofibrosis. However, skin and cardiac involvements seems to be very rare. We present a 56-year-old woman with post-polycythemic m...

A Rare Presentation of Extramedullary Hematopoiesis in Post-polycythemic Myelofibrosis.

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Konca Degertekin, Ceyla; Ozkurt, Zübeyde Nur; Akyürek, Nalan; Yağcı, Münci

2014-09-01

Polycythemia vera is a clonal proliferative disorder of the bone marrow that could possibly evolve into myelofibrosis in its natural course. Progression to myelofibrosis is usually a late stage complication and presents clinically with refractory cytopenias and extramedullary hematopoiesis (EMH). EMH can occur in any tissue during the course of post-polycythemic myelofibrosis. However, skin and cardiac involvements seems to be very rare. We present a 56-year-old woman with post-polycythemic myelofibrosis refractory to treatment, developing EMH after splenectomy in various organs, exceptionally the skin and the heart. Along with the case, the clinical presentations, treatment options, prognostic significance of EMH and the role of cytogenetics is discussed in the light of the literature.

Screening for MPL mutations in essential thrombocythemia and primary myelofibrosis: normal Mpl expression and absence of constitutive STAT3 and STAT5 activation in MPLW515L-positive platelets.

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Glembotsky, Ana C; Korin, Laura; Lev, Paola R; Chazarreta, Carlos D; Marta, Rosana F; Molinas, Felisa C; Heller, Paula G

2010-05-01

To evaluate the frequency of MPL W515L, W515K and S505N mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF) and to determine whether MPLW515L leads to impaired Mpl expression, constitutive STAT3 and STAT5 activation and enhanced response to thrombopoietin (TPO). Mutation detection was performed by allele-specific PCR and sequencing. Platelet Mpl expression was evaluated by flow cytometry, immunoblotting and real-time RT-PCR. Activation of STAT3 and STAT5 before and after stimulation with increasing concentrations of TPO was studied by immunoblotting. Plasma TPO was measured by ELISA. MPLW515L was detected in 1 of 100 patients with ET and 1 of 11 with PMF. Platelets from the PMF patient showed 100% mutant allele, which was Mpl surface and total protein expression were normal, and TPO levels were mildly increased in the MPLW515L-positive ET patient, while MPL transcripts did not differ from controls in both MPLW515L-positive patients. Constitutive STAT3 and STAT5 phosphorylation was absent and dose response to TPO-induced phosphorylation was not enhanced. The low frequency of MPL mutations in this cohort is in agreement with previous studies. The finding of normal Mpl levels in MPLW515L-positive platelets indicates this mutation does not lead to dysregulated Mpl expression, as frequently shown for myeloproliferative neoplasms. The lack of spontaneous STAT3 and STAT5 activation and the normal response to TPO is unexpected as MPLW515L leads to constitutive receptor activation and hypersensitivity to TPO in experimental models.

Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and Myelofibrosis

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Tognon Raquel

2012-02-01

Full Text Available Abstract Background Essential Thrombocythemia (ET and Primary Myelofibrosis (PMF are Chronic Myeloproliferative Neoplasms (MPN characterized by clonal myeloproliferation/myeloaccumulation without cell maturation impairment. The JAK2 V617F mutation and PRV1 gene overexpression may contribute to MPN physiopathology. We hypothesized that deregulation of the apoptotic machinery may also play a role in the pathogenesis of ET and PMF. In this study we evaluated the apoptosis-related gene and protein expression of BCL2 family members in bone marrow CD34+ hematopoietic stem cells (HSC and peripheral blood leukocytes from ET and PMF patients. We also tested whether the gene expression results were correlated with JAK2 V617F allele burden percentage, PRV1 overexpression, and clinical and laboratory parameters. Results By real time PCR assay, we observed that A1, MCL1, BIK and BID, as well as A1, BCLW and BAK gene expression were increased in ET and PMF CD34+ cells respectively, while pro-apoptotic BAX and anti-apoptotic BCL2 mRNA levels were found to be lower in ET and PMF CD34+ cells respectively, in relation to controls. In patients' leukocytes, we detected an upregulation of anti-apoptotic genes A1, BCL2, BCL-XL and BCLW. In contrast, pro-apoptotic BID and BIMEL expression were downregulated in ET leukocytes. Increased BCL-XL protein expression in PMF leukocytes and decreased BID protein expression in ET leukocytes were observed by Western Blot. In ET leukocytes, we found a correlation between JAK2 V617F allele burden and BAX, BIK and BAD gene expression and between A1, BAX and BIK and PRV1 gene expression. A negative correlation between PRV1 gene expression and platelet count was observed, as well as a positive correlation between PRV1 gene expression and splenomegaly. Conclusions Our results suggest the participation of intrinsic apoptosis pathway in the MPN physiopathology. In addition, PRV1 and JAK2 V617F allele burden were linked to deregulation

Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors

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Cerquozzi, S; Tefferi, A

2015-01-01

Polycythemia vera (PV) and essential thrombocythemia (ET) constitute two of the three BCR-ABL1-negative myeloproliferative neoplasms and are characterized by relatively long median survivals (approximately 14 and 20 years, respectively). Potentially fatal disease complications in PV and ET include disease transformation into myelofibrosis (MF) or acute myeloid leukemia (AML). The range of reported frequencies for post-PV MF were 4.9–6% at 10 years and 6–14% at 15 years and for post-ET MF were 0.8–4.9% at 10 years and 4–11% at 15 years. The corresponding figures for post-PV AML were 2.3–14.4% at 10 years and 5.5–18.7% at 15 years and for post-ET AML were 0.7–3% at 10 years and 2.1–5.3% at 15 years. Risk factors cited for post-PV MF include advanced age, leukocytosis, reticulin fibrosis, splenomegaly and JAK2V617F allele burden and for post-ET MF include advanced age, leukocytosis, anemia, reticulin fibrosis, absence of JAK2V617F, use of anagrelide and presence of ASXL1 mutation. Risk factors for post-PV AML include advanced age, leukocytosis, reticulin fibrosis, splenomegaly, abnormal karyotype, TP53 or RUNX1 mutations as well as use of pipobroman, radiophosphorus (P32) and busulfan and for post-ET AML include advanced age, leukocytosis, anemia, extreme thrombocytosis, thrombosis, reticulin fibrosis, TP53 or RUNX1 mutations. It is important to note that some of the aforementioned incidence figures and risk factor determinations are probably inaccurate and at times conflicting because of the retrospective nature of studies and the inadvertent labeling, in some studies, of patients with prefibrotic primary MF or ‘masked' PV, as ET. Ultimately, transformation of MPN leads to poor outcomes and management remains challenging. Further understanding of the molecular events leading to disease transformation is being investigated. PMID:26565403

Splenomegaly in myelofibrosis—new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors

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Randhawa Jasleen

2012-08-01

Full Text Available Abstract Splenomegaly is a common sign of primary myelofibrosis (PMF, post-polycythemia vera myelofibrosis (post-PV MF, and post-essential thrombocythemia myelofibrosis (post-ET MF that is associated with bothersome symptoms, which have a significant negative impact on patients’ quality of life. It may also be present in patients with advanced polycythemia vera (PV or essential thrombocythemia (ET. Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2 activating mutation (JAK2V617F that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2 inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.

Bone mineral density and microarchitecture in patients with essential thrombocythemia and polycythemia vera

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Farmer, S.; Shanbhogue, V. V.; Hansen, S.

2017-01-01

In this cross-sectional study of 45 patients with myeloproliferative neoplasms, we found no evidence of secondary osteoporosis. INTRODUCTION: Patients with essential thrombocythemia (ET) and polycythaemia vera (PV) are at increased risk of fractures but the underlying mechanisms have not been set...

Essential thrombocythemia: Rare cause of chorea

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Eswaradass Prasanna Venkatesan

2014-01-01

Full Text Available Essential thrombocythemia (ET is a clonal myeloproliferative disorder (MPD, characterized predominantly by a markedly elevated platelet count without known cause. It is rare hematological disorder. In ET clinical picture is dominated by a predisposition to vascular occlusive events and hemorrhages. Headache, transient ischemic attack, stroke, visual disturbances and light headedness are some of the neurological manifestations of ET. Here, we describe a 55 year-old female who presented to us with generalized chorea. On evaluation, she was found to have thrombocytosis. After ruling out the secondary causes of thrombocytosis and other MPD we confirmed diagnosis of ET in her by bone marrow studies. Polycythemia vera (PV another MPD closely related to ET may be present with generalized chorea. There are few case reports of PV presenting as chorea in the literature, but none with ET. We report the first case of ET presenting as generalized chorea.

Peripheral circulatory disorders in essential thrombocythemia.

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Małecki, Rafał; Gacka, Małgorzata; Fiodorenko-Dumas, Żanna; Dumas, Ilias; Kwiatkowski, Jacek; Adamiec, Rajmund; Kuliszkiewicz-Janus, Małgorzata

2018-03-01

A significant number of patients with essential thrombocythemia (ET) complain of symptoms including distal parts of the extremities (e.g., paresthesias or Raynaud's phenomenon). The aim of the present study was to examine peripheral circulation in the upper extremities of individuals with ET. The study included 45 ET patients and 30 control subjects. All participants were subjected to thermography, photoplethysmography, impedance plethysmography, and applanation tonometry pulse wave analysis. The patients with ET differed significantly from the control subjects in terms of 3rd finger skin temperature (mean 31.04 vs. 32.45°C), skin temperature gradient (mean 1.82 vs. 0.11°C), photoplethysmographic amplitude (median 0.25 vs. 0.74%), and pulse waveform in the radial artery (more frequent occurrence of type B waveform). Pulse wave parameters correlated with the skin temperature gradient. The study findings imply the altered regulation of peripheral circulation in ET, including a decreased flow and an increased resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Recent developments in myelofibrosis

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Mesa RA

2012-07-01

Full Text Available Raoul Tibes, James M Bogenberger, Ruben A MesaDivision of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USAAbstract: The myeloproliferative neoplasm of myelofibrosis (MF is clinically constituted by individuals both with primary MF, as well as those that evolved from an antecedent polycythemia vera or essential thrombocythemia. Individuals presenting with MF have a heterogeneous phenotype which can involve significant constitutional symptoms (night sweats, fevers, weight loss, fatigue, variable but frequently problematic splenomegaly, and multifactorial cytopenias. These individuals clearly have decreased survival. Refinement of MF prognostic scores can distinguish from survival as poor as 16 months, to a median survival of 185 months. Sadly, although curative, allogeneic stem cell transplant still has sobering success rates for individuals of the standard ages for MF. Recent reports suggest less than half of patients will be alive at 3 years after allotransplant above the age of 60 years. The most important recent advancement in MF therapy has been the development of Janus kinase 2 (JAK2 inhibitors led by ruxolitinib, now Food and Drug Administration approved in the United States, and several other JAK2 inhibitors (in testing including SAR302503, CYT387, and SB1518. In randomized, placebo-controlled studies, ruxolitinib was demonstrated to be superior for the improvement of splenomegaly and symptoms. These benefits are mirrored across other JAK2 inhibitors. Improving anemia remains an unmet need in MF and is currently being evaluated by clinical trials utilizing the JAK2 inhibitor CYT387, as well as pomalidomide. Additional areas of interest for MF therapy include the inhibition of histone/lysine deacetylases, hedgehog pathway inhibition, as well as combination strategies with JAK2 inhibitors.Keywords: myeloproliferative neoplasm, myelofibrosis, JAK2 inhibitors

Probable essential thrombocythemia in a dog

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Hopper, P.E.; Mandell, C.P.; Turrel, J.M.; Jain, N.C.; Tablin, F.; Zinkl, J.G.

1989-04-01

Essential thrombocythemia (ET), in an 11-year-old dog was characterized by persistently high platelet counts range, 4.19 X 10(6)/microliters to 4.95 X 10(6)/microliters, abnormal platelet morphology, marked megakaryocytic hyperplasia in the bone marrow, absence of circulating megakaryoblasts, and history of splenomegaly and gastrointestinal bleeding. Increased numbers of megakaryocytes and megakaryoblasts (15% to 20%) in the bone marrow were confirmed by a positive acetylcholinesterase reaction. Another significant finding was the presence of a basophilia in blood (4,836/microliters) and bone marrow. The marked persistent thrombocytosis, absence of reactive (secondary) thrombocytosis, abnormal platelet morphology, and quantitative and qualitative changes in the megakaryocytic series in the bone marrow suggested the presence of a myeloproliferative disease. Cytochemical and ultrastructural findings aided in the diagnosis of ET. The dog was treated with radiophosphorus. The results was a rapid decline in the numbers of megakaryoblasts and megakaryocytes in the bone marrow and platelets and basophils in the peripheral blood. The dog died unexpectedly of acute necrotizing pancreatitis and diabetes mellitus before a complete remission was achieved.

Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group.

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Geyer, Holly L; Kosiorek, Heidi; Dueck, Amylou C; Scherber, Robyn; Slot, Stefanie; Zweegman, Sonja; Te Boekhorst, Peter Aw; Senyak, Zhenya; Schouten, Harry C; Sackmann, Federico; Fuentes, Ana Kerguelen; Hernández-Maraver, Dolores; Pahl, Heike L; Griesshammer, Martin; Stegelmann, Frank; Döhner, Konstanze; Lehmann, Thomas; Bonatz, Karin; Reiter, Andreas; Boyer, Francoise; Etienne, Gabriel; Ianotto, Jean-Christophe; Ranta, Dana; Roy, Lydia; Cahn, Jean-Yves; Harrison, Claire N; Radia, Deepti; Muxi, Pablo; Maldonado, Norman; Besses, Carlos; Cervantes, Francisco; Johansson, Peter L; Barbui, Tiziano; Barosi, Giovanni; Vannucchi, Alessandro M; Paoli, Chiara; Passamonti, Francesco; Andreasson, Bjorn; Ferrari, Maria L; Rambaldi, Alessandro; Samuelsson, Jan; Cannon, Keith; Birgegard, Gunnar; Xiao, Zhijian; Xu, Zefeng; Zhang, Yue; Sun, Xiujuan; Xu, Junqing; Kiladjian, Jean-Jacques; Zhang, Peihong; Gale, Robert Peter; Mesa, Ruben A

2017-01-01

The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; Pgender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression. Copyright© Ferrata Storti Foundation.

Ruxolitinib for the treatment of myelofibrosis: a NICE single technology appraisal.

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Wade, Ros; Rose, Micah; Neilson, Aileen Rae; Stirk, Lisa; Rodriguez-Lopez, Rocio; Bowen, David; Craig, Dawn; Woolacott, Nerys

2013-10-01

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of ruxolitinib (Novartis) to submit clinical and cost-effectiveness evidence for ruxolitinib within its licensed indication (the treatment of disease-related splenomegaly or symptoms in adult patients with myelofibrosis), according to the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article provides a description of the company submission, the ERG review and the resulting NICE guidance TA289 issued in June 2013. The ERG critically reviewed the evidence presented in the manufacturer's submission and identified areas requiring clarification, for which the manufacturer provided additional evidence. The main clinical effectiveness data were derived from two phase III, multicentre, randomised controlled trials (RCTs): Controlled myelofibrosis study with oral JAK inhibitor treatment (COMFORT)-II compared ruxolitinib with best available therapy (BAT), and COMFORT-I compared ruxolitinib with placebo. These RCTs demonstrated that ruxolitinib confers significant benefits in terms of spleen size reduction and improvement in symptom burden. In the COMFORT-II trial, a reduction in spleen volume of ≥35 % was achieved in 28 % of ruxolitinib-treated patients compared with 0 % of patients in the BAT group (p Service (NHS) resources for treating disease-related splenomegaly or symptoms in adults with myelofibrosis. Ruxolitinib is not recommended for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythaemia vera myelofibrosis and post-essential thrombocythaemia myelofibrosis in NICE TA289.

Deep sequencing reveals double mutations in cis of MPL exon 10 in myeloproliferative neoplasms.

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Pietra, Daniela; Brisci, Angela; Rumi, Elisa; Boggi, Sabrina; Elena, Chiara; Pietrelli, Alessandro; Bordoni, Roberta; Ferrari, Maurizio; Passamonti, Francesco; De Bellis, Gianluca; Cremonesi, Laura; Cazzola, Mario

2011-04-01

Somatic mutations of MPL exon 10, mainly involving a W515 substitution, have been described in JAK2 (V617F)-negative patients with essential thrombocythemia and primary myelofibrosis. We used direct sequencing and high-resolution melt analysis to identify mutations of MPL exon 10 in 570 patients with myeloproliferative neoplasms, and allele specific PCR and deep sequencing to further characterize a subset of mutated patients. Somatic mutations were detected in 33 of 221 patients (15%) with JAK2 (V617F)-negative essential thrombocythemia or primary myelofibrosis. Only one patient with essential thrombocythemia carried both JAK2 (V617F) and MPL (W515L). High-resolution melt analysis identified abnormal patterns in all the MPL mutated cases, while direct sequencing did not detect the mutant MPL in one fifth of them. In 3 cases carrying double MPL mutations, deep sequencing analysis showed identical load and location in cis of the paired lesions, indicating their simultaneous occurrence on the same chromosome.

European LeukemiaNet study on the reproducibility of bone marrow features in masked polycythemia vera and differentiation from essential thrombocythemia.

Science.gov (United States)

Kvasnicka, Hans Michael; Orazi, Attilio; Thiele, Juergen; Barosi, Giovanni; Bueso-Ramos, Carlos E; Vannucchi, Alessandro M; Hasserjian, Robert P; Kiladjian, Jean-Jacques; Gianelli, Umberto; Silver, Richard; Mughal, Tariq I; Barbui, Tiziano

2017-10-01

The purpose of the study was to assess consensus and interobserver agreement among an international panel of six hematopathologists regarding characterization and reproducibility of bone marrow (BM) histologic features used to diagnose early stage myeloproliferative neoplasms, in particular differentiation of so-called masked/prodromal polycythemia vera (mPV) from JAK2-mutated essential thrombocythemia (ET). The six members of the hematopathology panel evaluated 98 BM specimens independently and in a blinded fashion without knowledge of clinical data. The specimens included 48 cases of mPV according to the originally published hemoglobin threshold values for this entity (male: 16.0-18.4 g/dL, female: 15.0-16.4 g/dL), 31 cases with overt PV according to the updated 2016 WHO criteria, and 19 control cases. The latter group included cases of JAK2-mutated ET, primary myelofibrosis, myelodysplastic syndrome, and various reactive conditions. Inter-rater agreement between the panelists was very high (overall agreement 92.6%, kappa 0.812), particularly with respect to separating mPV from ET. Virtually all cases of mPV were correctly classified as PV according to their BM morphology. In conclusion, a central blinded review of histology slides by six hematopathologists demonstrated that highly reproducible specific histological pattern characterize PV and confirmed the notion that there are no significant differences between mPV and overt PV in relation to BM morphology. © 2017 Wiley Periodicals, Inc.

Immune Thrombocytopenia and JAK2V617F Positive Essential Thrombocythemia: Literature Review and Case Report

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M. A. Sobas

2017-01-01

Full Text Available We present the case where immune thrombocytopenia (ITP and essential thrombocythemia (ET sequentially appeared in the space of twenty-one years of follow-up. Impaired platelet production is present in both diseases, but clinical presentation and treatment are different. On the basis of this case history a possible role of autoimmunity as a predisposing factor to myeloproliferation has been discussed.

Immune Thrombocytopenia and JAK2V617F Positive Essential Thrombocythemia: Literature Review and Case Report.

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Sobas, M A; Wróbel, T; Zduniak, K; Podolak-Dawidziak, M; Rybka, J; Biedroń, M; Sawicki, M; Dybko, J; Kuliczkowski, K

2017-01-01

We present the case where immune thrombocytopenia (ITP) and essential thrombocythemia (ET) sequentially appeared in the space of twenty-one years of follow-up. Impaired platelet production is present in both diseases, but clinical presentation and treatment are different. On the basis of this case history a possible role of autoimmunity as a predisposing factor to myeloproliferation has been discussed.

Circulating YKL-40 in patients with essential thrombocythemia and polycythemia vera treated with the novel histone deacetylase inhibitor vorinostat

DEFF Research Database (Denmark)

Andersen, Christen Lykkegaard; Bjørn, Mads Emil; McMullin, Mary Frances

2014-01-01

YKL-40 regulates vascular endothelial growth factors and induces tumor proliferation. We investigated YKL-40 before and after treatment with vorinostat in 31 polycythemia vera (PV) and 16 essential thrombocythemia (ET) patients. Baseline PV patient levels were 2 times higher than in healthy...

An Ulceronecrotic Foot Lesion in a Patient with Essential Thrombocythemia: Successful Treatment with Hydroxyurea

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Tokue Kato

2012-01-01

Full Text Available The patient was a 47-year-old woman with a painful ulcer that had appeared on the right 5th toe two weeks before she visited our hospital. Histopathological examination showed that thrombi were present in small blood vessels in the dermis and pancytosis was detected in a blood test, suggesting polycythemia-associated ulceration of the toe. Essential thrombocythemia was diagnosed based on bone marrow puncture and chromosomal test findings. Platelet count and the ulcer were improved by oral hydroxyurea.

Increased gene expression of histone deacetylases in patients with Philadelphia-negative chronic myeloproliferative neoplasms

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Skov, Vibe; Larsen, Thomas Stauffer; Thomassen, Mads

2012-01-01

Abstract Myeloproliferation, myeloaccumulation (decreased apoptosis), inflammation, bone marrow fibrosis and angiogenesis are cardinal features of the Philadelphia-negative chronic myeloproliferative neoplasms: essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF...

Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis.

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Marty, Caroline; Pecquet, Christian; Nivarthi, Harini; El-Khoury, Mira; Chachoua, Ilyas; Tulliez, Micheline; Villeval, Jean-Luc; Raslova, Hana; Kralovics, Robert; Constantinescu, Stefan N; Plo, Isabelle; Vainchenker, William

2016-03-10

Frameshift mutations in the calreticulin (CALR) gene are seen in about 30% of essential thrombocythemia and myelofibrosis patients. To address the contribution of the CALR mutants to the pathogenesis of myeloproliferative neoplasms, we engrafted lethally irradiated recipient mice with bone marrow cells transduced with retroviruses expressing these mutants. In contrast to wild-type CALR, CALRdel52 (type I) and, to a lesser extent, CALRins5 (type II) induced thrombocytosis due to a megakaryocyte (MK) hyperplasia. Disease was transplantable into secondary recipients. After 6 months, CALRdel52-, in contrast to rare CALRins5-, transduced mice developed a myelofibrosis associated with a splenomegaly and a marked osteosclerosis. Monitoring of virus-transduced populations indicated that CALRdel52 leads to expansion at earlier stages of hematopoiesis than CALRins5. However, both mutants still specifically amplified the MK lineage and platelet production. Moreover, a mutant deleted of the entire exon 9 (CALRdelex9) did not induce a disease, suggesting that the oncogenic property of CALR mutants was related to the new C-terminus peptide. To understand how the CALR mutants target the MK lineage, we used a cell-line model and demonstrated that the CALR mutants, but not CALRdelex9, specifically activate the thrombopoietin (TPO) receptor (MPL) to induce constitutive activation of Janus kinase 2 and signal transducer and activator of transcription 5/3/1. We confirmed in c-mpl- and tpo-deficient mice that expression of Mpl, but not of Tpo, was essential for the CALR mutants to induce thrombocytosis in vivo, although Tpo contributes to disease penetrance. Thus, CALR mutants are sufficient to induce thrombocytosis through MPL activation. © 2016 by The American Society of Hematology.

Bone morbidity in chronic myeloproliferative neoplasms

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Farmer, Sarah; Ocias, Lukas Frans; Vestergaard, Hanne

2015-01-01

Patients with the classical Philadelphia chromosome-negative chronic myeloproliferative neoplasms including essential thrombocythemia, polycythemia vera and primary myelofibrosis often suffer from comorbidities, in particular, cardiovascular diseases and thrombotic events. Apparently, there is also...

Treatment Options for Chronic Myeloproliferative Neoplasms

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... factors affect prognosis (chance of recovery) and treatment options for primary myelofibrosis. Prognosis (chance of recovery ) depends ... factors affect prognosis (chance of recovery) and treatment options for essential thrombocythemia. Prognosis (chance of recovery ) and ...

Treatment Option Overview (Chronic Myeloproliferative Neoplasms)

Science.gov (United States)

... factors affect prognosis (chance of recovery) and treatment options for primary myelofibrosis. Prognosis (chance of recovery ) depends ... factors affect prognosis (chance of recovery) and treatment options for essential thrombocythemia. Prognosis (chance of recovery ) and ...

Safety and efficacy of combination therapy of interferon-alpha2 + JAK1-2 Inhibitor in the philadelphia-negative chronic myeloproliferative neoplasms. Preliminary results from the danish combi-trial-an open label, single arm, non-randomized multicenter phase II study

DEFF Research Database (Denmark)

Mikkelsen, S. U.; Kjaer, L.; Skov, V.

2015-01-01

Background: The Philadelphia-negative, chronic myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (MF) (PMF). Chronic inflammation and a deregulated immune system are considered important for clonal evolution and disease...

Inheritance of the chronic myeloproliferative neoplasms. A systematic review

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Ranjan, Ajenthen; Penninga, E; Jelsig, Am

2012-01-01

This systematic review investigated the inheritance of the classical chronic myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and chronic myelogenous leukemia (CML). Sixty-one articles were included and provided 135...

Molecular Profiling of Peripheral Blood Cells from Patients with Polycythemia Vera and Related Neoplasms: Identification of Deregulated Genes of Significance for Inflammation and Immune Surveillance

DEFF Research Database (Denmark)

Skov, Vibe; Larsen, Thomas Stauffer; Thomassen, Mads

2012-01-01

Essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF) are haematopoietic stem cell neoplasms that may be associated with autoimmune or chronic inflammatory disorders. Earlier gene expression profiling studies have demonstrated aberrant expression of genes involved...

Age-Related Macular Degeneration in Patients With Chronic Myeloproliferative Neoplasms

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Bak, Marie; Sørensen, Torben Lykke; Flachs, Esben Meulengracht

2017-01-01

, and December 31, 2013, of essential thrombocythemia, polycythemia vera, myelofibrosis, or unclassifiable MPNs. For each patient, 10 age- and sex-matched controls were included. All patients without prior AMD were followed up from the date of diagnosis (or corresponding entry date for the controls) until......, 3063 with polycythemia vera, 547 with myelofibrosis, and 1720 with unclassifiable MPNs) and 4.3 (95% CI, 4.1-4.4) for the 77445 controls, while the 10-year risk of AMD was 2.4% (95% CI, 2.1%-2.8%) for patients with MPNs and 2.3% (95% CI, 2.2%-2.4%) for the controls. The risk of AMD was increased...... overall for patients with MPNs (adjusted HR, 1.3; 95% CI, 1.1-1.5), with adjusted HRs for the subtypes of 1.2 (95% CI, 1.0-1.6) for essential thrombocythemia, 1.4 (95% CI, 1.2-1.7) for polycythemia vera, 1.7 (95% CI, 0.8-4.0) for myelofibrosis, and 1.5 (95% CI, 1.1-2.1) for unclassifiable MPNs...

The Danish National Chronic Myeloid Neoplasia Registry

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Bak, Marie; Ibfelt, Else Helene; Stauffer Larsen, Thomas

2016-01-01

departmental levels and serve as a platform for research. STUDY POPULATION: The DCMR has nationwide coverage and contains information on patients diagnosed at hematology departments from January 2010 onward, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, unclassifiable...

Application of prognostic score IPSET-thrombosis in patients with essential thrombocythemia of a Brazilian public service

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Luana Magalhães Navarro

Full Text Available Summary Introduction: In patients with essential thrombocythemia (ET, the vascular complications contribute to morbidity and mortality. To better predict the occurrence of thrombotic events, an International Prognostic Score for Thrombosis in Essential Thrombocythemia (IPSET-thrombosis has recently been proposed. We present the application of this score and compare its results with the usual classification system. Method: We retrospectively evaluated the characteristics and risk factors for thrombosis of 46 patients with a diagnosis of ET seen in the last 6 years at Faculdade de Medicina do ABC (FMABC. Results: Thrombosis in the arterial territory was more prevalent than in venous sites. We observed that cardiovascular risk factors (hypertension, hypercholesterolemia, diabetes mellitus, and smoking were also risk factors for thrombosis (p<0.001. Age over 60 years and presence of JAK2 V617F mutation were not associated with the occurrence of thrombotic events. No patient classified by IPSET-thrombosis as low risk had a thrombotic event. Furthermore, using the IPSET-thrombosis scale, we identified two patients who had thrombotic events during follow-up and were otherwise classified in the low-risk group of the traditional classification. Leukocytosis at diagnosis was significantly associated with arterial thrombosis (p=0.02, while splenomegaly was associated with venous thrombotic events (p=0.01. Conclusion: Cardiovascular risk factors and leukocytosis were directly associated with arterial thrombosis. IPSET-thrombosis appears to be better than the traditional classification at identifying lower risk patients who do not need specific therapy.

[Essential thrombocythemia: baseline characteristics and risk factors for survival and thrombosis in a series of 214 patients].

Science.gov (United States)

Angona, Anna; Alvarez-Larrán, Alberto; Bellosillo, Beatriz; Martínez-Avilés, Luz; Garcia-Pallarols, Francesc; Longarón, Raquel; Ancochea, Àgueda; Besses, Carles

2015-03-15

Two prognostic models to predict overall survival and thrombosis-free survival have been proposed: International Prognostic Score for Essential Thrombocythemia (IPSET) and IPSET-Thrombosis, respectively, based on age, leukocytes count, history of previous thrombosis, the presence of cardiovascular risk factors and the JAK2 mutational status. The aim of the present study was to assess the clinical and biological characteristics at diagnosis and during evolution in essential thrombocythemia (ET) patients as well as the factors associated with survival and thrombosis and the usefulness of these new prognostic models. We have evaluated the clinical data and the mutation status of JAK2, MPL and calreticulin of 214 ET patients diagnosed in a single center between 1985 and 2012, classified according to classical risk stratification, IPSET and IPSET-Thrombosis. With a median follow-up of 6.9 years, overall survival was not associated with any variable by multivariate analysis. Thrombotic history and leukocytes>10×10(9)/l were associated with thrombosis-free survival (TFS). In our series, IPSET prognostic systems of survival and thrombosis did not provide more clinically relevant information regarding the classic risk of thrombosis stratification. Thrombotic history and leukocytosis>10×10(9)/l were significantly associated with lower TFS, while the prognostic IPSET-Thrombosis system did not provide more information than classical thrombotic risk assessment. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Myeloproliferative neoplasms

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Roaldsnes, Christina; Holst, René; Frederiksen, Henrik

2017-01-01

BACKGROUND: Polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) are clonal disorders collectively named as myeloproliferative neoplasms (MPN). Published data on epidemiology of MPN after the discovery of the JAK2 mutation and the 2008 WHO classifications are scarce. We...

The JAK2 V617F mutation involves B- and T-lymphocyte lineages in a subgroup of patients with Philadelphia-chromosome negative chronic myeloproliferative disorders

DEFF Research Database (Denmark)

Larsen, Thomas Stauffer; Christensen, Jacob Haaber; Hasselbalch, Hans Carl

2007-01-01

The JAK2 V617F mutation is a frequent genetic event in the three classical Philadelphia-chromosome negative chronic myeloproliferative disorders (Ph(neg.)-CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Its occurrence varies in frequency in regards...

Interferon-alpha in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. Status and perspectives

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Hasselbalch, Hans Carl; Larsen, Thomas Stauffer; Riley, Caroline Hasselbalch

2011-01-01

The Philadelphia-negative chronic myeloproliferative neoplasms encompass essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). A major break-through in the understanding of the pathogenesis of these neoplasms occurred in 2005 by the discovery of the JAK2 V617F...

Janus kinase inhibitors: jackpot or potluck?

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Pavithran Keechilat

2012-06-01

Full Text Available The reports of a unique mutation in the Janus kinase-2 gene (JAK2 in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN: primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

Are chronic myeloproliferative neoplasms associated with age-related macular degeneration?

DEFF Research Database (Denmark)

Bak, M.; Sorensen, T. L.; Flachs, E. M.

2015-01-01

population-based matched cohort study using Danish registries. We included all patients age 18+ or older with a first listed diagnosis of MPN in the Danish National Patient Registry between 1994 and 2013. Patients with Essential Thrombocythemia (ET), Polycythemia Vera (PV), Myelofibrosis (MF), Unclassifiable...

Essential Thrombocythemia in a Two-year-old Child, Responsive to Hydroxyurea but Not Aspirin

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Tariq N. Aladily

2017-06-01

Full Text Available Essential thrombocythemia (ET is a myeloproliferative neoplasm that occurs mostly in patients above the age of 50 years. Its incidence in children is very rare, with around 100 cases reported in the literature. High-risk patients are defined by previous life threatening major thrombotic or severe hemorrhagic complication or age > 60. Those patients probably benefit from cytoreductive therapy. On the other hand, antiplatelet drugs are recommended for patients with low risk group. Although rare, ET should be considered in the differential diagnosis of persistent thrombocytosis in children, even at a very young age. A constellation of clinical, pathologic ,and molecular testing are essential for diagnosis. Given the rarity of these cases, there is currently no consensus for treatment guidelines in children, especially in asymptomatic patients. We describe a case of a two-year old girl who presented with unexplained, isolated thrombocytosis which persisted for eight years. Bone marrow biopsy demonstrated typical features of ET. Over the course of the disease, hydroxyurea, but not aspirin, showed better control of symptoms and lowered the platelets level.

Ferrokinetic study of splenic erythropoiesis: Relationships among clinical diagnosis, myelofibrosis, splenomegaly, and extramedullary erythropoiesis

International Nuclear Information System (INIS)

Beguin, Y.; Fillet, G.; Bury, J.; Fairon, Y.

1989-01-01

Splenic erythropoiesis was demonstrated by surface counting of 59 Fe in 129 of 1,350 ferrokinetic studies performed over a 15 year period. These 129 studies were carried out in 108 patients, including 40 with chronic myelogenous leukemia (CML), 24 with agnogenic myeloid metaplasia (AMM), 18 with polycythemia vera (PV), six with a myelodysplastic syndrome, five with acute leukemia, three with prostate or breast carcinoma, two each with aplastic anemia or Hodgkin's disease, and one each with idiopathic thrombocythemia, multiple myeloma, chronic renal failure, or treated hypopituitarism. Splenomegaly was present in 83% of the studies and hepatomegaly in 72%. Grade II-III myelofibrosis was demonstrated in 62% of the cases. Hepatic erythropoiesis was present in 77% of the studies (only 38% in PV), and marrow erythropoiesis was undetectable in 33%. Total erythropoiesis was about twice normal (range 0.2 to 8 times normal) but was ineffective to varying degrees in 86% of the studies. Relationships between organomegaly, myelofibrosis, and extramedullary erythropoiesis, as well as differences among clinical disorders, are discussed. Differences observed between CML in chronic or blastic phase suggested that the erythroid cell line was involved in the proliferative process. It is concluded that splenic erythropoiesis (1) is encountered in a variety of clinical conditions; (2) is not necessarily associated with splenomegaly or myelofibrosis, even in the myeloproliferative disorders; (3) is part of a predominantly extramedullary (in the liver as well as in the spleen), expanded, and largely inefficient total erythropoiesis; and (4) can be evaluated in a semiquantitative manner by surface counting

Bone marrow histomorphology and JAK2 mutation status in essential thrombocythemia

DEFF Research Database (Denmark)

Stauffer Larsen, Thomas; Hasselbalch, Hans Carl; Pallisgaard, Niels

2007-01-01

for evaluation. 14 patients were reclassified as having prefibrotic idiopathic myelofibrosis (IMF), whilst the ET diagnosis was sustained in 19 patients. The individual bone marrow parameters of the reviewed diagnosis showed no correlation with JAK2 V617F mutation status, which was determined by a highly...

JAK2V617F Somatic Mutation In The General Population

DEFF Research Database (Denmark)

Nielsen, Camilla; Bojesen, Stig E; Nordestgaard, Børge G

2014-01-01

of myeloproliferative neoplasm from no disease (n=8 at re-examination) through essential thrombocythemia (n=20) and polycythemia vera (n=13) to primary myelofibrosis (n=7). Among those diagnosed with a myeloproliferative neoplasm only at re-examination in 2012, in the preceding years JAK2V617F mutation burden increased...

Molecular diagnostics of myeloproliferative neoplasms

DEFF Research Database (Denmark)

Langabeer, S. E.; Andrikovics, H.; Asp, J.

2015-01-01

Since the discovery of the JAK2 V617F mutation in the majority of the myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia and primary myelofibrosis ten years ago, further MPN-specific mutational events, notably in JAK2 exon 12, MPL exon 10 and CALR exon 9 have been...

Life for patients with myelofibrosis: the physical, emotional and financial impact, collected using narrative medicine-Results from the Italian 'Back to Life' project.

Science.gov (United States)

Palandri, Francesca; Benevolo, Giulia; Iurlo, Alessandra; Abruzzese, Elisabetta; Carella, Angelo M; Paoli, Chiara; Palumbo, Giuseppe A; Bonifacio, Massimiliano; Cilloni, Daniela; Andriani, Alessandro; Guarini, Attilio; Turri, Diamante; Elli, Elena Maria; Falcone, Antonietta; Anaclerico, Barbara; Musto, Pellegrino; Di Renzo, Nicola; Tiribelli, Mario; Zambello, Renato; Spinosa, Caterina; Ricco, Alessandra; Raucci, Letizia; Martino, Bruno; Annunziata, Mario; Pascale, Silvia; Liberati, Anna Marina; La Nasa, Giorgio; Maffioli, Margherita; Breccia, Massimo; Pugliese, Novella; Betti, Silvia; Giglio, Gianfranco; Cappuccio, Antonietta; Reale, Luigi

2018-06-01

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterised by an aggressive clinical course, with disabling symptoms and reduced survival. Patients experience a severely impaired quality of life and their families face the upheaval of daily routines and high disease-related financial costs. The aim of this study was to investigate the perceptions of Italian patients and their caregivers about living with MF and the burden of illness associated with MF. A quali-quantitative questionnaire and a prompted written narrative survey were administered to patients affected by primary or post-essential thrombocythemia/post-polycythaemia vera MF and their primary caregiver in 35 Italian haematological centres. In total, 287 questionnaires were returned by patients and 98 by caregivers, with 215 and 62, respectively, including the narrative. At the time of diagnosis, the most commonly expressed emotional states of patients were fear, distress and anger, confirming the difficulty of this phase. A high level of emotional distress was also reported by caregivers. Along the pathway of care, the ability to cope with the disease differed according to the quality of care received. The mean cost to each patient attributable to MF was estimated as €12,466 per year, with an estimated average annual cost of loss of income of €7774 per patient and €4692 per caregiver. Better understanding of the personal life of MF patients and their families could improve the relationships between health workers and patients, resulting in better focused healthcare pathways and more effective financial support to maintain patients in their social roles.

Anagrelide compared with hydroxyurea in essential thrombocythemia: a meta-analysis.

Science.gov (United States)

Samuelson, Bethany; Chai-Adisaksopha, Chatree; Garcia, David

2015-11-01

Cytoreductive therapy, with or without low-dose aspirin, is the mainstay of thrombotic risk reduction in patients with essential thrombocythemia (ET), but the optimal choice of agent remains unclear. The aim of this study was to meta-analyze currently available data comparing anagrelide to hydroxyurea for reduction of rates of thrombosis, bleeding and death among patients with ET. A literature search for randomized, controlled trials comparing anagrelide to hydroxyurea among patients with ET revealed two published studies. Statistical analysis was performed using fixed effects meta-analysis. Rates of thrombosis were similar between patients treated with hydroxyurea vs anagrelide (RR 0.86, 95 % CI 0.64-1.16). Rates of major bleeding were lower in patients treated with hydroxyurea (RR 0.37, 95 % CI 0.18-0.75). Rates of progression to acute myeloid leukemia were not statistically different (RR 1.50, 95 % CI 0.43-5.29). The composite of thrombosis, major bleeding and death favored hydroxyurea (RR 0.78, 95 % CI 0.63-0.97). In conclusion, our analysis supports use of hydroxyurea as a first-line cytoreductive agent for patients with ET, based largely on decreased rates of major bleeding. Anagrelide appears to be equally effective for protection against thrombotic events and may be an appropriate alternative for patients who are intolerant of hydroxyurea.

The Amelioration of Myelofibrosis with Thrombocytopenia by a JAK1/2 Inhibitor, Ruxolitinib, in a Post-polycythemia Vera Myelofibrosis Patient with a JAK2 Exon 12 Mutation.

Science.gov (United States)

Ikeda, Kazuhiko; Ueda, Koki; Sano, Takahiro; Ogawa, Kazuei; Ikezoe, Takayuki; Hashimoto, Yuko; Morishita, Soji; Komatsu, Norio; Ohto, Hitoshi; Takeishi, Yasuchika

2017-01-01

Less than 5% of patients with polycythemia vera (PV) show JAK2 exon 12 mutations. Although PV patients with JAK2 exon 12 mutations are known to develop post-PV myelofibrosis (MF) as well as PV with JAK2V617F, the role of JAK inhibitors in post-PV MF patients with JAK2 exon 12 mutations remains unknown. We describe how treatment with a JAK1/2 inhibitor, ruxolitinib, led to the rapid amelioration of marrow fibrosis, erythrocytosis and thrombocytopenia in a 77-year-old man with post-PV MF who carried a JAK2 exon 12 mutation (JAK2H538QK539L). This case suggests that ruxolitinib is a treatment option for post-PV MF in patients with thrombocytopenia or JAK2 exon 12 mutations.

Heparin-Induced Thrombocytopenia in a Patient with Essential Thrombocythemia: A Case Based Update

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Edva Noel

2015-01-01

Full Text Available Vascular thrombosis is a common clinical feature of both essential thrombocythemia (ET and heparin-induced thrombocytopenia (HIT. The development of HIT in a patient with ET is rare and underrecognized. We report the case of a 77-year-old woman with preexisting ET, who was admitted with acute coronary syndrome, and IV heparin was started. She was exposed to unfractionated heparin (UFH 5 days prior to this admission. Decrease in platelet count was noted, and HIT panel was sent. Heparin was discontinued. Patient developed atrial fibrillation, and Dabigatran was started. On day three, patient also developed multiple tiny cerebral infarctions and acute right popliteal DVT. On day ten of admission, HIT panel was positive, and Dabigatran was changed to Lepirudin. Two days later, Lepirudin was also discontinued because patient developed pseudoaneurysm on the right common femoral artery at the site of cardiac catheterization access. A progressive increase in the platelet count was noted after discontinuing heparin. Physicians should be aware of the coexistence of HIT and ET, accompanied challenges of the prompt diagnosis, and initiation of appropriate treatment.

JAK2 and MPL gene mutations in V617F-negative myeloproliferative neoplasms.

NARCIS (Netherlands)

Siemiatkowska, A.M.; Bieniaszewska, M.; Hellmann, A.; Limon, J.

2010-01-01

We report three novel mutations in JAK2 exons 12, 19 and 25 in V617F-negative patients with polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. Scanning of JAK2 exons 12-25 and MPL exon 10 revealed the presence of JAK2 alterations in six and MPL W515L/K mutations in five of 34

Circulating YKL-40 in myelofibrosis a potential novel biomarker of disease activity and the inflammatory state

DEFF Research Database (Denmark)

Bjørn, Mads Emil; Andersen, Christen Lykkegaard; Jensen, Morten Krogh

2014-01-01

Chronic myeloproliferative neoplasms (MPN), encompassing essential thrombocythaemia (ET), polycythaemia vera (PV) and myelofibrosis (PMF), are featured by a chronic inflammatory state which is pronounced in myelofibrosis The value of YKL-40 as a biomarker of disease burden has been demonstrated i...

Mutations with epigenetic effects in myeloproliferative neoplasms and recent progress in treatment: Proceedings from the 5th International Post-ASH Symposium

International Nuclear Information System (INIS)

Tefferi, A; Abdel-Wahab, O; Cervantes, F; Crispino, J D; Finazzi, G; Girodon, F; Gisslinger, H; Gotlib, J; Kiladjian, J-J; Levine, R L; Licht, J D; Mullally, A; Odenike, O; Pardanani, A; Silver, R T; Solary, E; Mughal, T

2011-01-01

Immediately following the 2010 annual American Society of Hematology (ASH) meeting, the 5th International Post-ASH Symposium on Chronic Myelogenous Leukemia and BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) took place on 7–8 December 2010 in Orlando, Florida, USA. During this meeting, the most recent advances in laboratory research and clinical practice, including those that were presented at the 2010 ASH meeting, were discussed among recognized authorities in the field. The current paper summarizes the proceedings of this meeting in BCR-ABL1-negative MPN. We provide a detailed overview of new mutations with putative epigenetic effects (TET oncogene family member 2 (TET2), additional sex comb-like 1 (ASXL1), isocitrate dehydrogenase (IDH) and enhancer of zeste homolog 2 (EZH2)) and an update on treatment with Janus kinase (JAK) inhibitors, pomalidomide, everolimus, interferon-α, midostaurin and cladribine. In addition, the new ‘Dynamic International Prognostic Scoring System (DIPSS)-plus' prognostic model for primary myelofibrosis (PMF) and the clinical relevance of distinguishing essential thrombocythemia from prefibrotic PMF are discussed

Mutations with epigenetic effects in myeloproliferative neoplasms and recent progress in treatment: Proceedings from the 5th International Post-ASH Symposium

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Tefferi, A [Division of Hematology, Department of Medicine, Rochester, MN (United States); Abdel-Wahab, O [Department of Medicine, Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Cervantes, F [Hematology Department, Hospital Clínic, Institut d' Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona (Spain); Crispino, J D [Department of Hematology, Northwestern University, Chicago, IL (United States); Finazzi, G [Hematology Department of Ospedali Riuniti di Bergamo, Bergamo (Italy); Girodon, F [Laboratoire d' Hématologie, Hôpital du Bocage, Dijon (France); Gisslinger, H [Division of Hematology and Blood Coagulation, Department of Internal Medicine I, Medical University of Vienna, Vienna (Austria); Gotlib, J [Division of Hematology, Stanford University School of Medicine, Stanford, CA (United States); Kiladjian, J-J [Centre d' Investigations Cliniques 9504, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Université Paris 7, Paris (France); Levine, R L [Department of Medicine, Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY (United States); Licht, J D [Department of Hematology, Northwestern University, Chicago, IL (United States); Mullally, A [Division of Hematology, Department of Medicine, Brigham and Women' s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (United States); Odenike, O [Section of Hematology and Oncology, University of Chicago, Chicago, IL (United States); Pardanani, A [Division of Hematology, Department of Medicine, Rochester, MN (United States); Silver, R T [Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY (United States); Solary, E [Inserm U1009, Institut Gustave Roussy, Université Paris XI, Villejuif (France); Mughal, T [Department of Haematology, Guys Hospital Medical School, London (United Kingdom); Division of Hematology, Department of Medicine, Rochester, MN (United States)

2011-03-01

Immediately following the 2010 annual American Society of Hematology (ASH) meeting, the 5th International Post-ASH Symposium on Chronic Myelogenous Leukemia and BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) took place on 7–8 December 2010 in Orlando, Florida, USA. During this meeting, the most recent advances in laboratory research and clinical practice, including those that were presented at the 2010 ASH meeting, were discussed among recognized authorities in the field. The current paper summarizes the proceedings of this meeting in BCR-ABL1-negative MPN. We provide a detailed overview of new mutations with putative epigenetic effects (TET oncogene family member 2 (TET2), additional sex comb-like 1 (ASXL1), isocitrate dehydrogenase (IDH) and enhancer of zeste homolog 2 (EZH2)) and an update on treatment with Janus kinase (JAK) inhibitors, pomalidomide, everolimus, interferon-α, midostaurin and cladribine. In addition, the new ‘Dynamic International Prognostic Scoring System (DIPSS)-plus' prognostic model for primary myelofibrosis (PMF) and the clinical relevance of distinguishing essential thrombocythemia from prefibrotic PMF are discussed.

Frequency and clinical features of the JAK2 V617F mutation in pediatric patients with sporadic essential thrombocythemia.

Science.gov (United States)

Nakatani, Takuya; Imamura, Toshihiko; Ishida, Hiroyuki; Wakaizumi, Katsuji; Yamamoto, Tohru; Otabe, Osamu; Ishigami, Tsuyoshi; Adachi, Souichi; Morimoto, Akira

2008-12-01

Pediatric essential thrombocythemia (ET) is a rare and heterogenous disease entity. While several recent studies have focused on the role of the JAK2 V617F mutation in pediatric ET, the frequency of pediatric ET cases with this mutation and the associated clinical features remain unclear. We examined six childhood cases who had been diagnosed with ET according to WHO criteria (onset age: 0.2-14 years) for the presence of the JAK2 V617F mutation, MPLW515L mutation and JAK2 exon 12 mutations. Two sensitive PCR-based methods were used for the JAK2 V617F genotyping. We also examined the expression of polycythemia rubra vera-1 (PRV-1), which is a diagnostic marker for clonal ET. We found that three of the six cases had the JAK2 V617F mutation and that all six cases expressed PRV-1 in their peripheral granulocytes. Neither MPL W515L mutation nor JAK2 exon 12 mutations was detected in the patients without JAK2 V617F mutation. The two patients who developed thrombocythemia during infancy were JAK2 V617F-negative. These findings suggest that the JAK2 V617F mutation is not rare in childhood sporadic ET cases, and that these cases might be older and myeloproliferative features.

Zap-70 positive chronic lymphocytic leukemia co-existing with Jak 2 V671F positive essential thrombocythemia: A common defective stem cell?

OpenAIRE

Tabaczewski, Piotr; Nadesan, Sushani; Lim, Seah H

2008-01-01

Essential thrombocythemia (ET) co-existing with chronic lymphocytic leukemia (CLL) is extremely rare. We report two cases of ET with Jak 2 V617F in Zap-70+ CLL. ET is a myeloproliferative stem cell disease. Zap-70 expression in CLL correlates with non-mutated immunoglobulin genes. The occurrence of a less mature CLL in patients with a pluripotential stem cell disease raises the possibility that an initial “trigger hit” occurred in a pre-Jak 2 common early progenitor in these patients. Subsequ...

The calreticulin (CALR) exon 9 mutations are promising targets for cancer immune therapy

DEFF Research Database (Denmark)

Holmström, M O; Martinenaite, E; Ahmad, S M

2017-01-01

The calreticulin (CALR) exon 9 mutations are found in ∼30% of patients with essential thrombocythemia and primary myelofibrosis. Recently, we reported spontaneous immune responses against the CALR mutations. Here, we describe that CALR-mutant (CALRmut)-specific T cells are able to specifically re...... CALR exon 9 mutations.Leukemia advance online publication, 15 August 2017; doi:10.1038/leu.2017.214....

The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion

OpenAIRE

Barbui, Tiziano; Thiele, Jürgen; Gisslinger, Heinz; Kvasnicka, Hans Michael; Vannucchi, Alessandro M.; Guglielmelli, Paola; Orazi, Attilio; Tefferi, Ayalew

2018-01-01

The new edition of the 2016 World Health Organization (WHO) classification system for tumors of the hematopoietic and lymphoid tissues was published in September 2017. Under the category of myeloproliferative neoplasms (MPNs), the revised document includes seven subcategories: chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia-not otherwise specified and MPN, unclassifiable...

Spontaneous Hemopericardium Leading to Cardiac Tamponade in a Patient with Essential Thrombocythemia

Directory of Open Access Journals (Sweden)

Anand Deshmukh

2011-01-01

thrombocythemia (ET has never been reported in the literature. We report a case of a 72-year-old Caucasian female who presented with spontaneous hemopericardium and tamponade requiring emergent pericardiocentesis. The patient was subsequently diagnosed to have ET. ET is characterized by elevated platelet counts that can lead to thrombosis but paradoxically it can also lead to a bleeding diathesis. Physicians should be aware of this complication so that timely life-saving measures can be taken if this complication arises.

Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera

OpenAIRE

Lussana, Federico; Carobbio, Alessandra; Salmoiraghi, Silvia; Guglielmelli, Paola; Vannucchi, Alessandro Maria; Bottazzi, Barbara; Leone, Roberto; Mantovani, Alberto; Barbui, Tiziano; Rambaldi, Alessandro

2017-01-01

Abstract Background The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs) and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. Methods We evaluated 305 with essential thrombocythemia (ET) and 172 polycythemia vera (PV) patients diagnosed according to the 2016 WHO cri...

Significance of combined detection of JAK2V617F, MPL and CALR gene mutations in patients with essential thrombocythemia.

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Ji, Liying; Qian, Mengyao; Wu, Nana; Wu, Jianmin

2017-03-01

The aim of this study was to analyze the mutation rate of JAK2V617F, MPLW515L/K and CALR genes in adult patients with essential thrombocythemia (ET) and the accuracy of the combined detection by the receiver operating curve. Three hundred and forty-two cases with high-platelets (≥300×10 9 /l) were consecutively selected. The patients were analyzed for routine blood examination, bone marrow biopsy and genetic testing. One hundred and fifty-four cases (45.03%) were diagnosed with ET and 188 cases of secondary thrombocythemia according to the hematopoietic and lymphoid tissue tumor classification standards of 2008. It was found that the mutant type of three genes showed three bands, whereas only one band for wild-type. The JAK2V617F and MPL mutations did not cause a change in the open reading frame and the CALR mutation resulted in its change. The mutation rate of JAK2V617F and CALR in ET group was significantly higher than that in the secondary thrombocythemia group (p<0.05). The positive mutation rate of MPL was only 4.55%. JAK2V617F-positive mutation alone was used to diagnose with ET. The area under the curve (AUC) was 0.721. The sensitivity was 72.4%, the specificity was 79.5% and the cut-off value was 0.25. When CALR-positive mutation alone was used to diagnose ET, the AUC, sensitivity, specificity and cut-off value were 0.664, 68.4, 82.4 and 0.09%, respectively. JAK2V617F combined with CALR mutation were used for diagnosis of ET. The AUC was 0.862, the sensitivity was 85.9%, the specificity was 87.8%, and the cut-off values were 0.21 and 0.07. In conclusion, the positive mutation rate of JAK2V617F and CALR in ET was higher, and the sensitivity, specificity and accuracy of the diagnosis of ET were significantly improved using the detection of JAK2V617F and CALR.

Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms.

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Rumi, Elisa; Pietra, Daniela; Guglielmelli, Paola; Bordoni, Roberta; Casetti, Ilaria; Milanesi, Chiara; Sant'Antonio, Emanuela; Ferretti, Virginia; Pancrazzi, Alessandro; Rotunno, Giada; Severgnini, Marco; Pietrelli, Alessandro; Astori, Cesare; Fugazza, Elena; Pascutto, Cristiana; Boveri, Emanuela; Passamonti, Francesco; De Bellis, Gianluca; Vannucchi, Alessandro; Cazzola, Mario

2013-05-23

We studied mutations of MPL exon 10 in patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF), first investigating a cohort of 892 consecutive patients. MPL mutation scanning was performed on granulocyte genomic DNA by using a high-resolution melt assay, and the mutant allele burden was evaluated by using deep sequencing. Somatic mutations of MPL, all but one involving codon W515, were detected in 26/661 (4%) patients with ET, 10/187 (5%) with PMF, and 7/44 (16%) patients with post-ET myelofibrosis. Comparison of JAK2 (V617F)-mutated and MPL-mutated patients showed only minor phenotypic differences. In an extended group of 62 MPL-mutated patients, the granulocyte mutant allele burden ranged from 1% to 95% and was significantly higher in patients with PMF or post-ET myelofibrosis compared with those with ET. Patients with higher mutation burdens had evidence of acquired copy-neutral loss of heterozygosity (CN-LOH) of chromosome 1p in granulocytes, consistent with a transition from heterozygosity to homozygosity for the MPL mutation in clonal cells. A significant association was found between MPL-mutant allele burden greater than 50% and marrow fibrosis. These observations suggest that acquired CN-LOH of chromosome 1p involving the MPL location may represent a molecular mechanism of fibrotic transformation in MPL-mutated myeloproliferative neoplasms.

Clinico-Pathological Profile and Outcomes of Patients with Polycythaemia Vera, Essential Thrombocythaemaia and Idiopathic Myelofibrosis: A Tertiary Care Center Experience from Southern Pakistan

International Nuclear Information System (INIS)

Shaikh, M. S.; Shaikh, M. U.; Adil, S. N.; Ahmed, Z. A.; Khurshid, M.

2016-01-01

Background: The P hiladelphia Negative Classic Myeloproliferative Neoplasms include polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF). These three disorders share several clinical and laboratory features including JAK2 V617F mutation. Our objectives were to determine the clinico-pathological profile and outcomes of Pakistani patients with polycythaemia vera (PV), essential thrombocythaemia (ET) and idiopathic myelofibrosis (IMF) in order to have an insight regarding behaviour of these conditions. Methods: A retrospective analysis of all the cases of PV, ET and IMF diagnosed at our institute from January 1995 to December 2013 was performed. Age, gender, clinical presentation, laboratory investigations, treatment provided and duration of follow-up were included for analysis. Appropriate statistics were utilized for calculation of data. Results: A total of 58 patients were diagnosed as PV, ET or IMF during the study period. Male to female ratio was 1.1:1. Forty five percent (n=27) patients came to medical attention due to abnormal laboratory results, 3 had cerebrovascular events, 3 had pruritus, and 1 patient each with gangrene and Budd-Chiari syndrome. Haemorrhage was not seen in any patient. Sixty percent (n=35) patients were treated with phlebotomy, hydroxyurea and aspirin alone or in combination. None of the patients transformed to myelofibrosis (MF) or myelodysplasia (MDS) during the mean (±SD) follow-up period of 57.2±50 months. One patient with ET transformed to acute myeloid leukaemia 9 years after the diagnosis. Conclusions: This study demonstrated a relatively more benign form of PV, ET and IMF with lesser frequency of symptoms, good response to treatment and less likelihood of transformation to MF, MDS or AML. (author)

JAK2, MPL, and CALR mutations in Chinese Han patients with essential thrombocythemia.

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Wang, Jing; Zhang, Biao; Chen, Bing; Zhou, Rong-Fu; Zhang, Qi-Guo; Li, Juan; Yang, Yong-Gong; Zhou, Min; Shao, Xiao-Yan; Xu, Yong; Xu, Xi-Hui; Ouyang, Jian; Xu, Jingyan; Ye, Qing

2017-04-01

Mutations in Janus kinase 2 (JAK2), myeloproliferative leukemia (MPL), and CALR are highly relevant to Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms. Assessing the prevalence of molecular mutations in Chinese Han patients with essential thrombocythemia (ET), and correlating their mutational profile with disease characteristics/phenotype. Of the 110 subjects studied, 62 carried the JAK2 V617F mutation, 21 had CALR mutations, one carried an MPL (W515) mutation, and 28 had non-mutated JAK2, CALR, and MPL (so-called triple-negative ET). Mutations in JAK2 exon 12 were not detected in any patient. Two ET patients had both CALR and JAK2 V617F mutations. Comparing the hematological parameters of the patients with JAK2 mutations with those of the patients with CALR mutations showed that the ET patients with CALR mutations were younger (p = 0.045) and had higher platelet counts (p = 0.043). Genotyping for CALR could be a useful diagnostic tool for JAK2/MPL-negative ET, since the data suggest that CALR is much more prevalent than MPL, therefore testing for CALR should be considered in patients who are JAK2 negative as its frequency is almost 20 times that of MPL mutation.

Characteristics and clinical correlates of MPL 515W>L/K mutation in essential thrombocythemia.

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Vannucchi, Alessandro M; Antonioli, Elisabetta; Guglielmelli, Paola; Pancrazzi, Alessandro; Guerini, Vittoria; Barosi, Giovanni; Ruggeri, Marco; Specchia, Giorgina; Lo-Coco, Francesco; Delaini, Federica; Villani, Laura; Finotto, Silvia; Ammatuna, Emanuele; Alterini, Renato; Carrai, Valentina; Capaccioli, Gloria; Di Lollo, Simonetta; Liso, Vincenzo; Rambaldi, Alessandro; Bosi, Alberto; Barbui, Tiziano

2008-08-01

Among 994 patients with essential thrombocythemia (ET) who were genotyped for the MPLW515L/K mutation, 30 patients carrying the mutation were identified (3.0%), 8 of whom also displayed the JAK2V671F mutation. MPLW515L/K patients presented lower hemoglobin levels and higher platelet counts than did wild type (wt) MPL; these differences were highly significant compared with MPLwt/JAK2V617F-positive patients. Reduced hemoglobin and increased platelet levels were preferentially associated with the W515L and W515K alleles, respectively. MPL mutation was a significant risk factor for microvessel disturbances, suggesting platelet hyperreactivity associated with constitutively active MPL; arterial thromboses were increased only in comparison to MPLwt/JAK2wt patients. MPLW515L/K patients presented reduced total and erythroid bone marrow cellularity, whereas the numbers of megakaryocytes, megakaryocytic clusters, and small-sized megakaryocytes were all significantly increased. These data indicate that MPLW515L/K mutations do not define a distinct phenotype in ET, although some differences depended on the JAK2V617F mutational status of the counterpart.

Characterization and Prognosis Significance of JAK2 (V617F), MPL, and CALR Mutations in Philadelphia-Negative Myeloproliferative Neoplasms

OpenAIRE

Singdong, Roongrudee; Siriboonpiputtana, Teerapong; Chareonsirisuthigul, Takol; Kongruang, Adcharee; Limsuwanachot, Nittaya; Sirirat, Tanasan; Chuncharunee, Suporn; Rerkamnuaychoke, Budsaba

2016-01-01

Background: The discovery of somatic acquired mutations of JAK2 (V617F) in Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) has not only improved rational disease classification and prognostication but also brings new understanding insight into the pathogenesis of diseases. Dosage effects of the JAK2 (V617F) allelic burden in Ph-negative MPNs may partially influence clinical ...

Clinical utility of routine MPL exon 10 analysis in the diagnosis of essential thrombocythaemia and primary myelofibrosis.

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Boyd, Elaine M; Bench, Anthony J; Goday-Fernández, Andrea; Anand, Shubha; Vaghela, Krishna J; Beer, Phillip; Scott, Mike A; Bareford, David; Green, Anthony R; Huntly, Brian; Erber, Wendy N

2010-04-01

Approximately 50% of essential thrombocythaemia and primary myelo-fibrosis patients do not have a JAK2 V617F mutation. Up to 5% of these are reported to have a MPL exon 10 mutation but testing for MPL is not routine as there are multiple mutation types. The ability to routinely assess both JAK2 and MPL mutations would be beneficial in the differential diagnosis of unexplained thrombocytosis or myelofibrosis. We developed and applied a high resolution melt (HRM) assay, capable of detecting all known MPL mutations in a single analysis, for the detection of MPL exon 10 mutations. We assessed 175 ET and PMF patients, including 67 that were JAK2 V617F-negative by real time polymerase chain reaction (PCR). Overall, 19/175 (11%) patients had a MPL exon 10 mutation, of whom 16 were JAK2 V617F-negative (16/67; 24%). MPL mutation types were W515L (11), W515K (4), W515R (2) and W515A (1). One patient had both W515L and S505N MPL mutations and these were present in the same haemopoietic colonies. Real time PCR for JAK2 V617F analysis and HRM for MPL exon 10 status identified one or more clonal marker in 71% of patients. This combined genetic approach increases the sensitivity of meeting the World Health Organization diagnostic criteria for these myeloproliferative neoplasms.

Phosphatidylserine-exposing blood and endothelial cells contribute to the hypercoagulable state in essential thrombocythemia patients.

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Tong, Dongxia; Yu, Muxin; Guo, Li; Li, Tao; Li, Jihe; Novakovic, Valerie A; Dong, Zengxiang; Tian, Ye; Kou, Junjie; Bi, Yayan; Wang, Jinghua; Zhou, Jin; Shi, Jialan

2018-04-01

The mechanisms of thrombogenicity in essential thrombocythemia (ET) are complex and not well defined. Our objective was to explore whether phosphatidylserine (PS) exposure on blood cells and endothelial cells (ECs) can account for the increased thrombosis and distinct thrombotic risks among mutational subtypes in ET. Using flow cytometry and confocal microscopy, we found that the levels of PS-exposing erythrocytes, platelets, leukocytes, and serum-cultured ECs were significantly higher in each ET group [JAK2, CALR, and triple-negative (TN) (all P cells and serum-cultured ECs led to markedly shortened coagulation time and dramatically increased levels of FXa, thrombin, and fibrin production. This procoagulant activity could be largely blocked by addition of lactadherin (approx. 70% inhibition). Confocal microscopy showed that the FVa/FXa complex and fibrin fibrils colocalized with PS on ET serum-cultured ECs. Additionally, we found a relationship between D-dimer, prothrombin fragment F1 + 2, and PS exposure. Our study reveals a previously unrecognized link between hypercoagulability and exposed PS on cells, which might also be associated with distinct thrombotic risks among mutational subtypes in ET. Thus, blocking PS-binding sites may represent a new therapeutic target for preventing thrombosis in ET.

Ligand-independent Thrombopoietin Mutant Receptor Requires Cell Surface Localization for Endogenous Activity*

OpenAIRE

Marty, Caroline; Chaligné, Ronan; Lacout, Catherine; Constantinescu, Stefan N.; Vainchenker, William; Villeval, Jean-Luc

2009-01-01

The activating W515L mutation in the thrombopoietin receptor (MPL) has been identified in primary myelofibrosis and essential thrombocythemia. MPL belongs to a subset of the cytokine receptor superfamily that requires the JAK2 kinase for signaling. We examined whether the ligand-independent MPLW515L mutant could signal intracellularly. Addition of the endoplasmic reticulum (ER) retention KDEL sequence to the receptor C terminus efficiently locked MPLW515L within its na...

A sensitive detection method for MPLW515L or MPLW515K mutation in chronic myeloproliferative disorders with locked nucleic acid-modified probes and real-time polymerase chain reaction.

OpenAIRE

Alessandro, Pancrazzi; Paola, Guglielmelli; Vanessa, Ponziani; Gaetano, Bergamaschi; Alberto, Bosi; Giovanni, Barosi; Alessandro M, Vannucchi

2008-01-01

Acquired mutations in the juxtamembrane region of MPL (W515K or W515L), the receptor for thrombopoietin, have been described in patients with primary myelofibrosis or essential thrombocythemia, which are chronic myeloproliferative disorders. We have developed a real-time polymerase chain reaction assay for the detection and quantification of MPL mutations that is based on locked nucleic acid fluorescent probes. Mutational analysis was performed using DNA from granulocytes. Reference curves we...

Genomic profile of a patient with triple negative essential thrombocythemia, unresponsive to therapy: A case report and literature review

Directory of Open Access Journals (Sweden)

Uzma Zaidi

2017-07-01

Full Text Available Clonal analysis of patients with triple negative myeloproliferative neoplasm (MPN has provided evidence of additional aberrations, including epigenetic alterations. To discover such novel genetic aberrations, patients were screened through next-generation sequencing using a myeloid sequencing panel of 54 genes using a genetic analyser. Genetic variants in 28 genes, including TET2, BCOR, BCR, and ABL1 were identified in a triple negative essential thrombocythemia (ET patient. The individual role of some of these variants in disease pathogenesis has yet to be studied. Somatic mutations in the same genes have been reported with variable frequencies in myeloid malignancies. However, no pathogenic impact of these variants could be found; therefore, long-term follow up of patients with genetic analysis of a large cohort and the use of whole genome sequencing is required to assess the effects of these variants.

Primary Myelofibrosis

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... attack is higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia vera include headaches and a feeling of fullness below the ribs on the left ...

Aspirin in polycythemia vera and essential thrombocythemia: current facts and perspectives.

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Landolfi, R; Patrono, C

1996-09-01

The role of aspirin in the antithrombotic strategy of patients with polycythemia vera (PV) and essential thrombocythemia (ET) is highly controversial. Long considered unsafe on the basis of a single clinical trial testing very high doses in PV patients, aspirin is being increasingly used at lower dosage. The rationale for the use of aspirin in patients with PV and ET is provided by the efficacy of this agent in the treatment of microcirculatory disturbances of thrombocythemic states associated with myeloproliferative disorders and by recent evidence that asymptomatic PV and ET patients have persistently increased thromboxane (TX) A2-biosynthesis. This increase, which most likely reflects enhanced platelet activation in vivo, is independent of the platelet mass and blood viscosity and largely supressed by a short term low-dose aspirin regimen (50 mg/day for 7 days). Since enhanced TXA2 biosynthesis may play a role in transducing the increased thrombotic risk associated with PV and ET, long-term low-dose aspirin administration has been proposed as a possible antithombotic strategy in these subjects. The safety of this treatment in PV patients has been recently reassessed by the Gruppo Italiano per lo Studio della Policitemia Vera (GISP) which has followed for over one year 112 patients randomized to receive 40 mg/day aspirin or placebo. In the same study, serum TXB2 measurements provided evidence that the low-dose aspirin regimen tested was fully effective in inhibiting platelet cyclooxygenase activity. On this basis, a large scale trial aimed at assessing the antithrombotic efficacy of this approach is currently being organized. In patients with ET both the minimal aspirin dose required for complete inhibition of platelet cyclooxygenase and the safety of long-term aspirin administration need to be established prior to extensive clinical evaluation of this strategy.

Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients.

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Cabagnols, Xénia; Favale, Fabrizia; Pasquier, Florence; Messaoudi, Kahia; Defour, Jean Philippe; Ianotto, Jean Christophe; Marzac, Christophe; Le Couédic, Jean Pierre; Droin, Nathalie; Chachoua, Ilyas; Favier, Remi; Diop, M'boyba Khadija; Ugo, Valérie; Casadevall, Nicole; Debili, Najet; Raslova, Hana; Bellanné-Chantelot, Christine; Constantinescu, Stefan N; Bluteau, Olivier; Plo, Isabelle; Vainchenker, William

2016-01-21

Mutations in signaling molecules of the cytokine receptor axis play a central role in myeloproliferative neoplasm (MPN) pathogenesis. Polycythemia vera is mainly related to JAK2 mutations, whereas a wider mutational spectrum is detected in essential thrombocythemia (ET) with mutations in JAK2, the thrombopoietin (TPO) receptor (MPL), and the calreticulin (CALR) genes. Here, we studied the mutational profile of 17 ET patients negative for JAK2V617F, MPLW515K/L, and CALR mutations, using whole-exome sequencing and next-generation sequencing (NGS) targeted on JAK2 and MPL. We found several signaling mutations including JAK2V617F at very low allele frequency, 1 homozygous SH2B3 mutation, 1 MPLS505N, 1 MPLW515R, and 2 MPLS204P mutations. In the remaining patients, 4 presented a clonal and 7 a polyclonal hematopoiesis, suggesting that certain triple-negative ETs are not MPNs. NGS on 26 additional triple-negative ETs detected only 1 MPLY591N mutation. Functional studies on MPLS204P and MPLY591N revealed that they are weak gain-of-function mutants increasing MPL signaling and conferring either TPO hypersensitivity or independence to expressing cells, but with a low efficiency. Further studies should be performed to precisely determine the frequency of MPLS204 and MPLY591 mutants in a bigger cohort of MPN. © 2016 by The American Society of Hematology.

β-Arrestin2 mediates progression of murine primary myelofibrosis.

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Rein, Lindsay Am; Wisler, James W; Kim, Jihee; Theriot, Barbara; Huang, LiYin; Price, Trevor; Yang, Haeyoon; Chen, Minyong; Chen, Wei; Sipkins, Dorothy; Fedoriw, Yuri; Walker, Julia Kl; Premont, Richard T; Lefkowitz, Robert J

2017-12-21

Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. β-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, β-arrestin2 (βarr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between βarr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor βarr2-knockout (βarr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted βarr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of βarr2-/- cells. In order to assess the effect of acute loss of βarr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional βarr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic βarr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that βarr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.

Chronic myeloproliferative disorders: A rarest case with oral manifestations and dental management

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Pritesh B Ruparelia

2012-01-01

Full Text Available Chronic myeloproliferative disorders (CMPD are rarest hematological disorders (malignant myeloid neoplasms. The three most common chronic myeloproliferative disorders are polycythemia vera, essential thrombocythemia and chronic idiopathic myelofibrosis. Clinical manifestations (including oral manifestations of these disorders are overlapping with each other and with other hematologic disorders, which makes the diagnosis of CMPD a challenging task. In this article we report a rare to rarest case of CMPD at dental outpatient department, its oral manifestations and its management in dental clinics.

Benefits and Risks of Antithrombotic Therapy in Essential Thrombocythemia: A Systematic Review.

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Chu, Derek K; Hillis, Christopher M; Leong, Darryl P; Anand, Sonia S; Siegal, Deborah M

2017-08-01

Patients with essential thrombocythemia (ET) are at high risk for both thrombosis and hemorrhage. To evaluate the risks and benefits of antithrombotic therapy in adults with ET. Multiple databases, including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, through 4 March 2017. Randomized and observational studies of antiplatelet or anticoagulant therapy, published in any language and reporting thrombotic or hemorrhagic events. Two reviewers independently extracted data, assessed risk of bias, and graded certainty of evidence. No relevant randomized trials were identified. Twenty-four observational studies (18 comparative and 6 single-group) involving 6153 patients followed for 31 711 patient-years were reviewed; most were deemed to have high risk of bias. Most patients receiving antiplatelet therapy (3613 of 4527 [80%]) received low-dose aspirin (50 to 150 mg/d); 914 (20%) received high-dose aspirin (300 to 600 mg/d), dipyridamole, or other agents. Overall, findings were inconsistent and imprecise. The reported incidence rates of thrombosis, any bleeding, and major bleeding without antiplatelet therapy ranged from 5 to 110 (median, 20), from 3 to 39 (median, 8), and from 2 to 53 (median, 6) cases per 1000 patient-years, respectively. The reported relative risks for thrombosis, any bleeding, and major bleeding with antiplatelet therapy compared with none ranged from 0.26 to 3.48 (median, 0.74), from 0.48 to 11.04 (median, 1.95), and from 0.48 to 5.17 (median, 1.30), respectively. Certainty of evidence was rated low or very low for all outcomes. No randomized trials, no extractable data on anticoagulants, lack of uniform bleeding definitions, and systematic reporting of outcomes. Available evidence about the risk-benefit ratio of antiplatelet therapy in adults with ET is highly uncertain. Regional Medical Associates. (PROSPERO: CRD42015027051).

Small RNA Sequencing Uncovers New miRNAs and moRNAs Differentially Expressed in Normal and Primary Myelofibrosis CD34+ Cells.

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Paola Guglielmelli

Full Text Available Myeloproliferative neoplasms (MPN are chronic myeloid cancers thought to arise at the level of CD34+ hematopoietic stem/progenitor cells. They include essential thrombocythemia (ET, polycythemia vera (PV and primary myelofibrosis (PMF. All can progress to acute leukemia, but PMF carries the worst prognosis. Increasing evidences indicate that deregulation of microRNAs (miRNAs might plays an important role in hematologic malignancies, including MPN. To attain deeper knowledge of short RNAs (sRNAs expression pattern in CD34+ cells and of their possible role in mediating post-transcriptional regulation in PMF, we sequenced with Illumina HiSeq2000 technology CD34+ cells from healthy subjects and PMF patients. We detected the expression of 784 known miRNAs, with a prevalence of miRNA up-regulation in PMF samples, and discovered 34 new miRNAs and 99 new miRNA-offset RNAs (moRNAs, in CD34+ cells. Thirty-seven small RNAs were differentially expressed in PMF patients compared with healthy subjects, according to microRNA sequencing data. Five miRNAs (miR-10b-5p, miR-19b-3p, miR-29a-3p, miR-379-5p, and miR-543 were deregulated also in PMF granulocytes. Moreover, 3'-moR-128-2 resulted consistently downregulated in PMF according to RNA-seq and qRT-PCR data both in CD34+ cells and granulocytes. Target predictions of these validated small RNAs de-regulated in PMF and functional enrichment analyses highlighted many interesting pathways involved in tumor development and progression, such as signaling by FGFR and DAP12 and Oncogene Induced Senescence. As a whole, data obtained in this study deepened the knowledge of miRNAs and moRNAs altered expression in PMF CD34+ cells and allowed to identify and validate a specific small RNA profile that distinguishes PMF granulocytes from those of normal subjects. We thus provided new information regarding the possible role of miRNAs and, specifically, of new moRNAs in this disease.

A case of mistaken identity: When lupus masquerades as primary myelofibrosis

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Edy Hasrouni

2013-08-01

Full Text Available Introduction: Autoimmune myelofibrosis is an uncommon hematologic disease characterized by anemia, bone marrow myelofibrosis, and an autoimmune feature. Myelofibrosis is often associated with other conditions, including infections, nutritional/endocrine dysfunction, toxin/drug exposure, and connective tissue diseases, including scleroderma and systemic lupus erythematosus. Absence of clonal markers ( JAK2 and heterogeneity of the symptoms often complicate the diagnosis. Case presentation: Here, we present two cases of systemic lupus erythematosus–induced autoimmune myelofibrosis. The first case is of a 36-year-old African American female with diagnosis of systemic lupus erythematosus at the age of 12 years. The second patient is a 44-year-old African American male with family history of systemic lupus erythematosus who developed anemia and constitutional symptoms later on. Both patients showed hypercellularity and fibrotic changes of the bone marrow. Moreover, mutational analysis showed that both patients were wild type for JAK2 (V617F and exon 12 and MPL (exon 10. Conclusions: These two cases illustrate that anemic patients with fibrotic changes in the bone marrow without other clinicopathologic features associated with primary myelofibrosis in the presence of clinical manifestations and history of an autoimmune disease should suggest an autoimmune myelofibrosis. These cases demonstrate that a good clinical history combined with molecular technologies and pathomorphologic criteria are helpful in distinguishing between primary myelofibrosis and a nonclonal myelofibrosis from an associated condition.

Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations.

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Verger, Emmanuelle; Cassinat, Bruno; Chauveau, Aurélie; Dosquet, Christine; Giraudier, Stephane; Schlageter, Marie-Hélène; Ianotto, Jean-Christophe; Yassin, Mohammed A; Al-Dewik, Nader; Carillo, Serge; Legouffe, Eric; Ugo, Valerie; Chomienne, Christine; Kiladjian, Jean-Jacques

2015-12-10

Myeloproliferative neoplasms are clonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters, clinical evolution, and prognosis. Few therapeutic options are available, among which interferon α (IFNα) presents interesting properties like the ability to induce hematologic responses (HRs) and molecular responses (MRs) in patients with JAK2 mutation. We report on the response to IFNα therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). HR was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and 2 patients even achieved complete MR. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next-generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2, and TP53 genes). The presence of additional mutations was associated with poorer MR on CALR mutant clones, with only minor or no MRs in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNα in a given patient, but no new mutation emerged during treatment. In all, this study shows that IFNα induces high rates of HRs and MRs in CALR-mutated ET, and that the presence of additional nondriver mutations may influence the MR to therapy. © 2015 by The American Society of Hematology.

Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis.

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Desterke, Christophe; Martinaud, Christophe; Guerton, Bernadette; Pieri, Lisa; Bogani, Costanza; Clay, Denis; Torossian, Frederic; Lataillade, Jean-Jacques; Hasselbach, Hans C; Gisslinger, Heinz; Demory, Jean-Loup; Dupriez, Brigitte; Boucheix, Claude; Rubinstein, Eric; Amsellem, Sophie; Vannucchi, Alessandro M; Le Bousse-Kerdilès, Marie-Caroline

2015-06-01

Primary myelofibrosis is characterized by clonal myeloproliferation, dysmegakaryopoiesis, extramedullary hematopoiesis associated with myelofibrosis and altered stroma in the bone marrow and spleen. The expression of CD9, a tetraspanin known to participate in megakaryopoiesis, platelet formation, cell migration and interaction with stroma, is deregulated in patients with primary myelofibrosis and is correlated with stage of myelofibrosis. We investigated whether CD9 participates in the dysmegakaryopoiesis observed in patients and whether it is involved in the altered interplay between megakaryocytes and stromal cells. We found that CD9 expression was modulated during megakaryocyte differentiation in primary myelofibrosis and that cell surface CD9 engagement by antibody ligation improved the dysmegakaryopoiesis by restoring the balance of MAPK and PI3K signaling. When co-cultured on bone marrow mesenchymal stromal cells from patients, megakaryocytes from patients with primary myelofibrosis displayed modified behaviors in terms of adhesion, cell survival and proliferation as compared to megakaryocytes from healthy donors. These modifications were reversed after antibody ligation of cell surface CD9, suggesting the participation of CD9 in the abnormal interplay between primary myelofibrosis megakaryocytes and stroma. Furthermore, silencing of CD9 reduced CXCL12 and CXCR4 expression in primary myelofibrosis megakaryocytes as well as their CXCL12-dependent migration. Collectively, our results indicate that CD9 plays a role in the dysmegakaryopoiesis that occurs in primary myelofibrosis and affects interactions between megakaryocytes and bone marrow stromal cells. These results strengthen the "bad seed in bad soil" hypothesis that we have previously proposed, in which alterations of reciprocal interactions between hematopoietic and stromal cells participate in the pathogenesis of primary myelofibrosis. Copyright© Ferrata Storti Foundation.

JAK2V617F mutation is associated with special alleles in essential thrombocythemia.

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Hsiao, Hui-Hua; Liu, Yi-Chang; Tsai, Hui-Jen; Lee, Ching-Ping; Hsu, Jui-Feng; Lin, Sheng-Fung

2011-03-01

Janus kinase 2 mutation (JAK2V617F) has been identified in myeloproliferative neoplasms. Furthermore, special single nucleoside polymorphisms (SNPs) have been found to be associated with the JAK2V617F mutation. Therefore, the associations among JAK2V617F and special SNPs and the allelic location between them were investigated in patients with essential thrombocythemia (ET). A total of 61 patients with ET and 106 healthy individuals were enrolled. The PCR-RFLP method was applied to investigate the pattern of three SNPs, rs10974944, rs12343867, and rs12340895. Allele-specific PCR was used to examine the allelic location between rs10974944 and JAK2V617F. Among the patients with ET, 34 (55.7%, 34/61) were JAK2V617F positive (heterozygous) while the other 27 (44.3%, 27/61) were negative, and there were no MPLW515L/K mutations noted. The pattern of special SNPs in JAK2V617F(+) was significantly different from that in normal individuals (p <0.05), while there was no difference between JAK2V617F(-) patients and normal individuals. Allele-specific PCR showed high association of a cis-location between the special G-allele of rs10974944 and JAK2V617F(+). Based on this small numbered study, the results show the association between special SNPs and JAK2V617F mutation and a cis-location between the special G-allelic form of rs10974944 and the JAK2V617F mutation. These data highlight a close relationship between them in patients with ET.

CLINICAL AND LABORATORY FEATURES OF ESSENTIAL THROMBOCYTOSIS AND PRIMARY MYELOFIBROSIS DEPENDING ON JAK2 AND CALR1 MUTATION STATUS

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E. G. lisina

2017-01-01

Full Text Available Introduction. JAK2V617F mutation is detected in approximately 50 % of patients with essential thrombocytosis (ET and primary myelofibrosis (PMF. In 2013 most of the JAK2 negative patients showed mutations in the CALR gene. Diagnostic value of JAK2 and CALR mutations is high, but their prognostic significance is not sufficiently clear. Data on impact of JAK2 and CALR mutational status on thrombotic complications in ET and myelofibrosis patients are contradictory.The aim of the study was to identify clinical and laboratory features in patients with ET and PMF in accordance with the mutational status of JAK2V617F and CALR gene.Materials and methods. Patients treated in Almazov National Medical Research Center (St. Petersburg, Chuvash Republican Clinical Hospital (Cheboksary, Irkutsk Regional Clinical Hospital (Irkutsk,  Kirov Research Institute of Hematology and Blood Transfusion (Kirov was included in the retrospective study. CALR mutation (1 and 2 types, MPL W515L/K and JAK2V617F mutation were detected in peripheral blood cells.Results. We identified that 21 % (n = 16 of ET patients had thrombotic complications, and they occurred more often among JAK2V617F positive patients (p <0.05. The median of hemoglobin level in PMF was the lowest in the group of triple negative patients. The level of leukocytes in PMF was higher in the group of triple negative patients than in the group with mutated CALR (p = 0.014.Conclusion. JAK2V617F mutation in ET patients was associated with a high risk of thrombosis. Patients with CALR mutations may have a favorable prognosis regarding to thrombotic complications. Some laboratory features of CALR mutations in ET and PMF patients have been revealed.

Application of inhibitor JAK1 and JAK2 ruxolitinib as pre- and posttransplant therapy in patients with myelofibrosis

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M. V. Barabanshchikova

2016-01-01

Full Text Available Primary myelofibrosis (PMF is а chronic BCRABL–negative myeloproliferative disorder with progressive clinical course. Allogeneic stem cell transplantation is the only treatment optionin patients with PMF with curative potential. Most of PMF patients have active disease phase at the moment of alloHSCT. The Januskinase inhibitor ruxolitinib is effective in decreasingof tumor mass before alloHSCT. Here we report our experience in administration of ruxolitinib as pre and posttransplant therapy of patients with PMF as well as patients with polycythemia vera and essential thrombocythaemia with transformation into myelofibrosis.

The association of JAK2V617F mutation and leukocytosis with thrombotic events in essential thrombocythemia.

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Hsiao, Hui-Hua; Yang, Ming-Yu; Liu, Yi-Chang; Lee, Ching-Ping; Yang, Wen-Chi; Liu, Ta-Chih; Chang, Chao-Sung; Lin, Sheng-Fung

2007-11-01

The Janus kinase 2 mutation, JAK2 (V617F), and megakaryocytic mutations, MPL (W515L/K), have been identified and correlated with a subtype of essential thrombocythemia (ET) patients. We investigated the frequency of mutations in ET patients and analyzed the relationship with their clinical features. Fifty-three ET patients were enrolled in the study. The amplification refractory mutation system was applied for the mutation survey of the JAK2V617F, while the polymerase chain reaction with sequencing was used for the mutation survey of MPLW515L/K. Thirty-five (66%) patients harboring the JAK2 (V617F) mutation, including 3 homozygous and 32 heterozygous changes, but no MPLW515L/K mutation, were found. During follow-up, 17 (32.1%) patients suffered from documented thrombotic events, with 15 having JAK2V617F mutations. Statistical analysis showed that patients with the JAK2 mutation had significantly higher leukocytes, hemoglobin level, and thrombotic event (p = 0.043, p = 0.001, and p = 0.029, respectively). Thrombotic events were also significantly correlated with leukocytosis and older age. The JAK2V617F mutation was noted in a certain population of ET patients and correlated with leukocytosis, high hemoglobin level, and thrombosis. Therefore, detection of the JAK2V617F mutation can affect not only the diagnosis, but also the management of ET patients.

Hypercalcemia in idiopathic myelofibrosis

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Voss, A; Schmidt, K; Hasselbalch, H

1992-01-01

A case of idiopathic myelofibrosis (IMF) presenting with hypercalcemia and hypercalcitriolemia is reported. It is proposed that ectopic production of the active vitamin D metabolite related to ongoing clonal expansion in the bone marrow accounts for the hypercalcemic state. Consistently low level...

A mutação JAK2 V617F e as síndromes mieloproliferativas JAK2 V617F mutation and the myeloproliferative disorders

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Bárbara C. R. Monte-Mór

2008-01-01

Full Text Available Síndromes mieloproliferativas (SMPs são doenças hematopoéticas de origem clonal que apresentam amplificação de uma ou mais linhagens mielóides. Policitemia vera (PV, trombocitemia essencial (TE, mielofibrose idiopática (MF e leucemia mielóide crônica (LMC são consideradas SMPs clássicas e apresentam características clínicas e biológicas comuns. Ao contrário de LMC, cuja etiologia está relacionada à proteína constitutivamente ativa Bcr-Abl, o mecanismo molecular de PV, TE e MF permaneceu por muito tempo desconhecido. Esta revisão se foca na recente descoberta da mutação JAK2 V617F em pacientes com PV, TE e MF, sua relação com o fenótipo mieloproliferativo e implicações na abordagem clínica de pacientes.Myeloproliferative disorders are clonal hematopoietic diseases that are characterized by the amplification of one or more myeloid lineages. Polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis and chronic myeloid leukemia are considered classic myeloproliferative disorders and share common clinical and biological features. While the genetic basis of chronic myeloid leukemia is shown to be the constitutive active protein BCR-ABL, the main molecular lesions in polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis remain unknown. This review focuses on the recent discovery of the JAK2 V617F mutation, its relationship to the myeloproliferative phenotype and implications in the clinical approach of patients.

Epigenetic changes in myelofibrosis

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Nielsen, Helene Myrtue; Andersen, Christen Lykkegaard; Westman, Maj

2017-01-01

This is the first study to compare genome-wide DNA methylation profiles of sorted blood cells from myelofibrosis (MF) patients and healthy controls. We found that differentially methylated CpG sites located to genes involved in 'cancer' and 'embryonic development' in MF CD34+ cells, in 'inflammat...

Autoimmune myelofibrosis. A steroid-responsive cause of bone marrow fibrosis associated with systemic lupus erythematosus.

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Paquette, R L; Meshkinpour, A; Rosen, P J

1994-05-01

Autoimmune myelofibrosis is an uncommon disorder in which patients present with anemia and thrombocytopenia in conjunction with limited clinical manifestations of autoimmune disease or an exacerbation of previously established SLE. The presence of leukoerythroblastosis in a patient with SLE may suggest the presence of myelofibrosis. Conversely, the absence of splenomegaly in a patient with presumed idiopathic myelofibrosis may suggest an autoimmune etiology. Patients with autoimmune myelofibrosis universally have a positive ANA test and frequently have either elevated anti-DNA titers or a positive LE cell preparation. Because physical manifestations of autoimmune disease may not be evident at presentation, all patients found to have myelofibrosis should have an ANA test. Peripheral blood cytopenias in autoimmune myelofibrosis frequently respond to glucocorticoids but regression of bone marrow fibrosis may be incomplete. Hematologic response to treatment parallels that of the associated autoimmune disease.

Myelofibrosis and acquired hemophilia A: a case report.

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Wrobel, Marie; Comio, Emilie; Gay, Valerie; Baroudi, Noureddine; Meyer, Pascal; Chuniaud-Louche, Christine; Hacini, Maya; Pica, Gian Matteo

2016-05-07

Myelofibrosis and acquired hemophilia A is a rare association. To the best of our knowledge only one case of myelofibrosis and acquired hemophilia A has been previously described. A 66-year-old Caucasian man diagnosed with myelofibrosis evolving in acute myeloid leukemia was referred to us for postoperative bleeding. Hemostatic studies showed prolonged activated partial thromboplastin time, decreased factor VIII coagulation, and a high factor VIII inhibitor titer; these findings led to a diagnosis of acquired hemophilia A for which he was treated with methylprednisolone and recombinant activated factor VII on admission. Due to a lack of response he was subsequently treated with rituximab combined with activated prothrombin complex concentrates. Furthermore, he received azacytidine to treat the underlying hematological malignancies. Immunosuppressive rituximab therapy resolved acquired hemophilia A with marked efficacy. Rapid and accurate diagnosis, effective hemostatic therapy, and timely treatment for underlying disease are important in the management of acquired hemophilia A secondary to hematological malignancy.

Different immunophenotypical apoptotic profiles characterise megakaryocytes of essential thrombocythaemia and primary myelofibrosis.

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Florena, A M; Tripodo, C; Di Bernardo, A; Iannitto, E; Guarnotta, C; Porcasi, R; Ingrao, S; Abbadessa, V; Franco, V

2009-04-01

Essential thrombocythaemia (ET) and primary myelofibrosis (PMF) share some clinical and pathological features, but show different biological behaviour and prognosis. The latest contributions to understanding the nature of these disorders have focused on bone marrow microenvironment remodelling and proliferative stress, recognising megakaryocytes (MKCs) as "key-cells". The aim of this study was to investigate the apoptotic profile of ET and PMF MKCs in order to further characterise the biology of these disorders. Bone marrow biopsy samples from 30 patients with ET, and 30 patients with PMF, were immunophenotypically studied for the expression of pro-apoptotic (Fas, Fas-L, Bax, Bad) and anti-apoptotic (Bcl-2, Bcl-XL, hTERT (human telomerase reverse transcriptase)) molecules and the "executioner" molecule caspase-3. The fraction of MKCs undergoing apoptosis was assessed by deoxynucleotidyl transferase-mediated dUTP nick-end labelling. Only the mitochondrial pathway seemed to be involved in MKC apoptosis. The anti-apoptotic molecule Bcl-XL was predominantly found in ET MKCs (50.5% of ET MKCs versus 35% of PMF MKCs; p = 0.036), while pro-apoptotic molecules Bax and Bad showed a prevalent expression in PMF MKCs (30.5% of ET MKCs versus 55% of PMF MKCs; 41% of ET MKCs versus 52% of PMF MKCs; p = 0.001 and p = 0.068, respectively). A significant fraction of PMF MKCs were committed to apoptosis according to caspase-3 expression and TUNEL, while only few ET cells were committed to apoptosis. hTERT was significantly more expressed in PMF (32% of ET MKCs versus 46% of PMF MKCs; p = 0.022), in agreement with the proliferative nature of this disease. It was found that ET and PMF MKCs, which barely differ in terms of morphology and aggregation, are characterised by markedly different apoptotic profiles. The rather high apoptotic fraction of PMF was able to support the fibrotic nature of this process, while the anti-apoptotic profile of ET cells fits well with their "steady

Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis

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Desterke, Christophe; Martinaud, Christophe; Guerton, Bernadette

2015-01-01

Primary myelofibrosis is characterized by clonal myeloproliferation, dysmegakaryopoiesis, extramedullary hematopoiesis associated with myelofibrosis and altered stroma in the bone marrow and spleen. The expression of CD9, a tetraspanin known to participate in megakaryopoiesis, platelet formation,...

Detection of MPL mutations by a novel allele-specific PCR-based strategy.

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Furtado, Larissa V; Weigelin, Helmut C; Elenitoba-Johnson, Kojo S J; Betz, Bryan L

2013-11-01

MPL mutation testing is recommended in patients with suspected primary myelofibrosis or essential thrombocythemia who lack the JAK2 V617F mutation. MPL mutations can occur at allelic levels below 15%, which may escape detection by commonly used mutation screening methods such as Sanger sequencing. We developed a novel multiplexed allele-specific PCR assay capable of detecting most recurrent MPL exon 10 mutations associated with primary myelofibrosis and essential thrombocythemia (W515L, W515K, W515A, and S505N) down to a sensitivity of 2.5% mutant allele. Test results were reviewed from 15 reference cases and 1380 consecutive specimens referred to our laboratory for testing. Assay performance was compared to Sanger sequencing across a series of 58 specimens with MPL mutations. Positive cases consisted of 45 with W515L, 6 with S505N, 5 with W515K, 1 with W515A, and 1 with both W515L and S505N. Seven cases had mutations below 5% that were undetected by Sanger sequencing. Ten additional cases had mutation levels between 5% and 15% that were not consistently detected by sequencing. All results were easily interpreted in the allele-specific test. This assay offers a sensitive and reliable solution for MPL mutation testing. Sanger sequencing appears insufficiently sensitive for robust MPL mutation detection. Our data also suggest the relative frequency of S505N mutations may be underestimated, highlighting the necessity for inclusion of this mutation in MPL test platforms. Copyright © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Simultaneous presence of two hematological malignancies: chronic lymphocytic leukemia and myelofibrosis in a patient.

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Palta, Anshu; Garg, Shailja; Chauhan, Sandeep; Varma, Neelam

2011-03-01

Coexistence of chronic lymphocytic leukemia (CLL) with myelofibrosis is a rare association with only isolated case reports in the literature. We report an unusual case of CLL in which the cause of anemia was coexistent myelofibrosis. In a case of CLL presenting with refractory anemia, besides common causes like autoimmune hemolytic anemia and marrow infiltration, other causes like myelofibrosis should be searched for.

DNA methylation profiling of sorted cells from myelofibrosis patients reveals aberrant epigenetic regulation of immune pathways and identifies early MPN driver genes

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Nielsen, Helene Myrtue; Andersen, Christen Lykkegaard; Kristensen, Lasse Sommer

2015-01-01

Background: Primary myelofibrosis (PMF) belongs to the heterogeneous group of chronic myeloproliferative neoplasms (MPN) together with essential thrombocytosis (ET) and polycythemia vera (PV). It has been suggested that these neoplasms represent a biological continuum from early cancer stage (ET...

The effect of alpha-interferon on bone marrow megakaryocytes and platelet production rate in essential thrombocythemia

International Nuclear Information System (INIS)

Wadenvik, H.; Kutti, J.; Ridell, B.; Revesz, P.; Jacobsson, S.; Magnusson, B.; Westin, J.; Vilen, L.

1991-01-01

In 10 patients with previously untreated essential thrombocythemia (ET), by using 111 In-labeled platelets and megakaryocyte morphometry, the relation between platelet production rate and bone marrow megakaryocytes was evaluated before and during alpha-2b-interferon (IFN) therapy. A highly significant decrease in platelet count occurred during IFN therapy; the platelet counts, at baseline and after 2 and 6 months of IFN therapy, were 1,102 +/- 345 x 10(9)/L, 524 +/- 169 x 10(9)/L (P less than .0001), and 476 +/- 139 x 10(9)/L (P less than .0001), respectively. The decrement in platelet count was mainly a result of diminished platelet production rate, which at baseline and after 2 and 6 months of IFN therapy was 89 +/- 30 x 10(10) platelets/d, 53 +/- 18 x 10(10) platelets/d (P = .0033), and 45 +/- 20 x 10(10) platelets/d (P less than .0001), respectively. Also, a slight shortening of platelet mean life-span (MLS) was observed in response to IFN treatment; platelet MLS was 7.96 +/- 0.69 days at baseline and 6.68 +/- 1.30 days (P = .012) after 6 months of IFN therapy. IFN induced a significant decrease in bone marrow megakaryocyte volume; both megakaryocyte nuclear and cytoplasmatic volumes were affected. The mean megakaryocyte volume was 372 +/- 126 x 10(2) pL/microL at baseline and 278 +/- 147 x 10(2) pL/microL (P = .049) after 6 months of IFN therapy. However, the number of megakaryocytes did not show any significant change in response to IFN. It is concluded that alpha-IFN reduces platelet production rate and the peripheral platelet count in ET mainly through an anti-proliferative action on the megakaryocytes and to a considerably lesser degree by a shortening of platelet MLS

Bone marrow stroma in idiopathic myelofibrosis and other haematological diseases. An immunohistochemical study

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Lisse, I; Hasselbalch, H; Junker, P

1991-01-01

Bone marrow stroma was investigated immunohistochemically in 31 patients with haematological diseases, mainly idiopathic myelofibrosis (n = 8) and related chronic myeloproliferative disorders (n = 14). The bone marrow from patients with idiopathic myelofibrosis and some CML patients showed marked...

Clinical, histopathologic, and genetic features of pediatric primary myelofibrosis--an entity different from adults.

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DeLario, Melissa R; Sheehan, Andrea M; Ataya, Ramona; Bertuch, Alison A; Vega, Carlos; Webb, C Renee; Lopez-Terrada, Dolores; Venkateswaran, Lakshmi

2012-05-01

Primary myelofibrosis is a chronic myeloproliferative neoplasm characterized by cytopenias, leukoerythroblastosis, extramedullary hematopoiesis, hepatosplenomegaly and bone marrow fibrosis. Primary myelofibrosis is a rare disorder in adults; children are even less commonly affected by this entity, with the largest pediatric case series reporting on three patients. Most literature suggests spontaneous resolution of myelofibrosis without long term complications in the majority of affected children. We describe the clinical, pathologic, and molecular characteristics and outcomes of nineteen children with primary myelofibrosis treated in our center from 1984 to 2011. Most patients had cytopenia significant enough to require supportive therapy. No child developed malignant transformation and only five of the 19 children (26%) had spontaneous resolution of disease. Sequence analyses for JAK2V617F and MPLW515L mutations were performed on bone marrow samples from 17 and six patients, respectively, and the results were negative. In conclusion, analysis of this large series of pediatric patients with primary myelofibrosis demonstrates distinct clinical, hematologic, bone marrow, and molecular features from adult patients. Copyright © 2012 Wiley Periodicals, Inc.

Pathogenetic Role of JAK2 V617F Mutation in Chronic Myeloproliferative Disorders

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Hui-Chi Hsu

2007-03-01

Full Text Available The molecular pathogenesis of chronic myeloproliferative disorders (MPDs is poorly understood. The hematopoietic progenitor cells of patients with polycythemia vera (PV or essential thrombocythemia (ET are characterized by hypersensitiv-ity to hematopoietic growth factors and formation of endogenous erythroid colonies. Recently, 4 groups reported almost simultaneously Janus kinase 2 (JAK2 V617F mutation in more than 80% of PV patients, 30% of patients with ET and in about 50% of patients with idiopathic myelofibrosis. The identification of the JAK2 mutation represents a major advance in the understanding of the molecular pathogenesis of MPDs that will likely permit a new classification and the development of novel therapeutic strategies for these diseases.

Lung Clear “Sugar” Cell Tumor and Jak V617f Positive Essential Thrombocythemia: A simple Coıncıdence?

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Volkan Yazak

2013-04-01

Full Text Available The primary clear cell tumor of the lung is an extremely rare benign tumor, which is called “sugar tumor”, because of the large content of glycogen. Here we are presenting essential thrombocythemia and lung clear cell tumor which was not reported before to the best of our knowledge. A 44 years old woman admitted to the clinic with complaint of lassitude lasting for 2 months. In her physical examination the spleen was 3 cm palpable from the costa arch In laboratory findings number of platelet was 1014000 mm³. A 3.5 cm in diameter pulmonary nodule is detected in right upper lobe in the graphy of the lungs. Subsequently  computed tomography  (CT of thorax was carried out. Due to the benign features in the display of  the detected nodule, a total excision with curative and diagnostic intentions was performed. Microscopically the tumor were composed of nests of rounded or oval cells with distinct cell borders and optically clear cytoplasm. The nuclei were small. Immunohistochemically the tumor cells expressed HMB-45, NSE and focal S100 antigen. It was diagnosed as clear  “sugar” cell tumor. In conclusion, in lung clear cell tumor, it is important to make evaluation in terms of myeloproliferative disease in adults whose thrombocytosis continue after the treatment.

Genetic Alterations in Essential Thrombocythemia Progression to Acute Myeloid Leukemia: A Case Series and Review of the Literature

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Jackline P. Ayres-Silva

2018-02-01

Full Text Available The genetic events associated with transformation of myeloproliferative neoplasms (MPNs to secondary acute myeloid leukemia (sAML, particularly in the subgroup of essential thrombocythemia (ET patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH and whole exome sequencing (WES to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47, and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu. All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation. Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.

JAK2 mutations and clinical practice in myeloproliferative neoplasms.

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Tefferi, Ayalew

2007-01-01

With the discovery in the last 3 years of novel Janus kinase 2 (JAK2) and thrombopoietin receptor (MPL) mutations, the pathogenetic understanding of and clinical practice for myeloproliferative neoplasms (MPNs) have entered a new era. Each one of these newly discovered mutations, including JAK2V617F, MPLW515L, and a JAK2 exon 12 mutation, has been shown to result in constitutive activation of JAK-STAT signaling and also induce a MPN phenotype in mice. Thus, JAK2 is now considered to be a legitimate target for drug development in MPNs, and small molecule JAK2 inhibitors have already gone through successful preclinical testing, and early-phase human trials in primary myelofibrosis have already begun. Furthermore, JAK2 mutation screening has now become a front-line diagnostic test in the evaluation of both "erythrocytosis" and thrombocytosis and the 2001 World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis have now been revised to incorporate JAK2V617F mutation screening.

Essential Thrombocythemia

Science.gov (United States)

... Treatment for information on diagnosis , staging , and treatment. Polycythemia Vera Key Points Polycythemia vera is a disease ... blood tests are used to diagnose polycythemia vera. Polycythemia vera is a disease in which too many ...

Chronic Idiopathic Myelofibrosis Presenting as Cauda Equina Compression due to Extramedullary Hematopoiesis: A Case Report

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Goh, Duck-Ho; Cho, Dae-Chul; Park, Seong-Hyun; Hwang, Jeong-Hyun; Sung, Joo-Kyung

2007-01-01

Extramedullary hematopoiesis (EMH) is occasionally reported in idiopathic myelofibrosis and is generally found in the liver, spleen, and lymph nodes several years after diagnosis. Myelofibrosis presenting as spinal cord compression, resulting from EMH tissue is very rare. A 39-yr-old man presented with back pain, subjective weakness and numbness in both legs. Sagittal magnetic resonance imaging showed multiple anterior epidural mass extending from L4 to S1 with compression of cauda equina and nerve root. The patient underwent gross total removal of the mass via L4, 5, and S1 laminectomy. Histological analysis showed islands of myelopoietic cells surrounded by fatty tissue, consistent with EMH, and bone marrow biopsy performed after surgery revealed hypercellular marrow and megakaryocytic hyperplasia and focal fibrosis. The final diagnosis was chronic idiopathic myelofibrosis leading to EMH in the lumbar spinal canal. Since there were no abnormal hematological findings except mild myelofibrosis, additional treatment such as radiothepary was not administered postoperatively for fear of radiotoxicity. On 6 month follow-up examination, the patient remained clinically stable without recurrence. This is the first case of chronic idiopathic myelofibrosis due to EMH tissue in the lumbar spinal canal in Korea. PMID:18162730

Extramedullary hematopoiesis of the conjunctiva presenting as active systemic disease in a patient with myelofibrosis.

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Cuttler, Nirupa; Heidemann, David; Cendrowski, Christopher; Armin, Ali-Reza; Folberg, Robert

2014-12-01

To report the clinicopathological correlation of extramedullary hematopoiesis (EMH) of the conjunctiva in a patient with a history of myelofibrosis. Case report. Elevated pink conjunctival lesions developed bilaterally in a 73-year-old man who had been treated for myelofibrosis for 13 years. EMH was detected in the examination of tissue from the lesion of the inferior fornix of the right eye. The appearance of conjunctival lesions in a patient with myelofibrosis may indicate underlying pathology of EMH that may necessitate a change in systemic treatment of this condition.

Myelofibrosis-Related Arthritis Successfully Treated with Hydroxyurea

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Xavier Guillot

2014-01-01

Full Text Available A 62-year-old woman suffering from one-year lasting, nonerosive peripheral arthritides with general health impairment and high acute-phase reactant levels was admitted to rheumatology department. The patient had suffered from chronic polyarthralgia and a thrombocytosis had been discovered 9 years before, with a recent increase in platelet count. All immunological blood tests were negative. Corticosteroid and methotrexate treatments improved pain, swollen joint count, and systemic inflammation. However, joints remained stiff and painful with two swollen wrists and persistent thrombocytosis. An iliac bone marrow biopsy was performed, showing primary myelofibrosis. Hydroxyurea treatment (500 mg per day allowed to achieve complete and prolonged clinical and biological remission. After 6 months, a new disease flare occurred. The patient reached remission again after hydroxyurea dose increased to 1500 mg per day. This supports the hypothesis of idiopathic myelofibrosis-associated seronegative polyarthritis. This is the first reported case in which haemopathy-targeted treatment using hydroxyurea induced arthritis remission.

Philadelphia chromosome-negative myeloproliferative disorders: biology and treatment.

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Hoffman, Ronald; Prchal, Josef T; Samuelson, Scott; Ciurea, Stefan O; Rondelli, Damiano

2007-01-01

The Philadelphia chromosome (Ph)-negative myeloproliferative disorders (MPDs) include essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and polycythemia vera (PV). All of these disorders are clonal hematologic malignancies originating at the level of the pluripotent hematopoietic stem cell. Recently, activating mutations of the intracellular cytokine-signaling molecule JAK2 have been identified in > 90% of patients with PV and in 50% of those with IMF and ET. In addition, a mutation of the thrombopoietin receptor, MPLW515L, has been documented in some patients with IMF. Both mutations activate JAK-STAT signaling pathways and likely play a role in disease progression. Both ET and PV are associated with prolonged clinical courses associated with frequent thrombotic and hemorrhagic events, and progression to myelofibrosis and acute leukemia. IMF has a much poorer prognosis and is associated with cytopenias, splenomegaly, extramedullary hematopoiesis, and bone marrow fibrosis. Stratification of risk for the development of complications from Ph-negative MPDs has guided the identification of appropriate therapies for this population. Intermediate/high-risk IMF or myelofibrosis after ET or PV is associated with a sufficiently poor prognosis to justify the use of allogeneic stem cell transplantation, which is capable of curing such patients. Reduced-intensity conditioning in preparation for allogeneic stem cell transplantation has permitted older patients with IMF to undergo transplantation with increasing success.

Splenic irradiation in myelofibrosis. Clinical findings and ferrokinetics

International Nuclear Information System (INIS)

Parmentier, C.; Charbord, P.; Tibi, M.; Tubiana, M.

1977-01-01

Nine patients were submitted to splenic or, in two cases, hepatosplenic irradiation; these patients presented a primary myelofibrosis or a spent polycythemia vera characterized by splenomegaly, anemia, and occasionally leucocytosis and thrombocytopenia. The hematological condition returned to normal in 2 patients. This improvement lasted 4 years after a first series of irradiation. The recurrence of splenomegaly and anemia indicated a second series of irradiation, the results of which were as good as those of the first series. Ineffective medullary and splenic erythropoiesis without preeminent aplasia appeared to be correlated with a beneficial effect of splenic irradiation. Absence of hepatomegaly and marked leucocytosis were less important prognostic factors. The modee of action of radiotherapy and the way in which it differs from splenectomy are discussed. The irradiation delivered moderate doses (450 rad in 18 sessions of 25 rad). Hepatic irradiation did not appear to be essential even in cases of intense hepatic myeloid metaplasia: in 2 patients liver erythropoiesis regressed when the spleen alone was irradiated

[Spinal cord compression due to extramedullary hematopoiesis in a patient with myelofibrosis].

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Hijikata, Yasuhiro; Ando, Tetsuo; Inagaki, Tomonori; Watanabe, Hirohisa; Ito, Mizuki; Sobue, Gen

2014-01-01

Development and growth of hematopoietic tissue outside of the bone marrow is termed extramedullary hematopoiesis (EMH). It occurs in patients with hematological diseases such as myelofibrosis and thalassemia. Liver and spleen are the usual sites of EMH. However, spinal cord compression caused by EMH is a rare complication. A 65-year-old man with myelofibrosis was admitted to our hospital with progressive paraparesis. Thoracic spine MRI revealed epidural masses causing cord compression. Histological examination of the epidural mass showed evidence of EMH consisting of megakaryocytic and erythroid hyperplasia. After surgical decompression and radiotherapy, lower limb weakness and sensory disturbance were significantly improved. MRI showed disappearance of the spinal cord compression. With this therapy, he had no recurrence until he died of myelofibrosis. Spinal EMH should be considered as a differential diagnosis in patients with hematological diseases presenting with paraparesis. Surgical decompression and radiotherapy are effective approaches for the treatment of paraparesis due to EMH.

Current approaches to challenging scenarios in myeloproliferative neoplasms.

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Zimran, Eran; Hoffman, Ronald; Kremyanskaya, Marina

2018-06-01

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia and primary myelofibrosis are clonal hematological malignancies that originate at the level of the hematopoietic stem cell, and are characterized by excessive proliferation of cells belonging to one or more of the myeloid lineages. Central to the pathogenesis of the MPNs is constitutive activation of the JAK/STAT signaling pathway due to a family of driver mutations affecting JAK2, CALR or MPL. These disorders share common clinical and laboratory features, a significant burden of systemic symptoms, increased risk of developing arterial and venous thrombotic events, and the potential to progress to myelofibrosis and acute leukemia. Areas covered: We identified four clinical situations which represent challenging management dilemmas for patients with MPNs. Our conclusions and recommendations are based on a literature search using MEDLINE and recent meeting abstracts using the keywords, focusing on publications directly addressing these scenarios and on recent contributions to the field. Expert commentary: Multi-center efforts to study large cohorts of MPN patients have led to more uniform and evidence-based approaches to key aspects in MPN management. However, treatment strategies to deal with specific clinical scenarios are lacking.

The role of cytokines in the initiation and progression of myelofibrosis

DEFF Research Database (Denmark)

Hasselbalch, Hans K

2013-01-01

Myelofibrosis (MF) is a life-threatening blood cancer characterized by progressive bone marrow fibrosis, splenomegaly, cytopenias, and debilitating constitutional symptoms. Abnormal expression and activity of a number of proinflammatory cytokines are associated with MF, in which immune dysregulat...... and progression is discussed, the impact of current therapies is reviewed, and new combination therapies are proposed, such as JAK1/2 inhibitors with interferons, statins, and epigenetic modifiers for patients with MF and related neoplasms.......Myelofibrosis (MF) is a life-threatening blood cancer characterized by progressive bone marrow fibrosis, splenomegaly, cytopenias, and debilitating constitutional symptoms. Abnormal expression and activity of a number of proinflammatory cytokines are associated with MF, in which immune...

[A case of cutaneous extramedullary hematopoiesis associated with idiopathic myelofibrosis].

Science.gov (United States)

Corella, F; Barnadas, M A; Bordes, R; Curell, R; Espinosa, I; Vergara, C; Alomar, A

2008-05-01

Cutaneous extramedullary hematopoiesis is a rare manifestation of chronic myeloproliferative processes, mainly chronic idiopathic myelofibrosis. In adults, it manifests as macules, papules, nodules, and ulcers on the trunk. The lesions usually appear soon after diagnosis and the possibility of a relationship between splenectomy and the appearance of extramedullary foci of hematopoiesis is still debated. Diagnosis is based on histopathology showing an infiltrate with different combinations of myeloid and erythroid cell precursors and megakaryocytes. Symptomatic treatment is provided alongside treatment of the underlying disease. We report a new case associated with chronic idiopathic myelofibrosis in which foci of cutaneous extramedullary hematopoiesis were observed 9 years after initial diagnosis. The lesions were progressive and the patient went on to develop acute myeloid leukemia.

Bone marrow scintigraphy. An aid to the diagnosis and prognosis of myelofibrosis

International Nuclear Information System (INIS)

Rain, J.D.; Najean, Y.

1993-01-01

During the last three years 77 patients with myelofibrosis were studied by scintigraphy, using 99m Tc colloids and 111 in transferring as tracers. Low axial uptake of the colloids, extension of the indium uptake beyond the axis towards the knees and sometimes the ankles and elbows, and splenic indium uptake are valuable diagnostic criteria, particularly useful to exclude myelofibrosis associated with a malignant disorder. The clinical severity of the disease, and in particular the disappearance of physiologically active bone marrow (indium uptake) can be predicted from isotopic studies. Bone marrow scintigraphy could contribute to the difficult decision of splenectomy

Chasing down the triple-negative myeloproliferative neoplasms: Implications for molecular diagnostics.

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Langabeer, Stephen E

2016-01-01

The majority of patients with classical myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia, and primary myelofibrosis harbor distinct disease-driving mutations within the JAK2 , CALR , or MPL genes. The term triple-negative has been recently applied to those MPN without evidence of these consistent mutations, prompting whole or targeted exome sequencing approaches to determine the driver mutational status of this subgroup. These strategies have identified numerous novel mutations that occur in alternative exons of both JAK2 and MPL , the majority of which result in functional activation. Current molecular diagnostic approaches may possess insufficient coverage to detect these alternative mutations, prompting further consideration of targeted exon sequencing into routine diagnostic practice. How to incorporate these illuminating findings into the expanding molecular diagnostic algorithm for MPN requires continual attention.

High Frequency of Copy-Neutral Loss of Heterozygosity in Patients with Myelofibrosis.

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Rego de Paula Junior, Milton; Nonino, Alexandre; Minuncio Nascimento, Juliana; Bonadio, Raphael S; Pic-Taylor, Aline; de Oliveira, Silviene F; Wellerson Pereira, Rinaldo; do Couto Mascarenhas, Cintia; Forte Mazzeu, Juliana

2018-01-01

Myelofibrosis is the rarest and most severe type of Philadelphia-negative classical myeloproliferative neoplasms. Although mutually exclusive driver mutations in JAK2, MPL, or CALR that activate JAK-STAT pathway have been related to the pathogenesis of the disease, chromosome abnormalities have also been associated with the phenotype and prognosis of the disease. Here, we report the use of a chromosomal microarray platform consisting of both oligo and SNP probes to improve the detection of chromosome abnormalities in patients with myelofibrosis. Sixteen patients with myelofibrosis were tested, and the results were compared to karyotype analysis. Driver mutations in JAK2, MPL, or CALR were investigated by PCR and MLPA. Conventional cytogenetics revealed chromosome abnormalities in 3 out of 16 cases (18.7%), while chromosomal microarray analysis detected copy-number variations (CNV) or copy-neutral loss of heterozygosity (CN-LOH) alterations in 11 out of 16 (68.7%) patients. These included 43 CN-LOH, 14 deletions, 1 trisomy, and 1 duplication. Ten patients showed multiple chromosomal abnormalities, varying from 2 to 13 CNVs or CN-LOHs. Mutational status for JAK2, CALR, and MPL by MLPA revealed a total of 3/16 (18.7%) patients positive for the JAK2 V617F mutation, 9 with CALR deletion or insertion and 1 positive for MPL mutation. Considering that most of the CNVs identified were smaller than the karyotype resolution and the high frequency of CN-LOHs in our study, we propose that chromosomal microarray platforms that combine oligos and SNP should be used as a first-tier genetic test in patients with myelofibrosis. © 2018 S. Karger AG, Basel.

Systemic lupus erythematosus and myelofibrosis: A case report and revision of literature

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F. Del Porto

Full Text Available Blood cytopenia represents one of the diagnostic criteria for systemic lupus erythematosus (SLE and may occur as the first symptom of the disease. Antibody-mediated peripheral destruction of blood cells is the main cause of cytopenia observed in patients affected by SLE, however, inflammatory anemia, nutritional deficiencies, immunosuppressive therapy and, more rarely, myelofibrosis (MF have also been documented. In the literature, 45 cases of autoimmune MF (AIMF and SLE have been previously reported. Here the 46th case of a 43-year-old female with a SLE and an underhand cytopenia, with a review of the literature. Keywords: Systemic lupus erythematosus, Autoimmune myelofibrosis, Blood cytopenia

Efficacy of ALK5 inhibition in myelofibrosis

OpenAIRE

Yue, Lanzhu; Bartenstein, Matthias; Zhao, Wanke; Ho, Wanting Tina; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao

2017-01-01

Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-? family members are profibrotic cytokines and we observed significant TGF-?1 isoform overexpression in a large co...

Depletion of STAT5 blocks TEL–SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice

International Nuclear Information System (INIS)

Sprissler, C; Belenki, D; Maurer, H; Aumann, K; Pfeifer, D; Klein, C; Müller, T A; Kissel, S; Hülsdünker, J; Alexandrovski, J; Brummer, T; Jumaa, H; Duyster, J; Dierks, C

2014-01-01

The spleen tyrosine kinase (SYK) was identified as an oncogenic driver in a broad spectrum of hematologic malignancies. The in vivo comparison of three SYK containing oncogenes, SYK wt , TEL–SYK and IL-2-inducible T-cell kinase (ITK)-SYK revealed a general myeloexpansion and the establishment of three different hematologic (pre)diseases. SYK wt enhanced the myeloid and T-cell compartment, without leukemia/lymphoma development. ITK–SYK caused lethal T-cell lymphomas and the cytoplasmic TEL–SYK fusion induced an acute panmyelosis with myelofibrosis-type acute myeloid leukemia (AML) with up to 50% immature megakaryoblasts infiltrating bone marrow, spleen and liver, additional MPN features (myelofibrosis and granulocyte expansion) and MDS stigmata with megakaryocytic and erythroid dysplasia. LKS cells were reduced and all subsets (LT/ST/MPP) showed reduced proliferation rates. SYK inhibitor treatment (R788) of diseased TEL–SYK mice reduced leukocytosis, spleen and liver infiltration, enhanced the hematocrit and prolonged survival time, but could not significantly reduce myelofibrosis. Stat5 was identified as a major downstream mediator of TEL–SYK in vitro as well as in vivo. Consequently, targeted deletion of Stat5 in vivo completely abrogated TEL–SYK-induced AML and myelofibrosis development, proving Stat5 as a major driver of SYK-induced transformation. Our experiments highlight the important role of SYK in AML and myelofibrosis and prove SYK and STAT5 inhibitors as potent treatment options for those diseases

Peritoneal carcinomatosis-like implants of extramedullary hematopoiesis. An insolite occurrence during splenectomy for myelofibrosis

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Marco Casaccia

Full Text Available Introduction: Primary myelofibrosis (MF is a myeloproliferative neoplasm that results in debilitating constitutional symptoms, splenomegaly, and cytopenias. In patients with symptomatic splenomegaly, splenectomy remains a viable treatment option for MF patients with medically refractory symptomatic splenomegaly that precludes the use of ruxolitinib. Case presentation: We present the clinical case of a patient who was admitted to our Department to perform a splenectomy in MF as a therapeutic step prior to an allogeneic stem cell transplantation (ASCT. A laparotomic splenectomy and excision of whitish wide-spread peritoneal and omental nodulations was performed. There were no operative complications and the surgery was completed with minimal blood loss. The histopathological exam revealed an extramedullary hematopoiesis in both spleen and peritoneal nodules. Conclusion: In primary myelofibrosis it must always be kept in mind the possible presence of peritoneal implants of extramedullary hematopoiesis and ascites of reactive genesis. We report a rare case of peritoneal carcinomatosis-like implants of extramedullary hematopoiesis found at splenectomy for MF. Keywords: Myelofibrosis, Splenomegaly, Splenectomy, Extramedullary hematopoiesis

VASCULAR PROLIFERATION AS AN UNUSUAL CAUSE OF HEMORRHAGIC DIATHESIS IN MYELOFIBROSIS

NARCIS (Netherlands)

ALBEDA, FW; VANDERMEER, J; VELLENGA, E

One year after splenectomy, a patient with myelofibrosis developed spontaneously large hematomas that were not due to coagulation abnormalities or functionally defective platelets. At autopsy, the liver, muscle, and skin showed extramedullary hematopoiesis associated with capillary proliferation and

A multinational, open-label, phase 2 study of ruxolitinib in Asian patients with myelofibrosis: Japanese subset analysis.

Science.gov (United States)

Oritani, Kenji; Okamoto, Shinichiro; Tauchi, Tetsuzo; Saito, Shigeki; Ohishi, Kohshi; Handa, Hiroshi; Takenaka, Katsuto; Gopalakrishna, Prashanth; Amagasaki, Taro; Ito, Kazuo; Akashi, Koichi

2015-03-01

Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor that has demonstrated rapid and durable improvements in splenomegaly and symptoms and a survival benefit in 2 phase 3 trials in patients with myelofibrosis. Ruxolitinib was well tolerated and effectively reduced splenomegaly and symptom burden in Asian patients with myelofibrosis in the Asian multinational, phase 2 Study A2202. We present a subset analysis of Japanese patients (n = 30) in Study A2202. At data cutoff, 22 patients were ongoing; 8 discontinued, mainly due to adverse events (n = 4). At week 24, 33 % of patients achieved ≥35 % reduction from baseline in spleen volume; 56.0 % achieved ≥50 % reduction from baseline in total symptom score, as measured by the 7-day Myelofibrosis Symptom Assessment Form v2.0. The most common adverse events were anemia (63 %), thrombocytopenia (40 %), nasopharyngitis (37 %), decreased platelet counts (30 %), and diarrhea (30 %). Dose reductions or interruptions due to hemoglobin decreases were more frequent in Japanese patients; no loss of efficacy and no discontinuations due to hematologic abnormalities were observed. Ruxolitinib was well tolerated in Japanese patients and provided substantial reductions in splenomegaly and myelofibrosis-related symptoms similar to those observed in the overall Asian population and phase 3 COMFORT studies.

Calreticulin mutation analysis in non-mutated Janus kinase 2 essential thrombocythemia patients in Chiang Mai University: analysis of three methods and clinical correlations.

Science.gov (United States)

Rattarittamrong, Ekarat; Tantiworawit, Adisak; Kumpunya, Noppamas; Wongtagan, Ornkamon; Tongphung, Ratchanoo; Phusua, Arunee; Chai-Adisaksopha, Chatree; Hantrakool, Sasinee; Rattanathammethee, Thanawat; Norasetthada, Lalita; Charoenkwan, Pimlak; Lekawanvijit, Suree

2018-03-09

The primary objective was to determine the prevalence of calreticulin (CALR) mutation in patients with non-JAK2V617F mutated essential thrombocythemia (ET). The secondary objectives were to evaluate the accuracy of CALR mutation analysis by high-resolution melting (HRM) analysis and real-time polymerase chain reaction (PCR) compared with DNA sequencing and to compare clinical characteristics of CALR mutated and JAK2V617F mutated ET. This was a prospective cohort study involving ET patients registered at Chiang Mai University in the period September 2015-September 2017 who were aged more than 2 years, and did not harbor JAK2V617F mutation. The presence of CALR mutation was established by DNA sequencing, HRM, and real-time PCR for type 1 and type 2 mutation. Clinical data were compared with that from ET patients with mutated JAK2V617F. Twenty-eight patients were enrolled onto the study. CALR mutations were found in 10 patients (35.7%). Three patients had type 1 mutation, 5 patients had type 2 mutation, 1 patient had type 18 mutation, and 1 patients had novel mutations (c.1093 C-G, c.1098_1131 del, c.1135 G-A). HRM could differentiate between the types of mutation in complete agreement with DNA sequencing. Patients with a CALR mutation showed a significantly greater male predominance and had a higher platelet count when compared with 42 JAK2V617F patients. The prevalence of CALR mutation in JAK2V617F-negative ET in this study is 35.7%. HRM is an effective method of detecting CALR mutation and is a more advantageous method of screening for CALR mutation.

Impact of JAK2V617F Mutation Burden on Disease Phenotype in Chinese Patients with JAK2V617F-positive Polycythemia Vera (PV) and Essential thrombocythemia (ET).

Science.gov (United States)

Zhao, Shixiang; Zhang, Xiang; Xu, Yang; Feng, Yufeng; Sheng, Wenhong; Cen, Jiannong; Wu, Depei; Han, Yue

2016-01-01

Most patients with polycythemia vera (PV) and half of essential thrombocythemia (ET) possess an activating JAK2V617F mutation. The objective of this study was to better define the effect of JAK2V617F mutant allele burden on clinical phenotypes in Chinese patients, especially thrombosis. By real-time polymerase chain reaction (RT-PCR), the JAK2V617F mutation burden was detected in 170 JAK2V617F-positive patients, including 54 PV and 116 ET. The results showed that JAK2V617F allele burden was higher in PV than in ET (PET (68.5% VS 26.7%) (PET patients showed increased JAK2V617F allele burden in the group with higher hemoglobin (HGB above 150 g/L) (PET. In PV patients, JAK2V617F mutation burden had influence on WBC counts. And the clinical characteristics of ET patients, such as WBC counts, hemoglobin level, splenomegaly and thrombosis, were influenced by JAK2V617F mutation burden. Male, high hemoglobin (HGB above 150 g/L), and increased JAK2V617F mutation burden (JAK2V617F allele burden ≥ 16.5%) were risks of thrombosis (PET patients by Logistic Regression.

Bone and bone-marrow blood flow in chronic granulocytic leukemia and primary myelofibrosis

International Nuclear Information System (INIS)

Lahtinen, R.; Lahtinen, T.; Romppanen, T.

1982-01-01

Blood flow in hematopoietic bone marrow and in nonhematopoietic bone has been measured with a Xe-133 washout method in 20 patients with chronic granulocytic leukemia (CGL) and in seven with primary myelofibrosis. Age-matched healthy persons served as controls. Bone-marrow blood flow in CGL was dependent upon the phase of the disease. In the metamorphosis phase, bone-marrow blood flow was high compared with that in the well-controlled phase. Apart from the initial phase, the mean values for bone blood flow in CGL were increased compared with the values of the healthy controls. In myelofibrosis the bone blood flow was also increased. Bone-marrow blood flow in these diseases was dependent upon the cellularity of bone marrow as measured morphometrically

Diffuse pulmonary uptake of indium-111 chloride in idiopathic myelofibrosis

International Nuclear Information System (INIS)

Vieras, F.; Boyd, C.M.; Mora, P.A.

1979-01-01

Unusual indium-111 accumulation and extramedullary hematopoiesis in the lungs of a patient with idiopathic myelofibrosis are described. The bone marrow scan taken 24 h after intravenous injection of 111 InCl 3 faithfully depicted the abnormal distribution of marrow elements as assessed histologically at autopsy, thereby supporting the usefulness of 111 InCl 3 for marrow imaging

Current opinion and consensus statement regarding the diagnosis, prognosis, and treatment of patients with essential thrombocythemia: a survey of the Spanish Group of Ph-negative Myeloproliferative Neoplasms (GEMFIN) using the Delphi method.

Science.gov (United States)

Besses, C; Hernández-Boluda, J C; Pérez Encinas, M; Raya, J M; Hernández-Rivas, J M; Jiménez Velasco, A; Martínez Lopez, J; Vicente, V; Burgaleta, C

2016-04-01

The current consensus on the diagnosis, prognosis, and treatment of essential thrombocythemia (ET) is based on experts' recommendations. However, several aspects of the diagnosis of, prognosis of, and therapy for ET are still controversial. The Delphi method was employed with an expert panel of members of the Spanish Group of Ph-negative Myeloproliferative Neoplasms in order to identify the degree of agreement on the diagnosis, prognosis, and treatment of ET. Nine leading experts selected a total of 41 clinical hematologists with well-known expertise in ET. An electronic questionnaire was used to collect the questions rated in a four-step scale. The questions were grouped into four blocks: diagnosis, risk stratification, goals of therapy, and treatment strategy. After the first round consisting of 80 questions, a second round including 14 additional questions focused on the recommendations advocated by experts of the European LeukemiaNet in 2011 was analyzed. The median and mean values for the first and second rounds were calculated. A summary of the conclusions considered as the most representative of each block of questions is presented. The Delphi method is a powerful instrument to address the current approaches and controversies surrounding ET.

The Impact of Splenectomy in Myelofibrosis Patients before Allogeneic Hematopoietic Stem Cell Transplantation.

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Robin, Marie; Zine, Maryem; Chevret, Sylvie; Meignin, Véronique; Munoz-Bongrand, Nicolas; Moatti, Hannah; Xhaard, Aliénor; Sicre de Fontbrune, Flore; Peffault de Latour, Régis; Sarfati, Emile; Socié, Gérard

2017-06-01

Performing a pretransplantation splenectomy in patients with myelofibrosis (MF) is a matter of debate, as while the procedure improves hematological recovery, it may lead to severe morbidities. We retrospectively analyzed data from 85 consecutive patients who underwent transplantation in our center for MF, including 39 patients who underwent splenectomy before their transplantation. A majority of them had primary MF (78%), were considered high-risk patients (84% dynamic international prognostic scoring system intermediate-2 or higher), and had received transplants from HLA-matched sibling donors (56%) after a reduced-intensity conditioning regimen (82%). One-half of all splenectomized patients presented surgical or postsurgical morbidities, most frequently thrombosis and hemorrhage. After adjustment using Cox models, pretransplantation splenectomy was not associated with nonrelapse mortality or post-transplantation relapse but with an improved overall survival (OS) and event-free survival (EFS). We conclude that some patients with huge splenomegaly may undergo pretransplantation splenectomy without a deleterious impact on post-transplantation outcomes. OS and EFS improvement should in confirmed in controlled study. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Critical appraisal of the role of ruxolitinib in myeloproliferative neoplasm-associated myelofibrosis

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Barosi G

2015-05-01

Full Text Available Giovanni Barosi,1 Vittorio Rosti,1 Robert Peter Gale2 1Center for the Study of Myelofibrosis, IRCCS Policlinico S Matteo Foundation, Pavia, Italy; 2Haematology Research Centre, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, UK Abstract: The recent approval of molecular-targeted therapies for myeloproliferative neoplasm-associated myelofibrosis (MPN-MF has dramatically changed its therapeutic landscape. Ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor, is now widely used for first- and second-line therapy in persons with MPN-MF, especially those with disease-related splenomegaly, intermediate- or high-risk disease, and constitutional symptoms. The goal of this work is to critically analyze data supporting use of ruxolitinib in the clinical settings approved by the US Food and Drug Administration (FDA and European Medicines Agency (EMA. We systematically reviewed the literature and analyzed the risk of biases in the two randomized studies (COMFORT I and COMFORT II on which FDA and EMA approval was based. Our strategy was to apply the Grading of Recommendation, Assessment, Development and Evaluation (GRADE approach by evaluating five dimensions of evidence: (1 overall risk of bias, (2 imprecision, (3 inconsistency, (4 indirectness, and (5 publication bias. Based on these criteria, we downgraded the evidence from the COMFORT I and COMFORT II trials for performance, attrition, and publication bias. In the disease-associated splenomegaly sphere, we upgraded the quality of evidence because of large effect size but downgraded it because of comparator choice and outcome indirectness (quality of evidence, low. In the sphere of treating persons with intermediate- or high-risk disease, we downgraded the evidence because of imprecision in effect size measurement and population indirectness. In the sphere of disease-associated symptoms, we upgraded the evidence because of the large effect size, but downgraded it

[Essential thrombocythemia and pregnancy].

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Baleiras, Carla; Silva, Ana; Serrano, Fátima

2003-01-01

Essencial Thrombocytemia is a rare chronic myeloproliferative disease of unknown etiology, characterized by markedly elevated platelet production (> 600,000/ml). It is more frequent among women above 50 years of age and may be associated with hemorrhagic or thrombotic tendencies. The authors report a case of Essencial Thrombocytemia diagnosed after several consecutive spontaneous abortions. Some clinical aspects, complications, differential diagnosis and management of this condition in pregnancy are also reviewed. An individualized, multidisciplinar approach and the treatment with acetylsalicylic acid, associated with interferon-alfa if necessary, will be the best therapeutic options for these patients.

Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera.

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Lussana, Federico; Carobbio, Alessandra; Salmoiraghi, Silvia; Guglielmelli, Paola; Vannucchi, Alessandro Maria; Bottazzi, Barbara; Leone, Roberto; Mantovani, Alberto; Barbui, Tiziano; Rambaldi, Alessandro

2017-02-22

The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs) and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3) and high-sensitivity C-reactive protein (hs-CRP) are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. We evaluated 305 with essential thrombocythemia (ET) and 172 polycythemia vera (PV) patients diagnosed according to the 2016 WHO criteria and with full molecular characterization for driver mutations. PTX3 levels were significantly increased in carriers of homozygous JAK2V617F mutation compared to all the other genotypes and triple negative ET patients, while hs-CRP levels were independent of the mutational profile. The risk of haematological evolution and death from any cause was about 2- and 1.5-fold increased in individuals with high PTX-3 levels, while the thrombosis rate tended to be lower. High hs-CRP levels were associated with risk of haematological evolution, death and also major thrombosis. After sequential adjustment for potential confounders (age, gender, diagnosis and treatments) and the presence of JAK2V617F homozygous status, high hs-CRP levels remained significant for all outcomes, while JAK2V617F homozygous status as well as treatments were the factors independently accounting for adverse outcomes among patients with high PTX3 levels. These results provide evidence that JAK2V617F mutation influences MPN-associated inflammation with a strong correlation between allele burden and PTX3 levels. Plasma levels of hs-CRP and PTX3 might be of prognostic value for patients with ET and PV, but their validation in future prospective studies is needed.

Clinical features of Japanese polycythemia vera and essential thrombocythemia patients harboring CALR, JAK2V617F, JAK2Ex12del, and MPLW515L/K mutations.

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Okabe, Masahiro; Yamaguchi, Hiroki; Usuki, Kensuke; Kobayashi, Yutaka; Kawata, Eri; Kuroda, Junya; Kimura, Shinya; Tajika, Kenji; Gomi, Seiji; Arima, Nobuyoshi; Mori, Sinichiro; Ito, Shigeki; Koizumi, Masayuki; Ito, Yoshikazu; Wakita, Satoshi; Arai, Kunihito; Kitano, Tomoaki; Kosaka, Fumiko; Dan, Kazuo; Inokuchi, Koiti

2016-01-01

The risk of complication of polycythemia vera (PV) and essential thrombocythemia (ET) by thrombosis in Japanese patients is clearly lower than in western populations, suggesting that genetic background such as race may influence the clinical features. This study aimed to clarify the relationship between genetic mutations and haplotypes and clinical features in Japanese patients with PV and ET. Clinical features were assessed prospectively among 74 PV and 303 ET patients. There were no clinical differences, including JAK2V617F allele burden, between PV patients harboring the various genetic mutations. However, CALR mutation-positive ET patients had a significantly lower WBC count, Hb value, Ht value, and neutrophil alkaline phosphatase score (NAP), and significantly more platelets, relative to JAK2V617F-positive ET patients and ET patients with no mutations. Compared to normal controls, the frequency of the JAK246/1 haplotype was significantly higher among patients with JAK2V617F, JAK2Ex12del, or MPL mutations, whereas no significant difference was found among CALR mutation-positive patients. CALR mutation-positive patients had a lower incidence of thrombosis relative to JAK2V617F-positive patients. Our findings suggest that JAK2V617F-positive ET patients and CALR mutation-positive patients have different mechanisms of occurrence and clinical features of ET, suggesting the potential need for therapy stratification in the future. Copyright © 2015 Elsevier Ltd. All rights reserved.

Myeloid Neoplasms in the Guise of Nutritional Deficiency

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Parthasarathy, Veda

2012-01-01

The classic BCR-ABL-negative myeloproliferative neoplasms (MPNs) which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are among the most frequent hematologic neoplasms. Because of their relatively smooth clinical course, it is likely that many of these MPNs actually go undetected. Considering the high prevalence of iron, folic-acid, and vitamin B12 deficiencies in developing countries, their coexistence with MPN can be expected frequently. In such situations where both disorders coexist, MPN is often overlooked. This causes considerable diagnostic delay. In this paper, two cases of PMF and one case of PV where the diagnosis of MPN was delayed for about 3 years are discussed. Presence of concomitant vitamin B12, folate, and iron deficiencies perhaps camouflaged the underlying MPN. Bearing in mind the possibility of MPN, even in the setting of apparent nutritional deficiency and performing a bone marrow evaluation, is the crucial step in unveiling the hidden MPN. PMID:23227377

[Evidence on chronic myeloproliferative neoplasms from landmark clinical trials].

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Yamaguchi, Hiroki

2015-08-01

Mutations in the JAK2 gene are thought to underlie the development of chronic myeloproliferative neoplasms (cMPN). Indeed, ≥95% of polycythemia vera patients, and half or more of essential thrombocythemia and primary myelofibrosis (PMF) patients, harbor the JAK2V617F mutation. Besides the JAK2V617F mutation, the JAK2 exon 12 deletion, the MPLW515L/K, and CALR mutation have been discovered and shown to be involved in the pathogenesis of these diseases. Based on these advancements in the study of cMPN, the JAK2 inhibitor was developed as a new therapy for PMF. Moreover, recent advancements in our ability to diagnose cMPN have paralleled the development of large clinical trials for patients with cMPN. This article provides explanatory information from these large clinical trials that is useful for the actual clinical practice of caring for patients with cMPN in Japan.

MPL mutations in myeloproliferative disorders

DEFF Research Database (Denmark)

Beer, Philip A.; Campbell, Peter J.; Scott, Linda M.

2008-01-01

Activating mutations of MPL exon 10 have been described in a minority of patients with idiopathic myelofibrosis (IMF) or essential thrombocythemia (ET), but their prevalence and clinical significance are unclear. Here we demonstrate that MPL mutations outside exon 10 are uncommon in platelet c......DNA and identify 4 different exon 10 mutations in granulocyte DNA from a retrospective cohort of 200 patients with ET or IMF. Allele-specific polymerase chain reaction was then used to genotype 776 samples from patients with ET entered into the PT-1 studies. MPL mutations were identified in 8.5% of JAK2 V617F......(-) patients and a single V617F(+) patient. Patients carrying the W515K allele had a significantly higher allele burden than did those with the W515L allele, suggesting a functional difference between the 2 variants. Compared with V617F(+) ET patients, those with MPL mutations displayed lower hemoglobin...

Driver mutations (JAK2V617F, MPLW515L/K or CALR, pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera

Directory of Open Access Journals (Sweden)

Federico Lussana

2017-02-01

Full Text Available Abstract Background The driver mutations JAK2V617F, MPLW515L/K and CALR influence disease phenotype of myeloproliferative neoplasms (MPNs and might sustain a condition of chronic inflammation. Pentraxin 3 (PTX3 and high-sensitivity C-reactive protein (hs-CRP are inflammatory biomarkers potentially useful for refining prognostic classification of MPNs. Methods We evaluated 305 with essential thrombocythemia (ET and 172 polycythemia vera (PV patients diagnosed according to the 2016 WHO criteria and with full molecular characterization for driver mutations. Results PTX3 levels were significantly increased in carriers of homozygous JAK2V617F mutation compared to all the other genotypes and triple negative ET patients, while hs-CRP levels were independent of the mutational profile. The risk of haematological evolution and death from any cause was about 2- and 1.5-fold increased in individuals with high PTX-3 levels, while the thrombosis rate tended to be lower. High hs-CRP levels were associated with risk of haematological evolution, death and also major thrombosis. After sequential adjustment for potential confounders (age, gender, diagnosis and treatments and the presence of JAK2V617F homozygous status, high hs-CRP levels remained significant for all outcomes, while JAK2V617F homozygous status as well as treatments were the factors independently accounting for adverse outcomes among patients with high PTX3 levels. Conclusions These results provide evidence that JAK2V617F mutation influences MPN-associated inflammation with a strong correlation between allele burden and PTX3 levels. Plasma levels of hs-CRP and PTX3 might be of prognostic value for patients with ET and PV, but their validation in future prospective studies is needed.

Bioactivity of essential oils in phytopathogenic and post-harvest fungi control.

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Santamarina, M P; Ibáñez, M D; Marqués, M; Roselló, J; Giménez, S; Blázquez, M A

2017-11-01

Commercial thyme and lavender essential oils were analysed by GC/MS. Sixty-six compounds accounting for 98.6-99.6% of total essential oil were identified. Thymol (52.14 ± 0.21%), followed by p-cymene (32.24 ± 0.16%), carvacrol (3.71 ± 0.01%) and γ-terpinene (3.34 ± 0.02%), were the main compounds in thyme essential oil, while large amounts of oxygenated monoterpenes linalool acetate (37.07 ± 0.24%) and linalool (30.16 ± 0.06%) were found in lavender one. In vitro antifungal activity of the essential oils was evaluated at 200 and 300 μg/mL against 10 phytopathogenic and post-harvest fungi, which significantly affect agriculture. Micelial growth inhibition was calculated for each tested fungus and dose. Thyme essential oil showed satisfactory results with 90-100% growth inhibition in almost all the assayed fungi at 300 μg/mL, while lavender essential oil showed no noteworthy inhibition data at either dose, and its growth was even enhanced. Thyme essential oil represents a natural alternative to control harvest and post-harvest fungi, and to extend the shelf-life of agriculture products.

Regenerative nodular hyperplasia, portal vein thrombosis and primary myelofibrosis: an unusual triple association.

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Sández Montagut, Víctor Manuel; Giráldez Gallego, Álvaro; Ontanilla Clavijo, Guilermo

2018-03-01

We report a case of a regenerative nodular hyperplasia with a portal vein cavernomatosis with a subsequent progression to symptomatic, occlusive thrombosis of the superior mesenteric vein. A thorough investigation resulted in a final diagnosis of primary myelofibrosis associated with the V617F mutation in the JAK2 gene.

Idiopathic myelofibrosis accompanied by peritoneal extramedullary hematopoiesis presenting as refractory ascites in a dog.

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Rautenbach, Yolandi; Goddard, Amelia; Clift, Sarah J

2017-03-01

A 2.5-year-old spayed female American Pit Bull Terrier dog presented with a primary complaint of chronic refractory ascites. The dog's CBC displayed a moderate to severe macrocytic, hypochromic, nonregenerative anemia, and a moderate leukopenia as result of a moderate neutropenia and monocytopenia. Microscopic examination of the blood smear showed marked anisocytosis, mild polychromasia, mild acanthocytosis and ovalocytosis, moderate schistocytosis and poikilocytosis, and 4 metarubricytes/100 WBC. Abdominal ultrasonography revealed a homogenous, mild to moderately hyperechoic appearing liver as well as marked amounts of speckled anechoic to slightly hypoechoic peritoneal fluid. Cytology of the ascitic fluid demonstrated a sterile transudate, with evidence of a chronic inflammatory reaction as well as erythroid and myeloid precursor cells, and a few megakaryocytes with occasional micromegakaryocytes. Histologic sections of bone marrow, spleen, and liver were examined, using routine H&E stains, as well as a variety of immunohistochemistry and other special stains. Histopathology of the bone marrow and spleen revealed varying degrees of fibrosis, erythroid, and myeloid hyperplasia, as well as multiple small hyperplastic clusters of megakaryocytes. The megakaryocytes displayed many features of atypia such as increased cytoplasmic basophilia and occasional abnormal chromatin clumping with mitoses. Histopathologic examination of the liver disclosed evidence of mild extramedullary hematopoiesis. This case represents the first report of canine idiopathic myelofibrosis associated with peritoneal extramedullary hematopoiesis, resulting in refractory ascites. Although idiopathic myelofibrosis is a relatively rare condition in dogs, this case demonstrates that ascites caused by peritoneal implants of hematopoietic tissue may be the initial manifestation of myelofibrosis. © 2016 American Society for Veterinary Clinical Pathology.

Acute Panmyelosis with Myelofibrosis - A Rare Subtype of Acute Myeloid Leukemia

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Tathagata Chatterjee

2013-06-01

Full Text Available One case of acute panmyelosis with myelofibrosis (APMF is being reported. A 45 year old male presented with abrupt onset of rapidly progressing low backache, weakness and pancytopenia. On examination there was no organomegaly. Peripheral blood examination revealed normocytic normochromic red blood cells with 10% circulating blasts. Flowcytometric examination of peripheral blood revealed blasts which were positive for CD 34 ,HLA- DR and myeloid associated antigens (i.e. CD13 and CD33.Blasts were negative for anti MPO. Bone marrow aspirate resulted in a dry tap. Bone marrow biopsy revealed panmyeloid proliferation with scattered blasts which were CD 34 positive on imunohistochemistry and negative for anti MPO. Reticulin stain showed grade III myelofibrosis (WHO. Differential diagnosis considered included AML-M7, MDS-RAEB II and AML with myelodysplasia . He was started on chemotherapy [idarubicin and cytarabine; 3+7 induction regimen followed by three cycles of HIDAC (High dose cytosine arabinoside] after which patient was in complete morphological remission with markedly reduced bone marrow fibrosis. He is now being worked up for allogeneic stem cell transplantation. Patient is asymptomatic at eight months of diagnosis. In conclusion these patients should be managed aggressively with AML therapy and this case report reaffirms the fact that APMF is subtype of AML.

An unusual type of myeloid sarcoma localization following myelofibrosis: A case report and literature review

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Nicola Orofino

2017-01-01

We report the case of a patient with MS following myelofibrosis with multiple subcutaneous, cutaneous and muscle localizations; the latter has been reported in the literature as anecdotal. In this way we aimed to enhance the understanding of this disease.

Navigating the evolving paradigms in the diagnosis and treatment of myeloproliferative disorders.

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Mesa, Ruben A

2007-01-01

The diagnosis and management of the BCR-ABL-negative myeloproliferative disorders (MPDs) of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are at an explosive crossroads of scientific investigation and evolving paradigms since the discovery of the tyrosine kinase-activating JAK2V617F mutation in 2005. Additional discovery of relevant molecular lesions (JAK2 exon 12 mutations and c-MplW515L/K) have only further enriched our understanding of MPD pathogenesis. The improved diagnostic certainty these molecular markers provide have resulted in the modification, and simplification, of the World Health Organization (WHO) diagnostic algorithms for MPDs. Despite these scientific advances, however, the initial management of MPDs continues to rely upon a risk-based strategy to minimize the risk of vascular events with control of erythrocytosis, targeted antiplatelet therapy, and risk-based myelosuppressive therapy. No current medical therapy has altered the natural trend of the MPDs to lead to overt severe myelofibrosis or acute leukemia. Investigations into targeted therapies for MPDs are proceeding at a brisk pace with agents aimed at immunomodulation, decreasing marrow stromal reaction to the aberrant clone, DNA hypomethylation, or the inhibition of tyrosine kinases. Specific inhibition of JAK2 itself appears promising by in vitro investigations, and clinical trials with multiple agents are planned to commence enrollment in 2007. The potential impact of JAK2 inhibitors on the manifestations of the MPDs is unclear, but is awaited with great interest.

Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: structural brain anomalies and myelofibrosis.

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Gripp, Karen W; Zand, Dina J; Demmer, Laurie; Anderson, Carol E; Dobyns, William B; Zackai, Elaine H; Denenberg, Elizabeth; Jenny, Kim; Stabley, Deborah L; Sol-Church, Katia

2013-10-01

Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with SOS1 mutations often associated with normal cognition and stature, RAF1 mutations entailing a high HCM risk, and certain PTPN11 mutations predisposing to juvenile myelomonocytic leukemia. The recently identified SHOC2 mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4/5 (80%); 3/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2-year-old patient with SHOC2 mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic JAK2 mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic SHOC2 mutations are causally involved in myelofibrosis. Copyright © 2013 Wiley Periodicals, Inc.

Genetics Home Reference: essential thrombocythemia

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... splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. Nat Genet. 1998 Jan;18(1):49-52. ... deficiency Depression Pelizaeus-Merzbacher-like disease type 1 All New & ...

Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis.

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Ying Han

Full Text Available Myelofibrosis is an indicator of poor prognosis in myeloproliferative neoplasms (MPNs, but the precise mechanism(s contributing to extracellular matrix remodeling and collagen deposition in the bone marrow (BM niche remains unanswered. In this study, we isolated mesenchymal stromal cells (MSCs from mice transplanted with wild-type thrombopoietin receptor (MPLWT and MPLW515L retroviral-transduced bone marrow. Using MSCs derived from MPLW515-transplant recipients, excessive collagen deposition was maintained in the absence of the virus and neoplastic hematopoietic cells suggested that the MSCs were reprogrammed in vivo. TGFβ production by malignant megakaryocytes plays a definitive role promoting myelofibrosis in MPNs. However, TGFβ was equally expressed by MSCs derived from MPLWT and MPLW515L expressing mice and the addition of neutralizing anti-TGFβ antibody only partially reduced collagen secretion in vitro. Interestingly, profibrotic MSCs displayed increased levels of pSmad3 and pSTAT3 suggesting that inflammatory mediators cooperating with the TGFβ-receptor signaling may maintain the aberrant phenotype ex vivo. FGFb is a known suppressor of TGFβ signaling. Reduced collagen deposition by FGFb-treated MSCs derived from MPLW515L mice suggests that the activating pathway is vulnerable to this suppressive mediator. Therefore, our findings have implications for the future investigation of therapies to reverse fibrosis in MPNs.

Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis.

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Han, Ying; Yue, Lanzhu; Wei, Max; Ren, Xiubao; Shao, Zonghong; Zhang, Ling; Levine, Ross L; Epling-Burnette, Pearlie K

2017-01-01

Myelofibrosis is an indicator of poor prognosis in myeloproliferative neoplasms (MPNs), but the precise mechanism(s) contributing to extracellular matrix remodeling and collagen deposition in the bone marrow (BM) niche remains unanswered. In this study, we isolated mesenchymal stromal cells (MSCs) from mice transplanted with wild-type thrombopoietin receptor (MPLWT) and MPLW515L retroviral-transduced bone marrow. Using MSCs derived from MPLW515-transplant recipients, excessive collagen deposition was maintained in the absence of the virus and neoplastic hematopoietic cells suggested that the MSCs were reprogrammed in vivo. TGFβ production by malignant megakaryocytes plays a definitive role promoting myelofibrosis in MPNs. However, TGFβ was equally expressed by MSCs derived from MPLWT and MPLW515L expressing mice and the addition of neutralizing anti-TGFβ antibody only partially reduced collagen secretion in vitro. Interestingly, profibrotic MSCs displayed increased levels of pSmad3 and pSTAT3 suggesting that inflammatory mediators cooperating with the TGFβ-receptor signaling may maintain the aberrant phenotype ex vivo. FGFb is a known suppressor of TGFβ signaling. Reduced collagen deposition by FGFb-treated MSCs derived from MPLW515L mice suggests that the activating pathway is vulnerable to this suppressive mediator. Therefore, our findings have implications for the future investigation of therapies to reverse fibrosis in MPNs.

Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases.

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Reilly, J T; Snowden, J A; Spearing, R L; Fitzgerald, P M; Jones, N; Watmore, A; Potter, A

1997-07-01

The prognostic significance of cytogenetic abnormalities was determined in 106 patients with well-characterized idiopathic myelofibrosis who were successfully karyotyped at diagnosis. 35% of the cases exhibited a clonal abnormality (37/106), whereas 65% (69/106) had a normal karyotype. Three characteristic defects, namely del(13q) (nine cases), del(20q) (eight cases) and partial trisomy 1q (seven cases), were present in 64.8% (24/37) of patients with clonal abnormalities. Kaplan-Meier plots and log rank analysis demonstrated an abnormal karyotype to be an adverse prognostic variable (P 10.3 x 10(9)/l; P=0.06) were also associated with a shorter survival. In contrast, sex, spleen and liver size, and percentage blast cells were not found to be significant. Multivariate analysis, using Cox's regression, revealed karyotype, haemoglobin concentration, platelet and leucocyte counts to retain their unfavourable prognostic significance. A simple and useful schema for predicting survival in idiopathic myelofibrosis has been produced by combining age, haemoglobin concentration and karyotype with median survival times varying from 180 months (good-risk group) to 16 months (poor-risk group).

Peritoneal carcinomatosis-like implants of extramedullary hematopoiesis. An insolite occurrence during splenectomy for myelofibrosis.

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Casaccia, Marco; Fornaro, Rosario; Frascio, Marco; Palombo, Denise; Stabilini, Cesare; Firpo, Emma; Gianetta, Ezio

2017-01-01

Primary myelofibrosis (MF) is a myeloproliferative neoplasm that results in debilitating constitutional symptoms, splenomegaly, and cytopenias. In patients with symptomatic splenomegaly, splenectomy remains a viable treatment option for MF patients with medically refractory symptomatic splenomegaly that precludes the use of ruxolitinib. We present the clinical case of a patient who was admitted to our Department to perform a splenectomy in MF as a therapeutic step prior to an allogeneic stem cell transplantation (ASCT). A laparotomic splenectomy and excision of whitish wide-spread peritoneal and omental nodulations was performed. There were no operative complications and the surgery was completed with minimal blood loss. The histopathological exam revealed an extramedullary hematopoiesis in both spleen and peritoneal nodules. In primary myelofibrosis it must always be kept in mind the possible presence of peritoneal implants of extramedullary hematopoiesis and ascites of reactive genesis. We report a rare case of peritoneal carcinomatosis-like implants of extramedullary hematopoiesis found at splenectomy for MF. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Thrombospondin-1 is not the major activator of TGF-β1 in thrombopoietin-induced myelofibrosis

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Evrard, Solène; Bluteau, Olivier; Tulliez, Micheline

2011-01-01

Transforming growth factor-β1 (TGF-β1) is the most important cytokine involved in the promotion of myelofibrosis. Mechanisms leading to its local activation in the bone marrow environment remain unclear. As a recent study has highlighted the role of thrombospondin-1 (TSP-1) in platelet-derived TG...

Mesenchymal Cell Reprogramming in Experimental MPLW515L Mouse Model of Myelofibrosis

OpenAIRE

Han, Ying; Yue, Lanzhu; Wei, Max; Ren, Xiubao; Shao, Zonghong; Zhang, Ling; Levine, Ross L.; Epling-Burnette, Pearlie K.

2017-01-01

Myelofibrosis is an indicator of poor prognosis in myeloproliferative neoplasms (MPNs), but the precise mechanism(s) contributing to extracellular matrix remodeling and collagen deposition in the bone marrow (BM) niche remains unanswered. In this study, we isolated mesenchymal stromal cells (MSCs) from mice transplanted with wild-type thrombopoietin receptor (MPL WT ) and MPL W515L retroviral-transduced bone marrow. Using MSCs derived from MPL W515 -transplant recipients, excessive collagen d...

[Myelofibrosis in a benzene-exposed cleaning worker].

Science.gov (United States)

Bausà, Roser; Navarro, Lydia; Cortès-Franch, Imma

Long-term exposure to benzene has been associated with several blood malignancies, including aplastic anemia, myeloproliferative neoplasms, and different leukemias. We present a case of primary myelofibrosis in a 59-year-old woman who worked as a cleaner at a car dealership and automobile mechanic shop. For 25 years, she used gasoline as a degreaser and solvent to clean engine parts, floors and work desks on a daily basis. She was referred by her primary care provider to the Occupational Health Unit of Barcelona to assess whether her illness was work-related. Review of her job history and working conditions revealed chronic exposure to benzene in the absence of adequate preventive measures. An association between benzene exposure and myeloproliferative disease was established, suspicious for an occupational disease. Copyright belongs to the Societat Catalana de Salut Laboral.

MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients.

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Pardanani, Animesh D; Levine, Ross L; Lasho, Terra; Pikman, Yana; Mesa, Ruben A; Wadleigh, Martha; Steensma, David P; Elliott, Michelle A; Wolanskyj, Alexandra P; Hogan, William J; McClure, Rebecca F; Litzow, Mark R; Gilliland, D Gary; Tefferi, Ayalew

2006-11-15

Recently, a gain-of-function MPL mutation, MPLW515L, was described in patients with JAK2V617F-negative myelofibrosis with myeloid metaplasia (MMM). To gain more information on mutational frequency, disease specificity, and clinical correlates, genomic DNA from 1182 patients with myeloproliferative and other myeloid disorders and 64 healthy controls was screened for MPL515 mutations, regardless of JAK2V617F mutational status: 290 with MMM, 242 with polycythemia vera, 318 with essential thrombocythemia (ET), 88 with myelodysplastic syndrome, 118 with chronic myelomonocytic leukemia, and 126 with acute myeloid leukemia (AML). MPL515 mutations, either MPLW515L (n = 17) or a previously undescribed MPLW515K (n = 5), were detected in 20 patients. The diagnosis of patients with mutant MPL alleles at the time of molecular testing was de novo MMM in 12 patients, ET in 4, post-ET MMM in 1, and MMM in blast crisis in 3. Six patients carried the MPLW515L and JAK2V617F alleles concurrently. We conclude that MPLW515L or MPLW515K mutations are present in patients with MMM or ET at a frequency of approximately 5% and 1%, respectively, but are not observed in patients with polycythemia vera (PV) or other myeloid disorders. Furthermore, MPL mutations may occur concurrently with the JAK2V617F mutation, suggesting that these alleles may have functional complementation in myeloproliferative disease.

The Role of Genotypes That Modify the Toxicity of Chemical Mutagens in the Risk for Myeloproliferative Neoplasms

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Carol Ann Gross-Davis

2015-02-01

Full Text Available Background: The etiology of myeloproliferative neoplasms (MPN (polycythemia vera; essential thrombocythemia; primary myelofibrosis is unknown, however they are associated with a somatic mutation—JAK2 V617F—suggesting a potential role for environmental mutagens. Methods: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921–1968 and residing in the area between 2000–2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease. Results: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3–5 fold increased risk. Conclusions: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs.

Impact of Inflammation on Myeloproliferative Neoplasm Symptom Development

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Holly L. Geyer

2015-01-01

Full Text Available Myeloproliferative neoplasms (essential thrombocythemia, ET; polycythemia vera, PV; myelofibrosis, MF are monoclonal malignancies associated with genomic instability, dysregulated signaling pathways, and subsequent overproduction of inflammatory markers. Acknowledged for their debilitating symptom profiles, recent investigations have aimed to determine the identity of these markers, the upstream sources stimulating their development, their prevalence within the MPN population, and the role they play in symptom development. Creation of dedicated Patient Reported Outcome (PRO tools, in combination with expanded access to cytokine analysis technology, has resulted in a surge of investigations evaluating the potential associations between symptoms and inflammation. Emerging data demonstrates clear relationships between individual MPN symptoms (fatigue, abdominal complaints, microvascular symptoms, and constitutional symptoms and cytokines, particularly IL-1, IL-6, IL-8, and TNF-α. Information is also compiling on the role symptoms paradoxically play in the development of cytokines, as in the case of fatigue-driven sedentary lifestyles. In this paper, we explore the symptoms inherent to the MPN disorders and the potential role inflammation plays in their development.

Defining the Thrombotic Risk in Patients with Myeloproliferative Neoplasms

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Fabrizio Vianello

2011-01-01

Full Text Available Polycythemia vera (PV and essential thrombocythemia (ET are two Philadelphia-negative myeloproliferative neoplasms (MPN associated with an acquired mutation in the JAK2 tyrosine kinase gene. There is a rare incidence of progression to myelofibrosis and myeloid metaplasia in both disorders, which may or may not precede transformation to acute myeloid leukemia, but thrombosis is the main cause of morbidity and mortality. The pathophysiology of thrombosis in patients with MPN is complex. Traditionally, abnormalities of platelet number and function have been claimed as the main players, but increased dynamic interactions between platelets, leukocytes, and the endothelium do probably represent a fundamental interplay in generating a thrombophilic state. In addition, endothelial dysfunction, a well-known risk factor for vascular disease, may play a role in the thrombotic risk of patients with PV and ET. The identification of plasma markers translating the hemostatic imbalance in patients with PV and ET would be extremely helpful in order to define the subgroup of patients with a significant clinical risk of thrombosis.

[MPLW515L point mutation in patients with myeloproliferative disease].

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Xia, Jun; Xu, Wei; Zhang, Su-Jiang; Fan, Lei; Qiao, Chun; Li, Jian-Yong

2008-12-01

In order to investigate the frequency of MPLW515L and JAK2V617F point mutations of the patients with myeloproliferative disease (MPD) in Nanjing area, MPLW515L and JAK2V617F point mutations were simultaneously detected by alleles specific polymerase chain reaction (AS-PCR) and sequencing in 190 MPD patients. The results showed that MPLW515L point mutation was detected in 1 out of 102 essential thrombocythemia (ET) patients (1.0%) and was not detected in 32 polycythemia vera (PV) patients, 13 idiopathic myelofibrosis (IMF) patients, 43 chronic myelogenous leukemia (CML) patients. JAK2V617F point mutation was detected in 20 out of 32 PV patients (62.5%), 43 out of 102 ET patients (42.2%), 5 out of 13 IMF patients (38.5%), and was not detected in 43 CML patients. It is concluded that MPLW515L point mutation exists in ET patient, but is not found in PV, IMF and CML. JAK2V617F point mutation exists in PV, ET and IMF, but not in CML.

Presence of calreticulin mutations in JAK2-negative polycythemia vera.

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Broséus, Julien; Park, Ji-Hye; Carillo, Serge; Hermouet, Sylvie; Girodon, François

2014-12-18

Calreticulin (CALR) mutations have been reported in Janus kinase 2 (JAK2)- and myeloproliferative leukemia (MPL)-negative essential thrombocythemia and primary myelofibrosis. In contrast, no CALR mutations have ever been reported in the context of polycythemia vera (PV). Here, we describe 2 JAK2(V617F)-JAK2(exon12)-negative PV patients who presented with a CALR mutation in peripheral granulocytes at the time of diagnosis. In both cases, the CALR mutation was a 52-bp deletion. Single burst-forming units-erythroid (BFU-E) from 1 patient were grown in vitro and genotyped: the same CALR del 52-bp mutation was noted in 31 of the 37 colonies examined; 30 of 31 BFU-E were heterozygous for CALR del 52 bp, and 1 of 31 BFU-E was homozygous for CALR del 52 bp. In summary, although unknown mutations leading to PV cannot be ruled out, our results suggest that CALR mutations can be associated with JAK2-negative PV. © 2014 by The American Society of Hematology.

Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development?

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Hasselbalch, Hans K

2013-01-01

The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms, in which a stem cell lesion induces an autonomous proliferative advantage. In addition to the JAK2V617 mutation several other mutations have been described. Recently chronic inflammation has be...

High frequency of endothelial colony forming cells marks a non-active myeloproliferative neoplasm with high risk of splanchnic vein thrombosis.

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Vittorio Rosti

Full Text Available Increased mobilization of circulating endothelial progenitor cells may represent a new biological hallmark of myeloproliferative neoplasms. We measured circulating endothelial colony forming cells (ECFCs in 106 patients with primary myelofibrosis, fibrotic stage, 49 with prefibrotic myelofibrosis, 59 with essential thrombocythemia or polycythemia vera, and 43 normal controls. Levels of ECFC frequency for patient's characteristics were estimated by using logistic regression in univariate and multivariate setting. The sensitivity, specificity, likelihood ratios, and positive predictive value of increased ECFC frequency were calculated for the significantly associated characteristics. Increased frequency of ECFCs resulted independently associated with history of splanchnic vein thrombosis (adjusted odds ratio = 6.61, 95% CI = 2.54-17.16, and a summary measure of non-active disease, i.e. hemoglobin of 13.8 g/dL or lower, white blood cells count of 7.8×10(9/L or lower, and platelet count of 400×10(9/L or lower (adjusted odds ratio = 4.43, 95% CI = 1.45-13.49 Thirteen patients with splanchnic vein thrombosis non associated with myeloproliferative neoplasms were recruited as controls. We excluded a causal role of splanchnic vein thrombosis in ECFCs increase, since no control had elevated ECFCs. We concluded that increased frequency of ECFCs represents the biological hallmark of a non-active myeloproliferative neoplasm with high risk of splanchnic vein thrombosis. The recognition of this disease category copes with the phenotypic mimicry of myeloproliferative neoplasms. Due to inherent performance limitations of ECFCs assay, there is an urgent need to arrive to an acceptable standardization of ECFC assessment.

A sensitive detection method for MPLW515L or MPLW515K mutation in chronic myeloproliferative disorders with locked nucleic acid-modified probes and real-time polymerase chain reaction.

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Pancrazzi, Alessandro; Guglielmelli, Paola; Ponziani, Vanessa; Bergamaschi, Gaetano; Bosi, Alberto; Barosi, Giovanni; Vannucchi, Alessandro M

2008-09-01

Acquired mutations in the juxtamembrane region of MPL (W515K or W515L), the receptor for thrombopoietin, have been described in patients with primary myelofibrosis or essential thrombocythemia, which are chronic myeloproliferative disorders. We have developed a real-time polymerase chain reaction assay for the detection and quantification of MPL mutations that is based on locked nucleic acid fluorescent probes. Mutational analysis was performed using DNA from granulocytes. Reference curves were obtained using cloned fragments of MPL containing either the wild-type or mutated sequence; the predicted sensitivity level was at least 0.1% mutant allele in a wild-type background. None of the 60 control subjects presented with a MPLW515L/K mutation. Of 217 patients with myelofibrosis, 19 (8.7%) harbored the MPLW515 mutation, 10 (52.6%) with the W515L allele. In one case, both the W515L and W515K alleles were detected by real-time polymerase chain reaction. By comparing results obtained with conventional sequencing, no erroneous genotype attribution using real-time polymerase chain reaction was found, whereas one patient considered wild type according to sequence analysis actually harbored a low W515L allele burden. This is a simple, sensitive, and cost-effective procedure for large-scale screening of the MPLW515L/K mutation in patients suspected to have a myeloproliferative disorder. It can also provide a quantitative estimate of mutant allele burden that might be useful for both patient prognosis and monitoring response to therapy.

Indirect and non-medical economic burden, quality-of-life, and disabilities of the myelofibrosis disease in Spain.

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Gimenez, Emmanuel; Besses, Carles; Boque, Concepcion; Velez, Patricia; Kerguelen, Ana; Cervantes, Francisco; Ferrer-Marin, Francisca; Perez-Encinas, Manuel; Rodriguez, Mercedes; Gonzalez, Juan Diego; Calzada, Reyes; Hernandez-Boluda, Juan Carlos

2014-06-01

Myelofibrosis is a non-frequent chronic myeloproliferative Philadelphia-negative chromosome neoplasm. It is a heavy incapacitating orphan disease and associated with high morbidity and mortality. In this context, indirect and non-medical costs are expected to be high. The main objective of this project is to estimate the economic burden of this disease in Spain. Thirty-three patients with a diagnosis of myelofibrosis for at least 1 year participated in a questionnaire in three Spanish centers. The study consisted of analyzing in various aspects the cost and impact of the disease; indeed, daily life time limitations with a need of informal care, symtomatology. Additionally, information concerning the clinical management of the disease was collected through a focus group of eight experts. The mean age was 65 years. 15 of 33 patients were at their productive stage. Six had difficulties at work and eight have received informal care. Bone and muscular pain were the main symptoms of patients (72%). The estimated global indirect and non-medical costs of the disease were 86,315€ per patient (20% working and 80% informal care), which reached 104,153€ at productive stage patients (45%) and 168,459€ for more symptomatic patients. The economic burden of indirect and non-medical costs of myelofibrosis are important (15,142€/annual) as a result, and should be considered in economic evaluation, as well as in preventive plans for patients and caregivers, despite the fact that studies with larger numbers of patients should be done.

Peritoneal carcinomatosis-like implants of extramedullary hematopoiesis. An insolite occurrence during splenectomy for myelofibrosis

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Casaccia, Marco; Fornaro, Rosario; Frascio, Marco; Palombo, Denise; Stabilini, Cesare; Firpo, Emma; Gianetta, Ezio

2017-01-01

Introduction: Primary myelofibrosis (MF) is a myeloproliferative neoplasm that results in debilitating constitutional symptoms, splenomegaly, and cytopenias. In patients with symptomatic splenomegaly, splenectomy remains a viable treatment option for MF patients with medically refractory symptomatic splenomegaly that precludes the use of ruxolitinib. Case presentation: We present the clinical case of a patient who was admitted to our Department to perform a splenectomy in MF as a therapeutic ...

Splanchnic vein thrombosis as a first manifestation of Primary myelofibrosis

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Campos-Cabrera, Gregorio; Campos-Cabrera, Virginia; Campos-Cabrera, Salvador; Campos-Villagómez, José-Luis; Romero-González, Alejandra

2017-01-01

Myeloproliferative neoplasms are chronic disorders of clonal hematopoietic stem cells, characterized by an overproduction of functional granulocytes, red blood cells and / or platelets, and one of the major complications is the occurrence of venous and arterial thrombotic problems caused by increased platelet aggregation and thrombin generation. In this study 11 cases of primary myelofibrosis (PM) were evaluated and 2 debuted with splanchnic venous thrombosis (SVT); so after seeing the results of this study and of world literature, it is suggested that in patients with SVT, diagnostic methods for PM like the JAK2V617F mutation should be included. Copyright: © 2017 SecretarÍa de Salud

Bone marrow scintigraphy. An aid to the diagnosis and prognosis of myelofibrosis. Scintigraphie medullaire. Apport pour le diagnostic et le pronostic des myelofibroses

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Rain, J.D.; Najean, Y. (Hopital Saint-Louis, 75 - Paris (France))

1993-05-01

During the last three years 77 patients with myelofibrosis were studied by scintigraphy, using 99m Tc colloids and 111 in transferring as tracers. Low axial uptake of the colloids, extension of the indium uptake beyond the axis towards the knees and sometimes the ankles and elbows, and splenic indium uptake are valuable diagnostic criteria, particularly useful to exclude myelofibrosis associated with a malignant disorder. The clinical severity of the disease, and in particular the disappearance of physiologically active bone marrow (indium uptake) can be predicted from isotopic studies. Bone marrow scintigraphy could contribute to the difficult decision of splenectomy.

Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes

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Mughal TI

2014-01-01

Full Text Available Tariq I Mughal,1 Kris Vaddi,2 Nicholas J Sarlis,2 Srdan Verstovsek31Tufts University School of Medicine, Boston, MA, 2Incyte Corporation, Wilmington, DE, 3Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USAAbstract: Myelofibrosis (MF is a rare chronic BCR-ABL1 (breakpoint cluster region-Abelson murine leukemia viral oncogene homologue 1-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, inefficient hematopoiesis, and shortened survival. The clinical manifestations of MF include splenomegaly, consequent to extramedullary hematopoiesis, cytopenias, and an array of potentially debilitating abdominal and constitutional symptoms. Dysregulated Janus kinase (JAK-signal transducer and activator of transcription signaling underlies secondary disease-associated effects in MF, such as myeloproliferation, bone marrow fibrosis, constitutional symptoms, and cachexia. Common fatal complications of MF include transformation to acute leukemia, thrombohemorrhagic events, organ failure, and infections. Potential complications from hepatosplenomegaly include portal hypertension and variceal bleeding, whereas extramedullary hematopoiesis outside the spleen and liver – depending on the affected organ – may result in intracranial hypertension, spinal cord compression, pulmonary hypertension, pleural effusions, lymphadenopathy, skin lesions, and/or exacerbation of abdominal symptoms. Although allogeneic stem cell transplantation is the only potentially curative therapy, it is suitable for few patients. The JAK1/JAK2 inhibitor ruxolitinib is effective in improving splenomegaly, MF-related symptoms, and quality-of-life measures. Emerging evidence that ruxolitinib may be associated with a survival benefit in intermediate- or high-risk MF suggests the possibility of a disease-modifying effect. Consequently, ruxolitinib could provide a treatment backbone to which other (conventional and novel

Bone-marrow imaging with indium-111 chloride in aplastic anemia and myelofibrosis: concise communication

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Sayle, B.A.; Helmer, R.E.; Birdsong, B.A.; Balachandran, S.; Gardner, F.H.

1982-01-01

Twenty-nine patients with aplastic anemia and 11 patients with myelofibrosis were evaluated with indium-111 chloride bone-marrow imaging, ferrokinetics, and bone-marrow core biopsies. There was good correlation between the erythrocyte cellularity of the marrow and the In-111 bone-marrow scan grades in most patients. In some, the overall scan grade tended to underestimate the erythroid elements because the core biopsy had been taken from the area of the greatest radionuclide concentration on the scan. In patients with aplastic anemia, there was good correlation between the plasma iron clearance t1/2 and the scan grade. Less agreement was found in the comparison between the Fe-59 sacral and organ counts and the red-cell iron utilization. In patients with myelofibrosis, there was poor correlation between the surface counts over the sacrum and the red-cell iron utilization. Plasma iron clearances were abnormally short and were unrelated to the transferrin saturation levels. Eighteen patients were studied several times to evaluate their responses to steroid therapy. In all, there was good correlation between the bone-marrow imaging, the erythrocyte cellularity, ferrokinetics, and the patient's response to therapy. Indium-111 bone-marrow imaging is useful both in evaluating marrow erythroid activity and in following the response to therapy in patients with these diseases

Primary myelofibrosis: own experience and news from diagnostic and treatment

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K. M. Abdulkadyrov

2015-06-01

Full Text Available The newest advances in primary myelofibrosis (PMF pathogenesis study, diagnostic and treatment approaches are presented in this article. The JAK-STAT signal pathway activation now recognized as main pathogenesis mechanism of PMF, it caused by JAK2, CALR, MPL genes mutations. Authors demonstrate their own data about epidemiology, clinical signs, diagnostic and treatment results of 315 PMF patients. The most frequent clinical symptoms are: anemia, leukocytosis, thrombocytosis, splenomegaly, constitutional symptoms. Diagnostic criteria, prognostic scales (including cytogenetic and molecular features issues are reviewed. Intermediate-1 risk grade is in the most proportion of patients. Therecommended PMF treatment algorithm is listed. The treatment methods, target drugs (Janus kinases inhibitors trials results are discussed.

Primary myelofibrosis: own experience and news from diagnostic and treatment

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K. M. Abdulkadyrov

2015-01-01

Full Text Available The newest advances in primary myelofibrosis (PMF pathogenesis study, diagnostic and treatment approaches are presented in this article. The JAK-STAT signal pathway activation now recognized as main pathogenesis mechanism of PMF, it caused by JAK2, CALR, MPL genes mutations. Authors demonstrate their own data about epidemiology, clinical signs, diagnostic and treatment results of 315 PMF patients. The most frequent clinical symptoms are: anemia, leukocytosis, thrombocytosis, splenomegaly, constitutional symptoms. Diagnostic criteria, prognostic scales (including cytogenetic and molecular features issues are reviewed. Intermediate-1 risk grade is in the most proportion of patients. Therecommended PMF treatment algorithm is listed. The treatment methods, target drugs (Janus kinases inhibitors trials results are discussed.

Long term molecular responses in a cohort of Danish patients with essential thrombocythemia, polycythemia vera and myelofibrosis treated with recombinant interferon alpha

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Stauffer Larsen, Thomas; Iversen, Katrine F; Hansen, Esben

2013-01-01

Within recent years data has accumulated demonstrating the efficacy of recombinant interferon alpha2 (rIFN-alpha2) in the treatment of chronic myeloproliferative neoplasms (MPNs). We report on clinical and molecular data in the largest cohort of JAK2 V617F mutant MPN Danish patients (n=102) being...

Pharmacoeconomics of ruxolitinib therapy in patients with myelofibrosis.

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Vandewalle, Björn; Andreozzi, Valeska; Almeida, João; Félix, Jorge

2016-01-01

Overall survival (OS) and other important clinical trial end-points seem increasingly more elusive in supporting rapid and efficient incorporation of innovative cancer drugs in clinical practice. This study proposes a clinical trial based pharmacoeconomic framework to assess the therapeutic and economic value of ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Individual patient level 144 week follow-up data from the COMFORT-II trial was used to account for the crossover effect on overall survival. Lifetime treatment benefits and costs were estimated considering detailed patterns of both ruxolitinib dose adjustments and blood transfusion needs. The authors estimate a 3.3 years increment in life expectancy (HR = 0.30; 95% CI = 0.17-0.55; p-value <0.001) and an incremental cost-effectiveness ratio of €40,000 per life year gained with the use of ruxolitinib. This study also demonstrates how valuable information from clinical trials can be used to support informed decisions about the early incorporation of innovative drugs.

TET2, ASXL1, IDH1, and IDH2 Single Nucleotide Polymorphisms in Turkish Patients with Chronic Myeloproliferative Neoplasms

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Nur Soyer

2017-06-01

Full Text Available We aimed to determine the genotype distribution, allele frequency, and prognostic impact of IDH1/2, TET2, and ASXL1 single nucleotide polymorphisms (SNPs in myeloproliferative neoplasms (MPNs. TET2 (rs763480, ASXL1 (rs2208131, and IDH1 (rs11554137 variant homozygous genotype frequencies were found at rates of 1.5%, 9.2%, and 2.3%, respectively. No IDH2 SNP was identified. IDH1 and TET2 frequencies were 5% in essential thrombocythemia (ET and 1.7% in ET and 5% in primary myelofibrosis (PMF, respectively. ASXL1 frequencies were 8.3%-10% in MPN subgroups. The TET2 mutant allele T and ASXL1 mutant allele G had the highest frequencies with 0.272 in the PMF and 0.322 in the polycythemia vera (PV group, respectively. There was no impact of the SNPs on prognosis. IDH1 frequency in MPNs was found similar to the literature. ASXL1 frequencies were similar between ET, PV, and PMF patients. The ASXL1 and TET2 allele frequencies of the Turkish population are similar to those of the European population. The role of SNPs in MPNs might be further evaluated in larger multicenter studies.

Molecular diagnostics of myeloproliferative neoplasms.

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Langabeer, Stephen E; Andrikovics, Hajnalka; Asp, Julia; Bellosillo, Beatriz; Carillo, Serge; Haslam, Karl; Kjaer, Lasse; Lippert, Eric; Mansier, Olivier; Oppliger Leibundgut, Elisabeth; Percy, Melanie J; Porret, Naomi; Palmqvist, Lars; Schwarz, Jiri; McMullin, Mary F; Schnittger, Susanne; Pallisgaard, Niels; Hermouet, Sylvie

2015-10-01

Since the discovery of the JAK2 V617F mutation in the majority of the myeloproliferative neoplasms (MPN) of polycythemia vera, essential thrombocythemia and primary myelofibrosis ten years ago, further MPN-specific mutational events, notably in JAK2 exon 12, MPL exon 10 and CALR exon 9 have been identified. These discoveries have been rapidly incorporated into evolving molecular diagnostic algorithms. Whilst many of these mutations appear to have prognostic implications, establishing MPN diagnosis is of immediate clinical importance with selection, implementation and the continual evaluation of the appropriate laboratory methodology to achieve this diagnosis similarly vital. The advantages and limitations of these approaches in identifying and quantitating the common MPN-associated mutations are considered herein with particular regard to their clinical utility. The evolution of molecular diagnostic applications and platforms has occurred in parallel with the discovery of MPN-associated mutations, and it therefore appears likely that emerging technologies such as next-generation sequencing and digital PCR will in the future play an increasing role in the molecular diagnosis of MPN. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Transjugular intrahepatic porto-systemic stent-shunt for therapy of bleeding esophageal varices due to extramedullary hematopoiesis in primary myelofibrosis: a case report.

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Phillip, Veit; Berger, Hermann; Straub, Melanie; Saugel, Bernd; Treiber, Matthias; Einwächter, Henrik; Schmid, Roland M; Huber, Wolfgang

2012-01-01

Primary myelofibrosis belongs to the group of myeloproliferative syndromes. Extramedullary hematopoiesis in the liver can lead to portal hypertension. We report a case of a patient with life-threatening, endoscopically not treatable bleeding from esophageal varices due to extramedullary hematopoiesis of the liver that was successfully treated with placement of a transjugular intrahepatic porto-systemic stent-shunt (TIPS). Therapy of variceal bleeding by TIPS insertion was successful. During a 29-month follow-up, no hepatic failure, hepatic encephalopathy, or further variceal bleeding episode occurred. TIPS placement is a well-established procedure for the treatment of complications due to portal hypertension mainly due to liver cirrhosis. This report illustrates that TIPS placement can also be a promising treatment option in patients with primary myelofibrosis and portal hypertension due to extramedullary hematopoiesis. Copyright © 2012 S. Karger AG, Basel.

Practical management of patients with myelofibrosis receiving ruxolitinib.

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Harrison, Claire; Mesa, Ruben; Ross, David; Mead, Adam; Keohane, Clodagh; Gotlib, Jason; Verstovsek, Srdan

2013-10-01

Myelofibrosis (MF) is characterized by bone marrow fibrosis, progressive anemia and extramedullary hematopoiesis, primarily manifested as splenomegaly. Patients also experience debilitating constitutional symptoms, including sequelae of splenomegaly, night sweats and fatigue. Ruxolitinib (INC424, INCB18424, Jakafi, Jakavi), a JAK1 and JAK2 inhibitor, was approved in November 2011 by the US FDA for the treatment of intermediate- or high-risk MF, and more recently in Europe and Canada for the treatment of MF-related splenomegaly or symptoms. These approvals were based on data from two randomized Phase III studies: COMFORT-I randomized against placebo, and COMFORT-II randomized against best available therapy. In these studies, ruxolitinib rapidly improved multiple disease manifestations of MF, reducing splenomegaly and improving quality of life of patients and potentially prolonging survival. However, as with other chemotherapies, ruxolitinib therapy is associated with some adverse events, such as anemia and thrombocytopenia. The aims of this article are to provide a brief overview of ruxolitinib therapy, to discuss some common adverse events associated with ruxolitinib therapy and to provide clinical management recommendations to maximize patients' benefit from ruxolitinib.

Extrahepatic Manifestations of Hepatitis B Virus Infection: Addison’s Disease and Myelofibrosis in a Patient with Persistent Hepatitis B Surface Antigenemia

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François Somlo

1993-01-01

Full Text Available A 60-year-old white male patient was admitted to the hospital with acute abdominal pain, seemingly a self-limited ileus. He was found to be hepatitis B surface antigen (HBsAg-positive. Previous dental treatment was suspected to be the initial source of the infection with hepatitis B virus. Five months later he was re-admitted with a diagnosis of adrenal insufficiency (Addison’s disease which responded well to steroids. Four years later he developed fever and leucocytosis. A bone marrow biopsy revealed myelofibrosis. He had several episodes of pyrexia during his lifetime. After a 12-year period the patient suffered a fatal myocardial infarction. At autopsy the adrenal glands were reduced to scarred remnants and HBsAg was found to be present in the residual adrenocortical cells by immunoflouresence methods. Bone marrow at autopsy revealed myelosclerosis as well HBsAg (via immunofluoresence. Hepatitis B virus was therefore closely correlated with the development of Addison’s disease and myelofibrosis in this case.

Successful Control of Acute Myelofibrosis with Lenalidomide

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G. Vassilopoulos

2010-01-01

Full Text Available Acute panmyelosis with myelofibrosis (APMF is a rare, fatal hematological neoplasm that is characterized by the acute onset of cytopenias and fibrosis in the bone marrow in the absence of splenomegaly or fibrosis-related morphological changes in the RBCs. We present the case of a 59-year-old female who presented with a two-month history of anemia, leucopenia and a normal platelet count. The marrow was heavily fibrotic, and no aspirate material could be obtained; the biopsy showed extensive infiltration with small to medium size megakaryocytes, dysplastic changes in the erythroid compartment, and left shift in the myeloid cells. The patient was treated for four months with anabolic steroids (Danazol, growth factors and received regular blood transfusions. At 4 months after diagnosis, the patient was started on Lenalidomide, 10 mg/day for a 21-d-course along with growth factor support. At 6 months after treatment, the patient was transfusion-independent, had normalized blood counts, and, at 32 months on continuous lenalidomide treatment, her needs for growth factor support have been minimized. Repeat bone marrow biopsies showed a patchy distribution of fibrosis with areas of normal cellularity and morphology. To our knowledge, this is the first case for a medication that could reverse the fatal outcome of APMF.

Efficacy of ALK5 inhibition in myelofibrosis

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Zhao, Wanke; Ho, Wanting Tina; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao; Steidl, Ulrich; Levine, Ross L.; Zhao, Zhizhuang Joe; Verma, Amit; Epling-Burnette, Pearlie K.

2017-01-01

Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF. PMID:28405618

Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide.

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Harrison, Claire N; Mead, Adam J; Panchal, Anesh; Fox, Sonia; Yap, Christina; Gbandi, Emmanouela; Houlton, Aimee; Alimam, Samah; Ewing, Joanne; Wood, Marion; Chen, Frederick; Coppell, Jason; Panoskaltsis, Nicki; Knapper, Steven; Ali, Sahra; Hamblin, Angela; Scherber, Robyn; Dueck, Amylou C; Cross, Nicholas C P; Mesa, Ruben; McMullin, Mary Frances

2017-10-26

Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis, and leukemia. Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET and polycythemia vera patients resistant or intolerant to HC. Here, findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively. There was no evidence of improvement in complete response within 1 year reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT ( P = .40). At 2 years, rates of thrombosis, hemorrhage, and transformation were not significantly different; however, some disease-related symptoms improved in patients receiving ruxolitinib relative to BAT. Molecular responses were uncommon; there were 2 complete molecular responses (CMR) and 1 partial molecular response in CALR- positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in 1 CMR patient, presumably because of the emergence of a different clone, raising questions about the relevance of CMR in ET patients. Grade 3 and 4 anemia occurred in 19% and 0% of ruxolitinib vs 0% (both grades) in the BAT arm, and grade 3 and 4 thrombocytopenia in 5.2% and 1.7% of ruxolitinib vs 0% (both grades) of BAT-treated patients. Rates of discontinuation or treatment switching did not differ between the 2 trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET. This trial was registered at www.isrctn.com as #ISRCTN61925716. © 2017 by The American Society of Hematology.

DEFINITION OF ACTIVATED THROMBOCYTE NUMBER WITH ANTIBODIES FOR ACTIVATED FIBRINOGEN AND P-SELECTIN IN PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA AND ANTIAGGREGATION DRUG EFFECT

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Samo Zver

2004-12-01

Full Text Available Background. Essential thrombocythemia (ET is a chronic myeloproliferative disease with a platelet count within the range of 400–2000 × 109/L. Higher percentage of platelets in the circulation of patients with ET express also activation markers on their membranes. Two of such markers are P-selectin and activated fibrinogen on platelet membranes. Because of frequent thrombembolic and also bleeding related complications, treatment of ET is mandatory. Patients whose platelet count is less than 1000 × 109/L and who did not suffer any thrombembolic complication during the course of the disease, are ussually treated with an antiaggregation drug, acetylsalicylic acid 100 mg/daily orally. Clopidogrel is an adenosyn-di-phosphate (ADP receptor antagonist in platelets. There is no routine clinical data about clopidogrel treatment in the patients with ET and only sporadic case reports can be find in the literature.Patients and methods. In our clinical study we compared antiaggregational effects of acetylsalicylic acid and clopidogrel, by measuring the P-selectin level and activated fibrinogen expression on platelet membranes.There were 35 ET patients included, within the age range between 21 and 78 years and with platelet counts within 451–952 × 109/L. None of the patients did suffer any thrombembolic complication during the course of the disease. During the sequential 14 day periods, patients received acetylsalicylic acid 100 mg/daily orally, followed by clopidogrel 75 mg/daily orally and ultimativelly, together acetylsalicylic acid 100 mg/daily orally plus clopidogrel 75 mg/daily orally. After each fourteen days period the level of P-selectin and activated fibrinogen activated platelets were determined with monoclonal antibodies on flow cytometer. Statistical evaluation was calculated on the difference of average values between the two small, independent pair groups with the t-test.Results. When the patients stopped with acetylsalicylic acid and

Treatment With JAK Inhibitors in Myelofibrosis Patients Nullifies the Prognostic Impact of Unfavorable Cytogenetics.

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Ma, Vincent T; Boonstra, Philip S; Menghrajani, Kamal; Perkins, Cecelia; Gowin, Krisstina L; Mesa, Ruben A; Gotlib, Jason R; Talpaz, Moshe

2018-05-01

In the era before Janus kinase (JAK) inhibitors, cytogenetic information was used to predict survival in myelofibrosis patients. However, the prognostic value of cytogenetics in the setting of JAK inhibitor therapy remains unknown. We performed a retrospective analysis of 180 patients with bone marrow biopsy-proven myelofibrosis from 3 US academic medical centers. We fit Cox proportional hazards models for overall survival and transformation-free survival on the bases of 3 factors: JAK inhibitor therapy as a time-dependent covariate, dichotomized cytogenetic status (favorable vs. unfavorable), and statistical interaction between the two. The median follow-up time was 37.1 months. Among patients treated with best available therapy, unfavorable cytogenetic status was associated with decreased survival (hazard ratio = 2.31; P = .025). At initiation of JAK inhibitor therapy, unfavorable cytogenetics was (nonsignificantly) associated with increased survival compared to favorable cytogenetics (hazard ratio = 0.292; P = .172). The ratio of hazard ratios was 0.126 (P = .034). These findings were similar after adjusting for standard clinical prognostic factors as well as when measured against transformation-free survival. The initiation of JAK inhibitor therapy appears to change the association between cytogenetics and overall survival. There was little difference in survival between treatment types in patients with favorable cytogenetics. However, the use of JAK inhibitor therapy among patients with unfavorable cytogenetics was not associated with worse survival compared to favorable cytogenetics. Our analyses suggest that initiation of JAK inhibitor therapy nullifies the negative prognostic implication of unfavorable cytogenetics established in the pre-JAK inhibitor therapy era. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

F-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Appearance of Extramedullary Hematopoesis in a Case of Primary Myelofibrosis

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Mukherjee, Anirban; Bal, Chandrasekhar; Tripathi, Madhavi; Das, Chandan Jyoti; Shamim, Shamim Ahmed

2017-01-01

A 44-year-old female with known primary myelofibrosis presented with shortness of breath. High Resolution Computed Tomography thorax revealed large heterogeneously enhancing extraparenchymal soft tissue density mass involving bilateral lung fields. F-18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography revealed mildly FDG avid soft tissue density mass with specks of calcification involving bilateral lung fields, liver, and spleen. Subsequent histopathologic evaluation from the right lung mass was suggestive of extramedullary hematopoesis. PMID:28533647

Cytokine Regulation of Microenvironmental Cells in Myeloproliferative Neoplasms

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Gregor Hoermann

2015-01-01

Full Text Available The term myeloproliferative neoplasms (MPN refers to a heterogeneous group of diseases including not only polycythemia vera (PV, essential thrombocythemia (ET, and primary myelofibrosis (PMF, but also chronic myeloid leukemia (CML, and systemic mastocytosis (SM. Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application.

Detection of MPLW515L/K mutations and determination of allele frequencies with a single-tube PCR assay.

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Takei, Hiraku; Morishita, Soji; Araki, Marito; Edahiro, Yoko; Sunami, Yoshitaka; Hironaka, Yumi; Noda, Naohiro; Sekiguchi, Yuji; Tsuneda, Satoshi; Ohsaka, Akimichi; Komatsu, Norio

2014-01-01

A gain-of-function mutation in the myeloproliferative leukemia virus (MPL) gene, which encodes the thrombopoietin receptor, has been identified in patients with essential thrombocythemia and primary myelofibrosis, subgroups of classic myeloproliferative neoplasms (MPNs). The presence of MPL gene mutations is a critical diagnostic criterion for these diseases. Here, we developed a rapid, simple, and cost-effective method of detecting two major MPL mutations, MPLW515L/K, in a single PCR assay; we termed this method DARMS (dual amplification refractory mutation system)-PCR. DARMS-PCR is designed to produce three different PCR products corresponding to MPLW515L, MPLW515K, and all MPL alleles. The amplicons are later detected and quantified using a capillary sequencer to determine the relative frequencies of the mutant and wild-type alleles. Applying DARMS-PCR to human specimens, we successfully identified MPL mutations in MPN patients, with the exception of patients bearing mutant allele frequencies below the detection limit (5%) of this method. The MPL mutant allele frequencies determined using DARMS-PCR correlated strongly with the values determined using deep sequencing. Thus, we demonstrated the potential of DARMS-PCR to detect MPL mutations and determine the allele frequencies in a timely and cost-effective manner.

Thrombocytosis and thrombosis.

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Vannucchi, Alessandro M; Barbui, Tiziano

2007-01-01

The aim of this review is to discuss current diagnostic approaches to, and classification of, patients presenting with thrombocytosis, in light of novel information derived from the discovery of specific molecular abnormalities in chronic myeloproliferative disorders (CMPD), which represent the most common cause of primary thrombocytosis. The JAK2V617F and the MPLW515L/K mutations have been found in patients with essential thrombocythemia, polycythemia vera, and primary myelofibrosis, and less frequently in other myeloproliferative disorders complicated by thrombocytosis. However, neither mutation is disease specific nor is it universally present in patients with elevated platelet counts due to a CMPD; therefore, distinguishing between reactive and primary forms of thrombocytosis, as well as among the different clinical entities that constitute the CMPD, still requires a multifaceted diagnostic approach that includes as a key step the accurate evaluation of bone marrow histology. The role of elevated platelet counts in thrombosis, which represent the predominant complication of CMPD,significantly affecting prognosis and quality of life as well as, paradoxically, in the pathogenesis of the hemorrhagic manifestations, will be discussed. Established and novel potential risk factors for thrombosis, including the clinical relevance of the JAK2V617F mutation, and current management strategies for thrombocytosis are also briefly discussed.

Molecular genetic tests for JAK2V617F, Exon12_JAK2 and MPLW515K/L are highly informative in the evaluation of patients suspected to have BCR-ABL1-negative myeloproliferative neoplasms.

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dos Santos, Marcos Tadeu; Mitne-Neto, Miguel; Miyashiro, Kozue; Chauffaille, Maria de Lourdes L Ferrari; Rizzatti, Edgar Gil

2014-02-01

Polycythaemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (MF), are the most common myeloproliferative neoplasms (MPN) in patients without the BCR-ABL1 gene rearrangement. They are caused by clonal expansion of haematopoietic stem cells and share, as a diagnostic criterion, the identification of JAK2V617F mutation. Classically, when other clinical criteria are present, a JAK2V617F negative case requires the analysis of Exon12_JAK2 for the diagnosis of PV, and of MPL515K/L mutations for the diagnosis of ET and MF. Here, we evaluated 78 samples from Brazilian patients suspected to have MPN, without stratification for PV, ET or MF. We found that 28 (35.9%) are JAK2V617F carriers; from the 50 remaining samples, one (2%) showed an Exon12_JAK2 mutation, and another (2%) was positive for MPLW515L mutation. In summary, the investigation of JAK2V617F, Exon12_JAK2 and MPLW515K/L was relevant for the diagnosis of 38.4% of patients suspected to have BCR-ABL1-negative MPN, suggesting that molecular genetic tests are useful for a quick and unequivocal diagnosis of MPN.

Detection of MPLW515L/K mutations and determination of allele frequencies with a single-tube PCR assay.

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Hiraku Takei

Full Text Available A gain-of-function mutation in the myeloproliferative leukemia virus (MPL gene, which encodes the thrombopoietin receptor, has been identified in patients with essential thrombocythemia and primary myelofibrosis, subgroups of classic myeloproliferative neoplasms (MPNs. The presence of MPL gene mutations is a critical diagnostic criterion for these diseases. Here, we developed a rapid, simple, and cost-effective method of detecting two major MPL mutations, MPLW515L/K, in a single PCR assay; we termed this method DARMS (dual amplification refractory mutation system-PCR. DARMS-PCR is designed to produce three different PCR products corresponding to MPLW515L, MPLW515K, and all MPL alleles. The amplicons are later detected and quantified using a capillary sequencer to determine the relative frequencies of the mutant and wild-type alleles. Applying DARMS-PCR to human specimens, we successfully identified MPL mutations in MPN patients, with the exception of patients bearing mutant allele frequencies below the detection limit (5% of this method. The MPL mutant allele frequencies determined using DARMS-PCR correlated strongly with the values determined using deep sequencing. Thus, we demonstrated the potential of DARMS-PCR to detect MPL mutations and determine the allele frequencies in a timely and cost-effective manner.

Expression of CALR mutants causes mpl-dependent thrombocytosis in zebrafish.

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Lim, K-H; Chang, Y-C; Chiang, Y-H; Lin, H-C; Chang, C-Y; Lin, C-S; Huang, L; Wang, W-T; Gon-Shen Chen, C; Chou, W-C; Kuo, Y-Y

2016-10-07

CALR mutations are identified in about 30% of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET) and primary myelofibrosis. Although the molecular pathogenesis of CALR mutations leading to MPNs has been studied using in vitro cell lines models, how mutant CALR may affect developmental hematopoiesis remains unknown. Here we took advantage of the zebrafish model to examine the effects of mutant CALR on early hematopoiesis and model human CALR-mutated MPNs. We identified three zebrafish genes orthologous to human CALR, referred to as calr, calr3a and calr3b. The expression of CALR-del52 and CALR-ins5 mutants caused an increase in the hematopoietic stem/progenitor cells followed by thrombocytosis without affecting normal angiogenesis. The expression of CALR mutants also perturbed early developmental hematopoiesis in zebrafish. Importantly, morpholino knockdown of mpl but not epor or csf3r could significantly attenuate the effects of mutant CALR. Furthermore, the expression of mutant CALR caused jak-stat signaling activation in zebrafish that could be blocked by JAK inhibitors (ruxolitinib and fedratinib). These findings showed that mutant CALR activates jak-stat signaling through an mpl-dependent mechanism to mediate pathogenic thrombopoiesis in zebrafish, and illustrated that the signaling machinery related to mutant CALR tumorigenesis are conserved between human and zebrafish.

Evaluation of the effect of aromatherapy with lavender essential oil on post-tonsillectomy pain in pediatric patients: a randomized controlled trial.

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Soltani, Rasool; Soheilipour, Saeed; Hajhashemi, Valiollah; Asghari, Gholamreza; Bagheri, Mahdi; Molavi, Mahdi

2013-09-01

To evaluate the effect of aromatherapy with Lavandula angustifolia essential oil on post-tonsillectomy pain in pediatric patients. This was a randomized controlled prospective clinical trial. In this study, 48 post-tonsillectomy patients aged 6-12 years were randomly assigned to two groups (24 patients in each group). After tonsillectomy surgery, all patients received acetaminophen (10-15 mg/kg/dose, PO) every 6h as necessary to relieve pain. The patients of the case group also inhaled lavender essential oil. The frequencies of daily use of acetaminophen and nocturnal awakening due to pain, and pain intensity (evaluated using visual analog scale [VAS]) were recorded for each patient for 3 days after surgery. Finally, the mean values of variables were compared between two groups separately for each post-operative day. The use of lavender essential oil caused statistically significant reduction in daily use of acetaminophen in all three post-operative days but had not significant effects on pain intensity and frequency of nocturnal awakening. Aromatherapy with lavender essential oil decreases the number of required analgesics following tonsillectomy in pediatric patients. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Whole blood transcriptional profiling reveals significant down-regulation of human leukocyte antigen class I and II genes in essential thrombocythemia, polycythemia vera and myelofibrosis

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Skov, Vibe; Riley, Caroline Hasselbalch; Thomassen, Mads

2013-01-01

Gene expression profiling studies in the Philadelphia-negative chronic myeloproliferative neoplasms have revealed significant deregulation of several immune and inflammation genes that might be of importance for clonal evolution due to defective tumor immune surveillance. Other mechanisms might b...

Assessment of bone marrow inflammation in patients with myelofibrosis: an {sup 18}F-fluorodeoxyglucose PET/CT study

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Derlin, Thorsten [Hannover Medical School, Department of Nuclear Medicine, Hannover (Germany); University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Alchalby, Haefaa; Triviai, Ioanna; Kroeger, Nicolaus [University Medical Center Hamburg-Eppendorf, Clinic for Stem Cell Transplantation, Hamburg (Germany); Bannas, Peter [University Medical Center Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg (Germany); Veldhoen, Simon [University Medical Center Wuerzburg, Department of Diagnostic and Interventional Radiology, Wuerzburg (Germany); Apostolova, Ivayla [Otto-von-Guericke University, Department of Radiology and Nuclear Medicine, Magdeburg (Germany); Bengel, Frank M. [Hannover Medical School, Department of Nuclear Medicine, Hannover (Germany)

2015-04-01

Myelofibrosis is a haematopoietic stem cell neoplasm characterized by bone marrow inflammation, reactive marrow fibrosis and extramedullary haematopoiesis. The aim of this study was to determine if {sup 18}F-FDG PET/CT can be used to noninvasively visualize and quantify the extent and activity of bone marrow involvement. In 30 patients, the biodistribution of {sup 18}F-FDG was analysed by measuring the standardized uptake value in the bone marrow compartment and spleen. Imaging findings were compared with laboratory, cytogenetic and histopathological data. Retention of {sup 18}F-FDG was observed in bone marrow and spleen. Bone marrow involvement varied, ranging from mildly increased uptake in the central skeleton to extensive uptake in most parts of the skeleton. The extent of bone marrow involvement decreased over time from initial diagnosis (r{sub s} = -0.43, p = 0.019). Metabolic activity of the bone marrow decreased as the histopathological grade of fibrosis increased (r{sub s} = -0.37, p = 0.04). There was a significant positive correlation between the metabolic activity of the bone marrow and that of the spleen (p = 0.04). {sup 18}F-FDG PET/CT is as a promising technique for the quantitation of bone marrow inflammation in myelofibrosis. Our data indicate that the intensity of bone marrow {sup 18}F-FDG uptake decreases as bone marrow fibrosis increases. Further evaluation in prospective studies is required to determine the potential clinical impact and prognostic significance of PET. (orig.)

Recent advances in the bcr-abl negative chronic myeloproliferative diseases

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Stroncek David F

2006-10-01

disease. Recently, two mutations have been found; W515L and W515K. These mutations have been evident in patients with essential thrombocythemia and idiopathic myelofibrosis but not in polycythemia vera. They presumably act by causing constitutional, activating conformational changes in the receptor. The discovery of JAK2 and Mpl mutations is leading to rapid advancements in understanding the pathophysiology and in the treatment of these diseases.

Palliative splenic irradiation in primary and post PV/ET myelofibrosis: outcomes and toxicity of three radiation schedules

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Mario Federico

2009-05-01

Full Text Available Splenectomy and splenic irradiation (SI are the sole treatment modalities to control drug resistant splenomegaly in patients with myelofibrosis (MF. SI has been used in poor surgical candidates but optimal total dose and fractionation are unclear. We retrospectively reviewed 14 MF patients with symptomatic splenomegaly. Patients received a median of 10 fractions in two weeks. Fraction size ranged from 0.2-1.4 Gy, and total dose varied from 2-10.8 Gy per RT course. Overall results indicate that 81.8% of radiation courses achieved a significant spleen reduction. Splenic pain relief and gastrointestinal symptoms reduction were obtained in 94% and 91% of courses, respectively. Severe cytopenias occurred in 13% of radiation courses. Furthermore patients were divided in three groups according to the radiation dose they received: 6 patients in the low-dose group (LDG received a normalized dose of 1.67 Gy; 4 patients in the intermediate-dose group (IDG received a normalized dose 4.37 Gy; the remaining 4 patients in the high-dose group (HDG received a normalized dose of 9.2 Gy. Subgroup analysis showed that if no differences in terms of treatment’s efficacy were seen among dose groups, hematologic toxicity rates distributed differently. Severe cytopenias occurred in 50% of courses in the HDG, and in the 14.3% and in 0% of the IDG and LDG respectively. Spleen reduction and pain relief lasted for a median of 5.5 months in all groups. Due to the efficacy and tolerability of the low-dose irradiation 4 patients from the LDG and IDG were retreated and received on the whole 12 RT courses. Multiple retreatments did not show decremental trends in terms of rates of response to radiation nor in terms of duration of clinical response. Moreover, retreatment courses did not cause an increased rate of adverse effects and none of the retreated patients experienced severe hematologic toxicities. The average time of clinical benefit in retreated patients was much longer

Understanding Splenomegaly in Myelofibrosis: Association with Molecular Pathogenesis

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Moo-Kon Song

2018-03-01

Full Text Available Myelofibrosis (MF is a clinical manifestation of chronic BCR-ABL1-negative chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis (EMH. EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells due to the dysregulated bone marrow (BM microenvironment leading to progressive splenomegaly. Several recent data have emphasized the role of several cytokines for splenic EMH. Alteration of CXCL12/CXCR4 pathway could also lead to splenic EMH by migrated clonal hematopoietic cells from BM to the spleen. Moreover, low Gata1 expression was found to be significantly associated with the EMH. Several gene mutations were found to be associated with significant splenomegaly in MF. In recent data, JAK2 V617F homozygous mutation was associated with a larger spleen size. In other data, CALR mutations in MF were signigicantly associated with longer larger splenomegaly-free survivals than others. In addition, MF patients with ≥1 mutations in AZXL1, EZH1 or IDH1/2 had significantly low spleen reduction response in ruxolitinib treatment. Developments of JAK inhibitors, such as ruxolitinib, pacritinib, momelotinib, and febratinib enabled the effective management in MF patients. Especially, significant spleen reduction responses of the drugs were demonstrated in several randomized clinical studies, although those could not eradicate allele burdens of MF.

Transjugular Intrahepatic Porto-Systemic Stent-Shunt for Therapy of Bleeding Esophageal Varices Due to Extramedullary Hematopoiesis in Primary Myelofibrosis: A Case Report

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Phillip, Veit;Berger, Hermann;Straub, Melanie;Saugel, Bernd;Treiber, Matthias;Einwächter, Henrik;Schmid, Roland M.;Huber, Wolfgang

2016-01-01

Background: Primary myelofibrosis belongs to the group of myeloproliferative syndromes. Extramedullary hematopoiesis in the liver can lead to portal hypertension. Patient and Methods: We report a case of a patient with life-threatening, endoscopically not treatable bleeding from esophageal varices due to extramedullary hematopoiesis of the liver that was successfully treated with placement of a transjugular intrahepatic porto-systemic stent-shunt (TIPS). Results: Therapy of variceal bleeding ...

Autoimmune myelofibrosis accompanied by Sjögren's syndrome in a 47, XXX/46, XX mosaic woman.

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Takahashi, Tohru

2014-01-01

This report describes a patient with autoimmune myelofibrosis accompanied by Sjögren's syndrome (SS). A 36-year-old woman was admitted due to petechiae, purpura, gingival bleeding, dyspnea on exertion, and a lack of concentration. She had pancytopenia and was diagnosed with SS. A bone marrow study showed hypercellular marrow with reticulin fibrosis. Lymphocytic infiltrates and aggregates composed of a mixture of T and B cells in the marrow were also observed. A chromosomal analysis of the marrow cells showed 47, XXX and an analysis of peripheral lymphocytes revealed 47, XXX/46, XX mosaic results. The patient's cytopenia resolved following treatment with oral prednisolone.

Pulmonary cryptococcosis in a ruxolitinib-treated patient with primary myelofibrosis

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Anna Hirano

2017-01-01

Full Text Available We present the case of a 79-year-old man who showed multiple pulmonary nodules on chest computed tomography (CT after being treated for 6 months with ruxolitinib, an inhibitor of Janus kinase (JAK 1 and 2, to treat primary myelofibrosis. We examined the lesions by bronchoscopy, and the biopsy specimen revealed fungus bodies of Cryptococcus with granulomatous inflammation. As a result, the patient was diagnosed with pulmonary cryptococcosis. The patient was treated with fluconazole (200 mg daily for 2 weeks with concomitant ruxolitinib administration, but the pulmonary lesions progressed. Subsequently, the patient was treated with voriconazole (300 mg daily for 3 weeks, but the lesions worsened further. The administration of ruxolitinib was therefore discontinued, and the dosage of voriconazole was increased to 400 mg daily. Three months later, the pulmonary lesions diminished in size. The present case of pulmonary cryptococcosis occurred in a patient treated with ruxolitinib. Treatment of pulmonary cryptococcosis with concomitant JAK inhibitor administration may result in poor treatment efficacy. It might be better to stop administration of JAK inhibitors, if possible, in patients being treated for pulmonary cryptococcosis.

An autopsy case of myelofibrosis seen in a proximally expoed survivor

International Nuclear Information System (INIS)

Harada, Tomoyuki; Matsuo, Kakaru; Shikaya, Takao; Takeshita, Kikuo; Toyoda, Shigeki.

1977-01-01

An autopsy case of myelofibrosis is reported and is literarily discussed. The patient was a 30-year-old man and was exposed to sublethal dose of radiation at 1.1 km from the hypocenter at the time of the explosion in Nagasaki Prefecture, when he was 10 months old. Serious bone marrow disturbances were suspected. About 25 years after the exposure, clinical symptoms like aplastic anemia were shown and this disease developed. Hepatosplenomegaly was not clinically found until the late period. The liver weighed 3180 g and the spleen weighed 1540 g at autopsy. Blood examination revealed low value of neutrophilic alkaline phosphatase only at the late period, and no abnormal chromosome was seen in the peripheral blood. Reticulum-like cells were not histologically found at biopsy, but were found at autopsy. Extramedullary hematopoiesis, always accompanied with bleeding, was observed not only in the spleen, the liver and the lymphnodes, but also in the dura mater, the stomach, the renal pelves and so on. It was the direct cause of death. (Kanao, N.)

A Review of Ruxolitinib for the Treatment of Myelofibrosis: A Critique of the Evidence.

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Wade, Ros; Hodgson, Robert; Biswas, Mousumi; Harden, Melissa; Woolacott, Nerys

2017-02-01

As part of the National Institute for Health and Care Excellence's (NICE) Single Technology Appraisal (STA) process, ruxolitinib was assessed to determine the clinical and cost effectiveness of its use in the treatment of disease-related splenomegaly or symptoms in adults with myelofibrosis. Ruxolitinib had previously been assessed as part of the STA process and was not recommended in NICE guidance issued in June 2013 (TA289). A review of TA289 was commissioned following the availability of new longer-term survival data; a price discount patient access scheme (PAS) was also introduced. The Centre for Reviews and Dissemination (CRD) and Centre for Health Economics (CHE) Technology Appraisal Group at the University of York was commissioned to act as the independent Evidence Review Group (ERG). This article provides a summary of the manufacturer or sponsor of the technology's (referred to as the company) submission, the ERG review and the resulting NICE guidance issued in March 2016. The main clinical effectiveness data were derived from two good-quality multicentre randomised controlled trials (RCTs): COMFORT-II compared ruxolitinib with best available therapy (BAT) and COMFORT-I compared ruxolitinib with placebo. Both RCTs demonstrated a statistically significant reduction in splenomegaly and its associated symptoms in intermediate-2 and high-risk myelofibrosis patients. Overall survival was statistically significantly improved with ruxolitinib compared with BAT at 3.5 years of follow-up in the COMFORT-II trial (hazard ratio 0.58, 95 % CI 0.36-0.93). Grade 3-4 adverse events were more frequent in the ruxolitinib group than in the BAT group; 42 % compared with 25 %. Evidence relating to patients with lower-risk disease or low platelet counts (50-100 × 10 9 /L) was less robust. The company's economic model was well-presented and had an appropriate model structure. The base-case incremental cost-effectiveness ratio (ICER) was estimated to be around £45,000 per

EXEL-8232, a small-molecule JAK2 inhibitor, effectively treats thrombocytosis and extramedullary hematopoiesis in a murine model of myeloproliferative neoplasm induced by MPLW515L.

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Wernig, G; Kharas, M G; Mullally, A; Leeman, D S; Okabe, R; George, T; Clary, D O; Gilliland, D G

2012-04-01

About 10% of patients with essential thrombocythemia (ET) or myelofibrosis (MF) that lack mutations in JAK2 harbor an activating mutation in the thrombopoietin receptor, MPLW515L. Distinct from the JAK2V617F retroviral transplant model, the MPLW515L model recapitulates many features of ET and MF, including severe fibrosis and thrombocytosis. We have tested EXEL-8232, an experimental potent JAK2 inhibitor, for efficacy in suppression of thrombocytosis in vivo and for its ability to attenuate MPLW515L myeloproliferative disease. EXEL-8232 was administered for 28 days q12 h by oral gavage at doses of 30 or 100 mg/kg, prospectively. Animals treated with EXEL-8232 at 100 mg/kg had normalized high platelet counts, eliminated extramedullary hematopoiesis in the spleen and eliminated bone marrow fibrosis, whereas the wild-type controls did not develop thrombocytopenia. Consistent with a clinical response in this model, we validated surrogate end points for response to treatment, including a reduction of endogenous colony growth and signaling inhibition in immature erythroid and myeloid primary cells both in vitro and upon treatment in vivo. We conclude that EXEL-8232 has efficacy in treatment of thrombocytosis in vivo in a murine model of ET and MF, and may be of therapeutic benefit for patients with MPL-mutant MPN.

Ligand-independent Thrombopoietin Mutant Receptor Requires Cell Surface Localization for Endogenous Activity*

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Marty, Caroline; Chaligné, Ronan; Lacout, Catherine; Constantinescu, Stefan N.; Vainchenker, William; Villeval, Jean-Luc

2009-01-01

The activating W515L mutation in the thrombopoietin receptor (MPL) has been identified in primary myelofibrosis and essential thrombocythemia. MPL belongs to a subset of the cytokine receptor superfamily that requires the JAK2 kinase for signaling. We examined whether the ligand-independent MPLW515L mutant could signal intracellularly. Addition of the endoplasmic reticulum (ER) retention KDEL sequence to the receptor C terminus efficiently locked MPLW515L within its natural ER/Golgi maturation pathway. In contrast to cells expressing the parental MPLW515L, MPLW515L-KDEL-expressing FDC-P1 cells were unable to grow autonomously and to produce tumors in nude mice. When observed, tumor nodules resulted from in vivo selection of cells leaking the receptor at their surface. JAK2 co-immunoprecipitated with MPLW515L-KDEL but was not phosphorylated. We generated disulfide-bonded MPLW515L homodimers by the S402C substitution, both in the normal and KDEL context. Unlike MPLW515L-KDEL, MPLW515L-S402C-KDEL signaled constitutively and exhibited cell surface localization. These data establish that MPLW515L with appended JAK2 matures through the ER/Golgi system in an inactive conformation and suggest that the MPLW515L/JAK2 complex requires membrane localization for JAK2 phosphorylation, resulting in autonomous receptor signaling. PMID:19261614

Oncogenes in myeloproliferative disorders.

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Tefferi, Ayalew; Gilliland, D Gary

2007-03-01

Myeloproliferative disorders (MPDs) constitute a group of hematopoietic malignancies that feature enhanced proliferation and survival of one or more myeloid lineage cells. William Dameshek is credited for introducing the term "MPDs" in 1951 when he used it to group chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) under one clinicopathologic category. Since then, other myeloid neoplasms have been added to the MPD member list: chronic neutrophilic (CNL), eosinophilic (CEL) and myelomonocytic (CMML) leukemias; juvenile myelomonocytic leukemia (JMML); hypereosinophilic syndrome (HES); systemic mastocytosis (SM); and others. Collectively, MPDs are stem cell-derived clonal proliferative diseases whose shared and diverse phenotypic characteristics can be attributed to dysregulated signal transduction--a consequence of acquired somatic mutations. The most recognized among the latter is BCR-ABL, the disease-causing mutation in CML. Other mutations of putative pathogenetic relevance in MPDs include: JAK2V617F in PV, ET, and PMF; JAK2 exon 12 mutations in PV; MPLW515L/K in PMF and ET; KITD816V in SM; FIP1L1-PDGFRA in CEL-SM; rearrangements of PDGFRB in CEL-CMML and FGFR1 in stem cell leukemia-lymphoma syndrome; and RAS/PTPN11/NF1 mutations in JMML. This increasing repertoire of mutant molecules has streamlined translational research and molecularly targeted drug development in MPDs.

CALR, JAK2 and MPL mutation status in Argentinean patients with BCR-ABL1- negative myeloproliferative neoplasms.

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Ojeda, Mara Jorgelina; Bragós, Irma Margarita; Calvo, Karina Lucrecia; Williams, Gladis Marcela; Carbonell, María Magdalena; Pratti, Arianna Flavia

2018-05-01

To establish the frequency of JAK2, MPL and CALR mutations in Argentinean patients with BCR-ABL1-negative  myeloproliferative neoplasms (MPN) and to compare their clinical and haematological features. Mutations of JAK2V617F, JAK2 exon 12, MPL W515L/K and CALR were analysed in 439 Argentinean patients with BCR-ABL1-negative MPN, including 176 polycythemia vera (PV), 214 essential thrombocythemia (ET) and 49 primary myelofibrosis (PMF). In 94.9% of PV, 85.5% ET and 85.2% PMF, we found mutations in JAK2, MPL or CALR. 74.9% carried JAK2V617F, 12.3% CALR mutations, 2.1% MPL mutations and 10.7% were triple negative. In ET, nine types of CALR mutations were identified, four of which were novel. PMF patients were limited to types 1 and 2, type 2 being more frequent. In ET, patients with CALR mutation were younger and had higher platelet counts than those with JAK2V617F and triple negative. In addition, JAK2V617F patients had high leucocyte and haemoglobin values compared with CALR-mutated and triple-negative patients. In PMF, patients with mutant CALR were associated with higher platelet counts. Our study underscores the importance of JAK2, MPL and CALR genotyping for accurate diagnosis of patients with BCR-ABL1-negative MPN.

Psychological Manifestations of Early Childhood Adversity in the Context of Chronic Hematologic Malignancy.

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McFarland, Daniel C; Shen, Megan Johnson; Polizzi, Heather; Mascarenhas, John; Kremyanskaya, Marina; Holland, Jimmie; Hoffman, Ronald

Myeloproliferative neoplasms (MPNs), a group of chronic hematologic malignancies, carry significant physical and psychological symptom burdens that significantly affect patients' quality of life. We sought to identify the relationship between early childhood adversity (ECA) and psychological distress in patients with MPNs, as ECA may compound symptom burden. Patients with MPNs were assessed for ECA (i.e., the Risky Families Questionnaire-subscales include abuse/neglect/chaotic home environment), distress (i.e., Distress Thermometer and Problem List), anxiety (i.e., Hospital Anxiety and Depression Scale-Anxiety [HADS-A]), depression (i.e., Hospital Anxiety and Depression Scale-Depression [HADS-D]), meeting standardized cutoff thresholds for distress (i.e., Distress Thermometer and Problem List≥ 4 or ≥ 7)/anxiety (HADS-A ≥8)/depression (HADS-D ≥ 8), and demographic factors. A total of 117 participants completed the study (78% response rate). ECA was associated with depression (p psychological outcomes. ECA was higher based on disease subtypes with greater symptom burden (other > polycythemia vera > myelofibrosis > essential thrombocythemia) (p = 0.047) and taking an antidepressant (p = 0.011). ECA is associated with psychological distress and meets screening criteria for anxiety and depression in patients with MPNs. ECA may help to explain individual patient trajectories, and further understanding may enhance patient-centered care among patients with MPNs. Copyright © 2017 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Vascular events in Korean patients with myeloproliferative neoplasms and their relationship to JAK2 mutation.

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Bang, Soo-Mee; Lee, Jong-Seok; Ahn, Jeong Yeal; Lee, Jae Hoon; Hyun, Myung Soo; Kim, Bong Seog; Park, Moo Rim; Chi, Hyun-Sook; Kim, Ho Young; Kim, Hyo Jung; Lee, Moon Hee; Kim, Hwak; Won, Jong Ho; Yoon, Hwi Joong; Oh, Do-Yeun; Nam, Eun-Mi; Bae, Sung Hwa; Kim, Byoung-Kook

2009-03-01

Evaluation of the Janus kinase 2 (JAK2) V617F mutation has been widely used for the diagnosis of myeloproliferative neoplasms (MPN). However, its prognostic relevance to clinical outcome is not completely understood. We investigated the association of JAK2 V617F with vascular events in Korean patients with myeloproliferative neoplasms (MPN). We studied 283 patients from 15 centers, who were diagnosed with MPN. The JAK2 V617F status was evaluated by allele-specific polymerase chain reaction (PCR) and sequencing. The patients' diagnoses were essential thrombocythemia (ET n = 146), polycythemia vera (PV n = 120), primary myelofibrosis (n = 12), and unclassifiable MPN (MPNu n = 5). JAK2 V617F was detected in 89 (61%) patients with ET, 103 (86%) with PV, four (33%) with myelofibrosis, and four (80%) with MPNu. A higher number of leukocytes, haemoglobin levels and BM cellularity as well as an older age, lower platelet counts, and diagnosis of PV were significantly correlated with JAK2 V617F. Eighty-three and 43 episodes of thrombosis and bleeding occurred in 100 patients each before and after the diagnosis. Vascular events more frequently occurred in 37% of patients with JAK2 V617F than in 29% of those without the mutation (p = 0.045). Among 175 patients whose samples were available for sequencing, 28 patients with homozygous JAK2 V617F had vascular events more frequently (57%) than those who were heterozygotes (39%) or had the wild type (27%) (p = 0.03). The multivariate analysis showed that a JAK2 homozygous mutation, hypercholesterolemia and older age were independent risk factors for a vascular event. The results of this study showed that Korean patients with MPN had a similar JAK2 mutation rate and frequency of vascular events when compared to Western patients. The presence of V617F was significantly related to vascular events. Therefore, initial evaluation for the JAK2 mutation and careful monitoring for vascular events should be performed in MPN patients.

Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis

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Broseus, Julien; Florensa, Lourdes; Zipperer, Esther; Schnittger, Susanne; Malcovati, Luca; Richebourg, Steven; Lippert, Eric; Cermak, Jaroslav; Evans, Jyoti; Mounier, Morgane; Raya, José Maria; Bailly, François; Gattermann, Norbert; Haferlach, Torsten; Garand, Richard; Allou, Kaoutar; Besses, Carlos; Germing, Ulrich; Haferlach, Claudia; Travaglino, Erica; Luno, Elisa; Pinan, Maria Angeles; Arenillas, Leonor; Rozman, Maria; Perez Sirvent, Maria Luz; Favre, Bernardine; Guy, Julien; Alonso, Esther; Ahwij, Nuhri; Jerez, Andrés; Hermouet, Sylvie; Maynadié, Marc; Cazzola, Mario; Girodon, François

2012-01-01

Background Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. Design and Methods We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases. Results In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600×109/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia (P<0.001) but better survival (P<0.001) and a higher risk of thrombosis (P=0.039) than patients with refractory anemia with ring sideroblasts. Conclusions The clinical course of refractory anemia with ring sideroblasts and marked thrombocytosis is better than that of refractory anemia with ring sideroblasts and worse than that of essential thrombocythemia. The higher risk of thrombotic events in this disorder suggests that anti-platelet therapy might be considered in this subset of patients. From a clinical point of view, it appears to be important to consider refractory anemia with ring sideroblasts and

Increased granulocytic, erythrocytic, and megakaryocytic progenitors in myelofibrosis with myeloid metaplasia

International Nuclear Information System (INIS)

Chikkappa, G.; Carsten, A.L.; Chanana, A.D.; Chandra, P.; Cronkite, E.P.

1978-01-01

Nucleated cells obtained from blood and/or bone marrow of patients with myelofibrosis with myeloid metaplasia (MMM) were cultured in diffusion chambers (DC) implanted into the peritoneal cavities of irradiated mice. A total of five blood studies and two bone marrow studies were performed using cells obtained from five patients. The DC were harvested at intervals from the host mice and the total and differential cellularity of DC contents were evaluated. The results obtained from MMM cultures were compared with those from similar cultures of blood cells and marrow cells of four and six normal individuals respectively. The proliferation and maturation of the granulocytic, erythrocytic, and megakaryocytic lines in MMM cultures occurred in an orderly fashion as they occur in vivo. The patterns of proliferation and maturation of the three cell lines in cultures after day 7 suggest that they primarily originate from progenitor cells. The numbers of granulocytes in the multiplicative pool, recognizable red cell precursors, and megakaryocytes recovered were significantly greater from the MMM cultures than those from the normal blood or marrow cultures. These results suggest that the blood and marrow cells of MMM patients have increased numbers of progenitors for granulocytes, erythrocytes and megakaryocytes

Radiation therapy for symptomatic hepatomegaly in myelofibrosis with myeloid metaplasia

Energy Technology Data Exchange (ETDEWEB)

Tefferi, A.; Jimenez, T.; Gray, L.A.; Mesa, R.A. [Division of Hematology and Internal Medicine, Rochester, MN (United States); Chen, M.G. [Division of Radiation Oncology, Mayo Clinic and Mayo Foundation, MN (United States)

2001-07-01

Objective: To describe the experience with liver irradiation in advanced cases of myelofibrosis with myeloid metaplasia (MMM). Methods: Over a 20-yr period, 14 patients with MMM were treated with a total of 25 courses of liver, abdominal, or abdominal and pelvic irradiation for symptomatic hepatomegaly with (5 patients) or without (9 patients) ascites. All 14 patients had advanced disease and 11 (79%) had previous splenectomy. The median radiation therapy (RT) dose per course was 150 cGy (range 50-1000) administered at a median of six fractions. Four patients received two to six courses. Results. Twelve of the 14 patients (86%) had a transient (median 3 months) subjective response from RT. However, in only 35% of these was there a transient (median 3 months) decrease in palpable liver size. Four of the five patients with ascites experienced a short-term response from RT. Eight of the 13 patients suitable for evaluation (62%) had treatment-associated cytopenia, often in the form of anemia and/or thrombocytopenia. At last follow-up, 10 patients (71%) had died after a median of 7 months (range 0.1-23) and 4 were alive at 3, 20, 33, and 57 months after RT. Conclusions: Low-dose abdominal RT for symptomatic hepatomegaly or ascites associated with advanced-stage MMM is myelosuppressive and provides only temporary and mainly subjective and short-lived relief. (au)

Comparative study of different methodologies to detect the JAK2 V617F mutation in chronic BCR-ABL1 negative myeloproliferative neoplasms

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Alline Didone

2016-04-01

Full Text Available Objectives: A mutation in the JAK2 gene, V617F, has been identified in several BCR-ABL1 negative myeloproliferative neoplasms (MPN: polycythemia vera (PV, essential thrombocythemia (ET, and primary myelofibrosis (PMF. Defining the presence or absence of this mutation is an essential part of clinical diagnostic algorithms and patient management. Here, we aimed to evaluate the performance of three PCR-based assays: Amplification Refractory Mutation System (ARMS, High-Resolution Melting analysis (HRM, and Sanger direct sequencing, and compare their results with those obtained by a PCR restriction fragment polymorphism assay (PCR-RFLP. Design and methods: We used blood samples from 136 patients (PV=20; PMF=20; ET=28, and other MPN suspected cases=68. Results: Comparable results were observed among the four assays in patients with PV, PMF, and MPN suspected cases. In patients with a diagnosis of ET, the JAK2 V617F mutation was detected in 67.8% of them by the PCR-ARMS and PCR-HRM assay and in 64% of them by the conventional Sanger sequence approach. The PCR-ARMS and PCR-HRM assays were 100% concordant. With these tests, only one of the 20 patients with ET and one of the three patients with clinically suspected MPN gave different results compared with those obtained by the PCR-RFLP. Conclusions: Our results have demonstrated that the PCR-ARMS and PCR-HRM assays could detect the JAK2 V617F mutation effectively in MPN patients, but PCR-HRM assays are rapid and the most cost-effective procedures. Keywords: Myeloproliferative, JAK2 V617F, Mutation, Wild type, Screening

Protein synthesis is essential not only for consolidation but also for maintenance and post-retrieval reconsolidation of acrobatic motor skill in rats.

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Peng, Ji-Yun; Li, Bao-Ming

2009-05-28

It has been reported that consolidation of motor skill, a type of non-declarative memories, requires protein synthesis, as hippocampus-dependent declarative memory does. However, little is known about the importance of protein synthesis in maintenance and especially post-retrieval reconsolidation of acrobatic motor skill. Here, we show that protein synthesis is essential not only for the consolidation but also for the maintenance and reconsolidation of a rotarod-running skill. Intra-ventricle infusion of the protein synthesis inhibitor anisomycin 0 h but not 2 h post-training caused a severe deficit in the acquisition of the rotarod-running skill. Protein synthesis inhibition (PSI) also caused a deficit in the maintenance of the rotarod-running skill, as well-trained rats demonstrated a deficit in the rotarod-running performance upon treatment with anisomycin. Similarly, PSI impaired the post-retrieval reconsolidation of the rotarod-running skill: well-trained rats treated with anisomycin 0 h but not 0.5, 2 and 4 h after the task performance exhibited amnesia for the running skill later on. Interestingly, rats treated with anisomycin 6 and 12 h post-retrieval exhibited amnesia for the running skill. Thus, protein synthesis is essential not only for the consolidation but also for the maintenance and post-retrieval reconsolidation of rotarod-running acrobatic motor skill.

Transcriptome analysis of bone marrow mesenchymal stromal cells from patients with primary myelofibrosis

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Christophe Martinaud

2015-09-01

Full Text Available Primary myelofibrosis (PMF is a clonal myeloproliferative neoplasm whose severity and treatment complexity are attributed to the presence of bone marrow (BM fibrosis and alterations of stroma impairing the production of normal blood cells. Despite the recently discovered mutations including the JAK2V617F mutation in about half of patients, the primitive event responsible for the clonal proliferation is still unknown. In the highly inflammatory context of PMF, the presence of fibrosis associated with a neoangiogenesis and an osteosclerosis concomitant to the myeloproliferation and to the increase number of circulating hematopoietic progenitors suggests that the crosstalk between hematopoietic and stromal cells is deregulated in the PMF BM microenvironmental niches. Within these niches, mesenchymal stromal cells (BM-MSC play a hematopoietic supportive role in the production of growth factors and extracellular matrix which regulate the proliferation, differentiation, adhesion and migration of hematopoietic stem/progenitor cells. A transcriptome analysis of BM-MSC in PMF patients will help to characterize their molecular alterations and to understand their involvement in the hematopoietic stem/progenitor cell deregulation that features PMF.

Bleeding, thrombosis, and anticoagulation in myeloproliferative neoplasms (MPN: analysis from the German SAL-MPN-registry

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A. Kaifie

2016-03-01

Full Text Available Abstract Background Patients with Ph-negative myeloproliferative neoplasms (MPN, such as polycythemia vera (PV, essential thrombocythemia (ET, and primary myelofibrosis (PMF, are at increased risk for thrombosis/thromboembolism and major bleeding. Due to the morbidity and mortality of these events, antiplatelet and/or anticoagulant agents are commonly employed as primary and/or secondary prophylaxis. On the other hand, disease-related bleeding complications (i.e., from esophageal varices are common in patients with MPN. This analysis was performed to define the frequency of such events, identify risk factors, and assess antiplatelet/anticoagulant therapy in a cohort of patients with MPN. Methods The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008. For statistical analysis, descriptive methods and tests for significant differences as well as contingency tables were used to identify the odds of potential risk factors for vascular events. Results MPN subgroups significantly differed in sex distribution, age at diagnosis, blood counts, LDH levels, JAK2V617F positivity, and spleen size (length. While most thromboembolic events occurred around the time of MPN diagnosis, one third of these events occurred after that date. Splanchnic vein thrombosis was most frequent in post-PV-MF and MPN-U patients. The chance of developing a thromboembolic event was significantly elevated if patients suffered from post-PV-MF (OR 3.43; 95 % CI = 1.39–8.48 and splenomegaly (OR 1.76; 95 % CI = 1.15–2.71. Significant odds for major bleeding were previous thromboembolic events (OR = 2.71; 95 % CI = 1.36–5.40, splenomegaly (OR = 2.22; 95 % CI 1.01–4.89, and the administration of heparin (OR = 5.64; 95 % CI = 1.84–17.34. Major bleeding episodes were significantly less frequent in ET patients compared to other MPN subgroups

Disease: H01612 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available 5 update on diagnosis, risk-stratification and management. ... JOURNAL ... Am J Hematol 90:162-73 (2015) DOI:10.... TITLE ... Pharmacological management of essential thrombocythemia. ... JOURNAL ... Expert Opin Pharmacother 14:

Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms

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Vladan P. Čokić

2015-01-01

Full Text Available The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34+ cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34+ cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.

The mutation profile of JAK2, MPL and CALR in Mexican patients with Philadelphia chromosome-negative myeloproliferative neoplasms.

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Labastida-Mercado, Nancy; Galindo-Becerra, Samantha; Garcés-Eisele, Javier; Colunga-Pedraza, Perla; Guzman-Olvera, Valeria; Reyes-Nuñez, Virginia; Ruiz-Delgado, Guillermo J; Ruiz-Argüelles, Guillermo J

2015-03-01

By using molecular markers, it is possible to gain information on both the classification and etiopathogenesis of chronic myeloproliferative neoplasias (MPN). In a group of 27 Mexican mestizo patients with MPNs, we studied seven molecular markers: the BCR/ABL1 fusion gene, the JAK2 V617F mutation, the JAK2 exon 12 mutations, the MPL W515L mutation, the MPL W515K mutation, and the calreticulin (CALR) exon 9 deletion or insertion. Patients with the BCR/ABL1 fusion gene were excluded. We studied 14 patients with essential thrombocythemia (ET), eight with polycythemia vera (PV), four with primary myelofibrosis (MF), and one with undifferentiated MPN. We found twelve individuals with the JAK2 V617F mutation; five of them had been clinically classified as PV, five as ET, and one as MF. One patient with the MPL W515L was identified with a clinical picture of ET. Five patients with the CALR mutation were identified, four ET and one MF. No individuals with either the MPL W515K mutation or the JAK2 exon 12 mutations were identified. The most consistent relationship was that between PV and the JAK2 V617F mutation (p=.01). Despite its small size, the study shows much less prevalence of JAK2 mutation in PV, ET and MF, which does not match international data. Copyright © 2015 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

High resolution melting analysis: a rapid and accurate method to detect CALR mutations.

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Cristina Bilbao-Sieyro

Full Text Available The recent discovery of CALR mutations in essential thrombocythemia (ET and primary myelofibrosis (PMF patients without JAK2/MPL mutations has emerged as a relevant finding for the molecular diagnosis of these myeloproliferative neoplasms (MPN. We tested the feasibility of high-resolution melting (HRM as a screening method for rapid detection of CALR mutations.CALR was studied in wild-type JAK2/MPL patients including 34 ET, 21 persistent thrombocytosis suggestive of MPN and 98 suspected secondary thrombocytosis. CALR mutation analysis was performed through HRM and Sanger sequencing. We compared clinical features of CALR-mutated versus 45 JAK2/MPL-mutated subjects in ET.Nineteen samples showed distinct HRM patterns from wild-type. Of them, 18 were mutations and one a polymorphism as confirmed by direct sequencing. CALR mutations were present in 44% of ET (15/34, 14% of persistent thrombocytosis suggestive of MPN (3/21 and none of the secondary thrombocytosis (0/98. Of the 18 mutants, 9 were 52 bp deletions, 8 were 5 bp insertions and other was a complex mutation with insertion/deletion. No mutations were found after sequencing analysis of 45 samples displaying wild-type HRM curves. HRM technique was reproducible, no false positive or negative were detected and the limit of detection was of 3%.This study establishes a sensitive, reliable and rapid HRM method to screen for the presence of CALR mutations.

Association of TNF polymorphisms with JAK2 (V617F) myeloproliferative neoplasms in Brazilian patients.

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Macedo, Luciana Conci; de Cesare Quintero, Fernanda; Pagliari-E-Silva, Sara; Pagnano, Katia Borgia Barbosa; Rodrigues, Camila; de Alencar, Josiane Bazzo; Sell, Ana Maria; Visentainer, Jeane Eliete Laguila

2016-03-01

The classical chromosome Philadelphia-negative myeloproliferative neoplasms (MPNs) are a group of disorders that share clinical, hematological, and histological features. Proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) are elevated in patients with MPN. The aim of this study was to verify the association between the polymorphisms of TNF gene (-308G/A and -238 G/A) in BCR-ABL-negative MPN in our population. Blood samples obtained from MPN patients were genotyped for the JAK2V617F mutation and both TNF polymorphisms using PCR-RFLP. Thirty three (26.8%) patients with polycythemia vera (PV), 35 (28.7%) essential thrombocythemia (ET), 22 (17.7%) primary myelofibrosis (PMF), and 33 (26.8%) with unclassifiable MPN (MPNu) were included in the study. The JAK2 V617F mutation was detected in 94 (76.42%) patients. Were observed a significant increase on the frequency of the TNF-238 GA genotype in MPN patients compared to controls (OR=2.21, 95% CI=1.02-4.80, P<0.04). The distribution of the genotypes and allelic frequencies of TNF-308 was significantly different among the MPNs, JAK2V617F positive, PV and PMF, and controls. Our data has demonstrated that the polymorphisms on TNF-238 GA, TNF-308 GA were associated to MPN development in this population, triggered by JAK2 V617F mutation. Copyright © 2015. Published by Elsevier Inc.

Frequency of heterozygous TET2 deletions in myeloproliferative neoplasms

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Joseph Tripodi

2010-09-01

Full Text Available Joseph Tripodi1, Ronald Hoffman1, Vesna Najfeld2, Rona Weinberg31The Myeloproliferative Disorders Program, Tisch Cancer Institute, Department of Medicine and 2Department of Medicine and Pathology, Mount Sinai School of Medicine, 3The Myeloproliferative Disorders Program, Cellular Therapy Laboratory, The New York Blood Center, New York, NY, USAAbstract: The Philadelphia chromosome (Ph-negative myeloproliferative neoplasms (MPNs, including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are a group of clonal hematopoietic stem cell disorders with overlapping clinical and cytogenetic features and a variable tendency to evolve into acute leukemia. These diseases not only share overlapping chromosomal abnormalities but also a number of acquired somatic mutations. Recently, mutations in a putative tumor suppressor gene, ten-eleven translocation 2 (TET2 on chromosome 4q24 have been identified in 12% of patients with MPN. Additionally 4q24 chromosomal rearrangements in MPN, including TET2 deletions, have also been observed using conventional cytogenetics. The goal of this study was to investigate the frequency of genomic TET2 rearrangements in MPN using fluorescence in situ hybridization as a more sensitive method for screening and identifying genomic deletions. Among 146 MPN patients, we identified two patients (1.4% who showed a common 4q24 deletion, including TET2. Our observations also indicated that the frequency of TET2 deletion is increased in patients with an abnormal karyotype (5%.Keywords: TET2, myeloproliferative neoplasms, fluorescence in situ hybridization, cytogenetics

Protein synthesis is essential not only for consolidation but also for maintenance and post-retrieval reconsolidation of acrobatic motor skill in rats

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Peng Ji-Yun

2009-05-01

Full Text Available Abstract It has been reported that consolidation of motor skill, a type of non-declarative memories, requires protein synthesis, as hippocampus-dependent declarative memory does. However, little is known about the importance of protein synthesis in maintenance and especially post-retrieval reconsolidation of acrobatic motor skill. Here, we show that protein synthesis is essential not only for the consolidation but also for the maintenance and reconsolidation of a rotarod-running skill. Intra-ventricle infusion of the protein synthesis inhibitor anisomycin 0 h but not 2 h post-training caused a severe deficit in the acquisition of the rotarod-running skill. Protein synthesis inhibition (PSI also caused a deficit in the maintenance of the rotarod-running skill, as well-trained rats demonstrated a deficit in the rotarod-running performance upon treatment with anisomycin. Similarly, PSI impaired the post-retrieval reconsolidation of the rotarod-running skill: well-trained rats treated with anisomycin 0 h but not 0.5, 2 and 4 h after the task performance exhibited amnesia for the running skill later on. Interestingly, rats treated with anisomycin 6 and 12 h post-retrieval exhibited amnesia for the running skill. Thus, protein synthesis is essential not only for the consolidation but also for the maintenance and post-retrieval reconsolidation of rotarod-running acrobatic motor skill.

Primary myelofibrosis with or without mutant MPL: comparison of survival and clinical features involving 603 patients.

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Pardanani, A; Guglielmelli, P; Lasho, T L; Pancrazzi, A; Finke, C M; Vannucchi, A M; Tefferi, A

2011-12-01

MPL and JAK2V617F mutation analysis was performed in 603 patients with primary myelofibrosis (PMF) seen at the Mayo Clinic, USA (n=329) or University of Florence, Italy (n=274). Mutant MPL was detected in 49 (8.1%) patients and JAK2V617F in 350 (58%); 4 patients showed both mutations. MPLW515L/K was the commonest mutation; 2 patients showed novel mutations (L513ins and Q516-P518insAAAA). The US and Italy patient cohorts were separately analyzed for comparison of survival and clinical features between MPL-mutated, JAK2-mutated and JAK2/MPL-unmutated cases. JAK2/MPL-unmutated patients were significantly younger than their JAK2-mutated counterparts, in both patient cohorts (PMPL was associated with older age (PMPL has narrow and inconsistent phenotypic effect in PMF and does not influence overall or leukemia-free survival.

A novel immunohistochemical sequential multi-labelling and erasing technique enables epitope characterization of bone marrow pericytes in primary myelofibrosis

DEFF Research Database (Denmark)

Madelung, Ann; Bzorek, Michael; Bondo, Henrik

2012-01-01

: In Philadelphia (Ph)-negative chronic myeloproliferative neoplasms, increased microvascular density, bizarre vessel architecture and increased number of pericytes are among the distinct histopathological features. The aim of this study was to characterize bone marrow pericytes in primary myelofibrosis (PMF) using...... a novel multi-labelling immunohistochemical technique. Methods and results: Bone marrow biopsies from a normal donor (n = 1) and patients with PMF (n = 3) were subjected to an immunohistochemical sequential multi-labelling and erasing technique (SE-technique). Antigens of interest in the first and....../or second layer were detected with an immunoperoxidase system and visualized with aminoethylcarbazole. After imaging, erasing and blocking of immunoreagents, the slides were stained with a traditional double immunolabelling procedure. In addition, we applied a Photoshop(®) colour palette, creating a single...

CD177: A member of the Ly-6 gene superfamily involved with neutrophil proliferation and polycythemia vera

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Bettinotti Maria

2004-03-01

Full Text Available Abstract Genes in the Leukocyte Antigen 6 (Ly-6 superfamily encode glycosyl-phosphatidylinositol (GPI anchored glycoproteins (gp with conserved domains of 70 to 100 amino acids and 8 to 10 cysteine residues. Murine Ly-6 genes encode important lymphocyte and hematopoietic stem cell antigens. Recently, a new member of the human Ly-6 gene superfamily has been described, CD177. CD177 is polymorphic and has at least two alleles, PRV-1 and NB1. CD177 was first described as PRV-1, a gene that is overexpressed in neutrophils from approximately 95% of patients with polycythemia vera and from about half of patients with essential thrombocythemia. CD177 encodes NB1 gp, a 58–64 kD GPI gp that is expressed by neutrophils and neutrophil precursors. NB1 gp carries Human Neutrophil Antigen (HNA-2a. Investigators working to identify the gene encoding NB1 gp called the CD177 allele they described NB1. NB1 gp is unusual in that neutrophils from some healthy people lack the NB1 gp completely and in most people NB1 gp is expressed by a subpopulation of neutrophils. The function of NB1 gp and the role of CD177 in the pathogenesis and clinical course of polycythemia vera and essential thrombocythemia are not yet known. However, measuring neutrophil CD177 mRNA levels has become an important marker for diagnosing the myeloproliferative disorders polycythemia vera and essential thrombocythemia.

Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study

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Frederiksen, Henrik; Farkas, Dóra Körmendiné; Christiansen, Christian Fynbo

2011-01-01

Patients with chronic myeloproliferative neoplasms, including essential thrombocythemia (ET), polycythemia vera (PV), and chronic myeloid leukemia (CML), are at increased risk of new hematologic malignancies, but their risk of nonhematologic malignancies remains unknown. In the present study, we...

JAK and MPL mutations in myeloid malignancies.

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Tefferi, Ayalew

2008-03-01

The Janus family of non-receptor tyrosine kinases (JAK1, JAK2, JAK3 and tyrosine kinase 2) transduces signals downstream of type I and II cytokine receptors via signal transducers and activators of transcription (STATs). JAK3 is important in lymphoid and JAK2 in myeloid cell proliferation and differentiation. The thrombopoietin receptor MPL is one of several JAK2 cognate receptors and is essential for myelopoiesis in general and megakaryopoiesis in particular. Germline loss-of-function (LOF) JAK3 and MPL mutations cause severe combined immunodeficiency and congenital amegakaryocytic thrombocytopenia, respectively. Germline gain-of-function (GOF) MPL mutation (MPLS505N) causes familial thrombocytosis. Somatic JAK3 (e.g. JAK3A572V, JAK3V722I, JAK3P132T) and fusion JAK2 (e.g. ETV6-JAK2, PCM1-JAK2, BCR-JAK2) mutations have respectively been described in acute megakaryocytic leukemia and acute leukemia/chronic myeloid malignancies. However, current attention is focused on JAK2 (e.g. JAK2V617F, JAK2 exon 12 mutations) and MPL (e.g. MPLW515L/K/S, MPLS505N) mutations associated with myeloproliferative neoplasms (MPNs). A JAK2 mutation, primarily JAK2V617F, is invariably associated with polycythemia vera (PV). The latter mutation also occurs in the majority of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). MPL mutational frequency in MPNs is substantially less (<10%). In general, despite a certain degree of genotype - phenotype correlations, the prognostic relevance of harbouring one of these mutations, or their allele burden when present, remains dubious. Regardless, based on the logical assumption that amplified JAK-STAT signalling is central to the pathogenesis of PV, ET and PMF, several anti-JAK2 tyrosine kinase inhibitors have been developed and are currently being tested in humans with these disorders.

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.

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Yana Pikman

2006-07-01

Full Text Available The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV, essential thrombocytosis (ET, and myelofibrosis with myeloid metaplasia (MF. Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR, the thrombopoietin receptor (MPL, or the granulocyte-colony stimulating factor receptor (GCSFR.DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L in 9% (4/45 of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12/L, marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis.Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD exhibits certain features of

MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.

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Pikman, Yana; Lee, Benjamin H; Mercher, Thomas; McDowell, Elizabeth; Ebert, Benjamin L; Gozo, Maricel; Cuker, Adam; Wernig, Gerlinde; Moore, Sandra; Galinsky, Ilene; DeAngelo, Daniel J; Clark, Jennifer J; Lee, Stephanie J; Golub, Todd R; Wadleigh, Martha; Gilliland, D Gary; Levine, Ross L

2006-07-01

The JAK2V617F allele has recently been identified in patients with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis with myeloid metaplasia (MF). Subsequent analysis has shown that constitutive activation of the JAK-STAT signal transduction pathway is an important pathogenetic event in these patients, and that enzymatic inhibition of JAK2V617F may be of therapeutic benefit in this context. However, a significant proportion of patients with ET or MF are JAK2V617F-negative. We hypothesized that activation of the JAK-STAT pathway might also occur as a consequence of activating mutations in certain hematopoietic-specific cytokine receptors, including the erythropoietin receptor (EPOR), the thrombopoietin receptor (MPL), or the granulocyte-colony stimulating factor receptor (GCSFR). DNA sequence analysis of the exons encoding the transmembrane and juxtamembrane domains of EPOR, MPL, and GCSFR, and comparison with germline DNA derived from buccal swabs, identified a somatic activating mutation in the transmembrane domain of MPL (W515L) in 9% (4/45) of JAKV617F-negative MF. Expression of MPLW515L in 32D, UT7, or Ba/F3 cells conferred cytokine-independent growth and thrombopoietin hypersensitivity, and resulted in constitutive phosphorylation of JAK2, STAT3, STAT5, AKT, and ERK. Furthermore, a small molecule JAK kinase inhibitor inhibited MPLW515L-mediated proliferation and JAK-STAT signaling in vitro. In a murine bone marrow transplant assay, expression of MPLW515L, but not wild-type MPL, resulted in a fully penetrant myeloproliferative disorder characterized by marked thrombocytosis (Plt count 1.9-4.0 x 10(12)/L), marked splenomegaly due to extramedullary hematopoiesis, and increased reticulin fibrosis. Activation of JAK-STAT signaling via MPLW515L is an important pathogenetic event in patients with JAK2V617F-negative MF. The bone marrow transplant model of MPLW515L-mediated myeloproliferative disorders (MPD) exhibits certain features of human MF

The effects of hematopoietic stem cell transplant on splenic extramedullary hematopoiesis in patients with myeloproliferative neoplasm-associated myelofibrosis.

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Pizzi, Marco; Gergis, Usama; Chaviano, Felicia; Orazi, Attilio

2016-09-01

Hematopoietic stem cell transplant (HSCT) is the only curative treatment for myeloproliferative neoplasm-associated myelofibrosis (MPN-MF). The main clinical manifestation of MPN-MF is splenomegaly secondary to extramedullary hematopoiesis (EMH). The effects of HSCT on splenic EMH and associated vascular and stromal changes are unknown. This study compares the findings seen in spleens following HSCT with those of nontransplanted patients, normal controls, and matched bone marrow (BM) samples. This study included three transplanted MPN-MF spleens, three nontransplanted MPN-MF spleens, and three normal controls. Spleens were assessed for: (a) presence/extent of EMH; (b) presence of Gamna-Gandy bodies; (c) splenic fibrosis; (d) CD34-positive microvessel density; (e) CD8-positive sinusoids; (f) frequency of smooth muscle actin-positive myoid cells; and (g) nerve growth factor receptor-positive adventitial reticulum cells. In two cases, matched BM samples were assessed for cellularity, presence of atypical megakaryocytes, and fibrosis. Compared with normal controls, all MPN-MF spleens were larger in size, had EMH, red pulp fibrosis, higher CD34-positive microvessel density, and decreased CD8-positive sinusoids. Compared with nontransplanted cases, post-HSCT spleens showed disappearance or reduction of EMH. Gamna-Gandy bodies were increased; no differences in the remaining parameters were found. A reduction of splenic EMH was associated with normalization of BM cellularity and megakaryopoiesis. HSCT reduces/abrogates splenic EMH and is associated with an increased number of Gamna-Gandy bodies, which may suggest vascular damage. The lack of stromal changes in spleens removed shortly after transplant is in line with similar observations in the BM, where a longer interval is often necessary for resolution of fibrosis. Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

In Vitro Control of Post-Harvest Fruit Rot Fungi by Some Plant Essential Oil Components

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Gian Luigi Rana

2012-02-01

Full Text Available Eight substances that are main components of the essential oils from three Mediterranean aromatic plants (Verbena officinalis, Thymus vulgaris and Origanum vulgare, previously found active against some phytopathogenic Fungi and Stramenopila, have been tested in vitro against five etiological agents of post-harvest fruit decay, Botrytis cinerea, Penicillium italicum, P. expansum, Phytophthora citrophthora and Rhizopus stolonifer. The tested compounds were β-fellandrene, β-pinene, camphene, carvacrol, citral, o-cymene, γ-terpinene and thymol. Citral exhibited a fungicidal action against P. citrophthora; carvacrol and thymol showed a fungistatic activity against P. citrophthora and R. stolonifer. Citral and carvacrol at 250 ppm, and thymol at 150 and 250 ppm stopped the growth of B. cinerea. Moreover, thymol showed fungistatic and fungicidal action against P. italicum. Finally, the mycelium growth of P. expansum was inhibited in the presence of 250 ppm of thymol and carvacrol. These results represent an important step toward the goal to use some essential oils or their components as natural preservatives for fruits and foodstuffs, due to their safety for consumer healthy and positive effect on shelf life extension of agricultural fresh products.

High absolute basophil count is a powerful independent predictor of inferior overall survival in patients with primary myelofibrosis.

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Lucijanic, Marko; Livun, Ana; Stoos-Veic, Tajana; Pejsa, Vlatko; Jaksic, Ozren; Cicic, David; Lucijanic, Jelena; Romic, Zeljko; Orehovec, Biserka; Aralica, Gorana; Miletic, Marko; Kusec, Rajko

2018-05-01

To investigate the clinical and prognostic significance of absolute basophil count (ABC) in patients with primary myelofibrosis (PMF). We retrospectively investigated 58 patients with PMF treated in our institution in the period from 2006 to 2017. ABC was obtained in addition to other hematological and clinical parameters. Patients were separated into high and low ABC groups using the Receiver operating characteristic curve analysis. ABC was higher in PMF patients than in healthy controls (P constitutional symptoms (P = 0.030) and massive splenomegaly (P = 0.014). ABC was also positively correlated with absolute monocyte count (AMC) (P processes. Hence, both have a potential for improvement of current prognostic scores. Basophils represent a part of malignant clone in PMF and are associated with unfavorable disease features and poor prognosis which is independent of currently established prognostic scoring system and monocytosis.

Calreticulin Mutations in Myeloproliferative Neoplasms

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Noa Lavi

2014-10-01

Full Text Available With the discovery of the JAK2V617F mutation in patients with Philadelphia chromosome-negative (Ph− myeloproliferative neoplasms (MPNs in 2005, major advances have been made in the diagnosis of MPNs, in understanding of their pathogenesis involving the JAK/STAT pathway, and finally in the development of novel therapies targeting this pathway. Nevertheless, it remains unknown which mutations exist in approximately one-third of patients with non-mutated JAK2 or MPL essential thrombocythemia (ET and primary myelofibrosis (PMF. At the end of 2013, two studies identified recurrent mutations in the gene encoding calreticulin (CALR using whole-exome sequencing. These mutations were revealed in the majority of ET and PMF patients with non-mutated JAK2 or MPL but not in polycythemia vera patients. Somatic 52-bp deletions (type 1 mutations and recurrent 5-bp insertions (type 2 mutations in exon 9 of the CALR gene (the last exon encoding the C-terminal amino acids of the protein calreticulin were detected and found always to generate frameshift mutations. All detected mutant calreticulin proteins shared a novel amino acid sequence at the C-terminal. Mutations in CALR are acquired early in the clonal history of the disease, and they cause activation of JAK/STAT signaling. The CALR mutations are the second most frequent mutations in Ph− MPN patients after the JAK2V617F mutation, and their detection has significantly improved the diagnostic approach for ET and PMF. The characteristics of the CALR mutations as well as their diagnostic, clinical, and pathogenesis implications are discussed in this review.

Frequencies, Laboratory Features, and Granulocyte Activation in Chinese Patients with CALR-Mutated Myeloproliferative Neoplasms.

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Haixiu Guo

Full Text Available Somatic mutations in the CALR gene have been recently identified as acquired alterations in myeloproliferative neoplasms (MPNs. In this study, we evaluated mutation frequencies, laboratory features, and granulocyte activation in Chinese patients with MPNs. A combination of qualitative allele-specific polymerase chain reaction and Sanger sequencing was used to detect three driver mutations (i.e., CALR, JAK2V617F, and MPL. CALR mutations were identified in 8.4% of cases with essential thrombocythemia (ET and 5.3% of cases with primary myelofibrosis (PMF. Moreover, 25% of polycythemia vera, 29.5% of ET, and 48.1% of PMF were negative for all three mutations (JAK2V617F, MPL, and CALR. Compared with those patients with JAK2V617F mutation, CALR-mutated ET patients displayed unique hematological phenotypes, including higher platelet counts, and lower leukocyte counts and hemoglobin levels. Significant differences were not found between Chinese PMF patients with mutants CALR and JAK2V617F in terms of laboratory features. Interestingly, patients with CALR mutations showed markedly decreased levels of leukocyte alkaline phosphatase (LAP expression, whereas those with JAK2V617F mutation presented with elevated levels. Overall, a lower mutant rate of CALR gene and a higher triple-negative rate were identified in the cohort of Chinese patients with MPNs. This result indicates that an undiscovered mutant gene may have a significant role in these patients. Moreover, these pathological features further imply that the disease biology varies considerably between mutants CALR and JAK2V617F.

JAK2 46/1 haplotype is associated with JAK2 V617F--positive myeloproliferative neoplasms in Brazilian patients.

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Macedo, L C; Santos, B C; Pagliarini-e-Silva, S; Pagnano, K B B; Rodrigues, C; Quintero, F C; Ferreira, M E; Baraldi, E C; Ambrosio-Albuquerque, E P; Sell, A M; Visentainer, J E L

2015-10-01

This study aimed to verify the association between the JAK2 46/1 haplotype (V617F positive) and some hematological parameters in BCR-ABL-negative chronic myeloproliferative neoplasms (cMPNs) in our population. The blood samples obtained from the patients with cMPN were genotyped for the JAK2 V617F mutation and JAK2 rs10974944 SNP screening using a PCR-RFLP assay. The JAK2 V617F mutation was detected in 80.15% of patients. The G variant of rs10974944 was more frequent in all MPNs, especially those that were JAK2 V617F positive, than in the control population. We also compared the 46/1 haplotype status in each MPN disease entity, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and MPNu with controls. The G allele frequency relative to controls was significantly enriched in patients with PV and ET, but not in those with PMF and MPNu. PV and ET patients especially, all of whom had the JAK2 V617F mutation, showed significant excess of the G allele. The frequency of JAK2 V617F mutation was associated with elevated hematological parameters, but when we analyze the occurrence of the mutation and the presence of the G allele, just the high hemoglobin was significantly. In agreement with previous reports, JAK2 46/1 haplotype for JAK2 V617F was associated with cMPN positive in Brazilian patients. © 2015 John Wiley & Sons Ltd.

Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet.

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Barbui, Tiziano; Barosi, Giovanni; Birgegard, Gunnar; Cervantes, Francisco; Finazzi, Guido; Griesshammer, Martin; Harrison, Claire; Hasselbalch, Hans Carl; Hehlmann, Rudiger; Hoffman, Ronald; Kiladjian, Jean-Jacques; Kröger, Nicolaus; Mesa, Ruben; McMullin, Mary F; Pardanani, Animesh; Passamonti, Francesco; Vannucchi, Alessandro M; Reiter, Andreas; Silver, Richard T; Verstovsek, Srdan; Tefferi, Ayalew

2011-02-20

We present a review of critical concepts and produce recommendations on the management of Philadelphia-negative classical myeloproliferative neoplasms, including monitoring, response definition, first- and second-line therapy, and therapy for special issues. Key questions were selected according the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk if age is greater than 60 years or there is a history of previous thrombosis. Risk stratification in primary myelofibrosis (PMF) should start with the International Prognostic Scoring System (IPSS) for newly diagnosed patients and dynamic IPSS for patients being seen during their disease course, with the addition of cytogenetics evaluation and transfusion status. High-risk patients with PV should be managed with phlebotomy, low-dose aspirin, and cytoreduction, with either hydroxyurea or interferon at any age. High-risk patients with ET should be managed with cytoreduction, using hydroxyurea at any age. Monitoring response in PV and ET should use the ELN clinicohematologic criteria. Corticosteroids, androgens, erythropoiesis-stimulating agents, and immunomodulators are recommended to treat anemia of PMF, whereas hydroxyurea is the first-line treatment of PMF-associated splenomegaly. Indications for splenectomy include symptomatic portal hypertension, drug-refractory painful splenomegaly, and frequent RBC transfusions. The risk of allogeneic stem-cell transplantation-related complications is justified in transplantation-eligible patients whose median survival time is expected to be less than 5 years.

Detection of CALR and MPL Mutations in Low Allelic Burden JAK2 V617F Essential Thrombocythemia.

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Usseglio, Fabrice; Beaufils, Nathalie; Calleja, Anne; Raynaud, Sophie; Gabert, Jean

2017-01-01

Myeloproliferative neoplasms are clonal hematopoietic stem cell disorders characterized by aberrant proliferation and an increased tendency toward leukemic transformation. The genes JAK2, MPL, and CALR are frequently altered in these syndromes, and their mutations are often a strong argument for diagnosis. We analyzed the mutational profiles of these three genes in a cohort of 164 suspected myeloproliferative neoplasms. JAK2 V617F mutation was detected by real-time PCR, whereas high-resolution melting analysis followed by Sanger sequencing were used for searching for mutations in JAK2 exon 12, CALR, and MPL. JAK2 V617F mutation was associated with CALR (n = 4) and MPL (n = 4) mutations in 8 of 103 essential thrombocytosis patients. These cases were harboring a JAK2 V617F allelic burden of MPL genes in myeloproliferative neoplasms and suggest that CALR and MPL should be analyzed not only in JAK2-negative patients but also in low V617F mutation patients. Follow-up of these double-mutation cases will be important for determining whether this group of patients presents particular evolution or complications. Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Philadelphia-negative classical myeloproliferative neoplasms

DEFF Research Database (Denmark)

Barbui, T.; Barosi, G.; Birgegard, G.

2011-01-01

the criterion of clinical relevance. Statements were produced using a Delphi process, and two consensus conferences involving a panel of 21 experts appointed by the European LeukemiaNet (ELN) were convened. Patients with polycythemia vera (PV) and essential thrombocythemia (ET) should be defined as high risk...

A new era for IFN-α in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms

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Hasselbalch, H.C.

2011-01-01

In recent years, several studies have shown that IFN-α2 is able to induce molecular remissions with undetectable JAK2V617F in a subset of patients with essential thrombocythemia (ET) and polycythemia vera (PV), even with normalization of the bone marrow and sustained molecular remissions after...

Minimal residual disease after long-term interferon-alpha2 treatment

DEFF Research Database (Denmark)

Utke Rank, Cecilie; Weis Bjerrum, Ole; Larsen, Thomas Stauffer

2016-01-01

Essential thrombocythemia (ET) and polycythemia vera (PV) are Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) characterized by the JAK2 V617F mutation, which can be found in more than 98% of PV patients and in ∼ 50% of ET patients. Assessment of the JAK2 V617F allele...

The role of growth differentiation factor 15 in the pathogenesis of primary myelofibrosis

International Nuclear Information System (INIS)

Uchiyama, Tatsuki; Kawabata, Hiroshi; Miura, Yasuo; Yoshioka, Satoshi; Iwasa, Masaki; Yao, Hisayuki; Sakamoto, Soichiro; Fujimoto, Masakazu; Haga, Hironori; Kadowaki, Norimitsu; Maekawa, Taira; Takaori-Kondo, Akifumi

2015-01-01

Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine that belongs to the transforming growth factor-β superfamily. Elevated serum concentrations of this cytokine have been reported in patients with various malignancies. To assess the potential roles of GDF15 in hematologic malignancies, we measured its serum levels in patients with these diseases. We found that serum GDF15 levels were elevated in almost all these patients, particularly in patients with primary myelofibrosis (PMF). Immunohistochemical staining of bone marrow (BM) specimens revealed that GDF15 was strongly expressed by megakaryocytes, which may be sources of increased serum GDF15 in PMF patients. Therefore, we further assessed the contribution of GDF15 to the pathogenesis of PMF. Recombinant human (rh) GDF15 enhanced the growth of human BM mesenchymal stromal cells (BM-MSCs), and it enhanced the potential of these cells to support human hematopoietic progenitor cell growth in a co-culture system. rhGDF15 enhanced the growth of human primary fibroblasts, but it did not affect their expression of profibrotic genes. rhGDF15 induced osteoblastic differentiation of BM-MSCs in vitro, and pretreatment of BM-MSCs with rGDF15 enhanced the induction of bone formation in a xenograft mouse model. These results suggest that serum levels of GDF15 in PMF are elevated, that megakaryocytes are sources of this cytokine in BM, and that GDF15 may modulate the pathogenesis of PMF by enhancing proliferation and promoting osteogenic differentiation of BM-MSCs

Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms

International Nuclear Information System (INIS)

Rice, K L; Lin, X; Wolniak, K; Ebert, B L; Berkofsky-Fessler, W; Buzzai, M; Sun, Y; Xi, C; Elkin, P; Levine, R; Golub, T; Gilliland, D G; Crispino, J D; Licht, J D; Zhang, W

2011-01-01

Polycythemia vera (PV), essential thrombocythemia and primary myelofibrosis, are myeloproliferative neoplasms (MPNs) with distinct clinical features and are associated with the JAK2V617F mutation. To identify genomic anomalies involved in the pathogenesis of these disorders, we profiled 87 MPN patients using Affymetrix 250K single-nucleotide polymorphism (SNP) arrays. Aberrations affecting chr9 were the most frequently observed and included 9pLOH (n=16), trisomy 9 (n=6) and amplifications of 9p13.3–23.3 (n=1), 9q33.1–34.13 (n=1) and 9q34.13 (n=6). Patients with trisomy 9 were associated with elevated JAK2V617F mutant allele burden, suggesting that gain of chr9 represents an alternative mechanism for increasing JAK2V617F dosage. Gene expression profiling of patients with and without chr9 abnormalities (+9, 9pLOH), identified genes potentially involved in disease pathogenesis including JAK2, STAT5B and MAPK14. We also observed recurrent gains of 1p36.31–36.33 (n=6), 17q21.2–q21.31 (n=5) and 17q25.1–25.3 (n=5) and deletions affecting 18p11.31–11.32 (n=8). Combined SNP and gene expression analysis identified aberrations affecting components of a non-canonical PRC2 complex (EZH1, SUZ12 and JARID2) and genes comprising a ‘HSC signature' (MLLT3, SMARCA2 and PBX1). We show that NFIB, which is amplified in 7/87 MPN patients and upregulated in PV CD34+ cells, protects cells from apoptosis induced by cytokine withdrawal

Safety and efficacy of ruxolitinib in splanchnic vein thrombosis associated with myeloproliferative neoplasms.

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Pieri, Lisa; Paoli, Chiara; Arena, Umberto; Marra, Fabio; Mori, Fabio; Zucchini, Mery; Colagrande, Stefano; Castellani, Alessandro; Masciulli, Arianna; Rosti, Vittorio; De Stefano, Valerio; Betti, Silvia; Finazzi, Guido; Ferrari, Maria Luisa; Rumi, Elisa; Ruggeri, Marco; Nichele, Ilaria; Guglielmelli, Paola; Fjerza, Rajmonda; Mannarelli, Carmela; Fanelli, Tiziana; Merli, Lucia; Corbizi Fattori, Giuditta; Massa, Margherita; Cimino, Giuseppe; Rambaldi, Alessandro; Barosi, Giovanni; Cazzola, Mario; Barbui, Tiziano; Vannucchi, Alessandro M

2017-02-01

Splanchnic vein thrombosis (SVT) is one of the vascular complications of myeloproliferative neoplasms (MPN). We designed a phase 2 clinical trial to evaluate safety and efficacy of ruxolitinib in reducing splenomegaly and improving disease-related symptoms in patients with MPN-associated SVT. Patients diagnosed with myelofibrosis (12 cases), polycythemia vera (5 cases) and essential thrombocythemia (4 cases) received ruxolitinib for 24 weeks in the core study period. Spleen volume was assessed by magnetic resonance imaging (MRI) and splanchnic vein circulation by echo-Doppler analysis. Nineteen patients carried JAK2V617F, one had MPLW515L, and one CALRL367fs*46 mutation. Eighteen patients had spleno-portal-mesenteric thrombosis, two had Budd-Chiari syndrome, and one had both sites involved; 16 patients had esophageal varices. Ruxolitinib was well tolerated with hematological toxicities consistent with those of patients without SVT and no hemorrhagic adverse events were recorded. After 24 weeks of treatment, spleen volume reduction ≥35% by MRI was achieved by 6/21 (29%) patients, and a ≥50% spleen length reduction by palpation at any time up to week 24 was obtained by 13/21 (62%) patients. At week 72, 8 of the 13 (62%) patients maintained the spleen response by palpation. No significant effect of treatment on esophageal varices or in splanchnic circulation was observed. MPN-related symptoms, evaluated by MPN-symptom assessment form (SAF) TSS questionnaire, improved significantly during the first 4 weeks and remained stable up to week 24. In conclusion, this trial shows that ruxolitinib is safe in patients with MPN-associated SVT, and effective in reducing spleen size and disease-related symptoms. © 2016 Wiley Periodicals, Inc.

Development of a Targeted Next-Generation Sequencing Assay to Detect Diagnostically Relevant Mutations of JAK2, CALR, and MPL in Myeloproliferative Neoplasms.

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Frawley, Thomas; O'Brien, Cathal P; Conneally, Eibhlin; Vandenberghe, Elisabeth; Percy, Melanie; Langabeer, Stephen E; Haslam, Karl

2018-02-01

The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), consisting of polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are a heterogeneous group of neoplasms that harbor driver mutations in the JAK2, CALR, and MPL genes. The detection of mutations in these genes has been incorporated into the recent World Health Organization (WHO) diagnostic criteria for MPN. Given a pressing clinical need to screen for mutations in these genes in a routine diagnostic setting, a targeted next-generation sequencing (NGS) assay for the detection of MPN-associated mutations located in JAK2 exon 14, JAK2 exon 12, CALR exon 9, and MPL exon 10 was developed to provide a single platform alternative to reflexive, stepwise diagnostic algorithms. Polymerase chain reaction (PCR) primers were designed to target mutation hotspots in JAK2 exon 14, JAK2 exon 12, MPL exon 10, and CALR exon 9. Multiplexed PCR conditions were optimized by using qualitative PCR followed by NGS. Diagnostic genomic DNA from 35 MPN patients, known to harbor driver mutations in one of the target genes, was used to validate the assay. One hundred percent concordance was observed between the previously-identified mutations and those detected by NGS, with no false positives, nor any known mutations missed (specificity = 100%, CI = 0.96, sensitivity = 100%, CI = 0.89). Improved resolution of mutation sequences was also revealed by NGS analysis. Detection of diagnostically relevant driver mutations of MPN is enhanced by employing a targeted multiplex NGS approach. This assay presents a robust solution to classical MPN mutation screening, providing an alternative to time-consuming sequential analyses.

Patient characteristics and outcomes in adolescents and young adults with classical Philadelphia chromosome-negative myeloproliferative neoplasms.

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Boddu, Prajwal; Masarova, Lucia; Verstovsek, Srdan; Strati, Paolo; Kantarjian, Hagop; Cortes, Jorge; Estrov, Zeev; Pierce, Sherry; Pemmaraju, Naveen

2018-01-01

Little is known about the outcomes of Philadelphia-negative myeloproliferative neoplasms (MPNs) in adolescents and young adults (AYA). We reviewed all patients with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) treated at our institution from 1988 to 2016 who were aged 16 to 39 years (AYA) and described their outcomes in comparison to older MPN population. Of 2206 patients, 185 (8.3%) were identified as AYA: 105 (57%) ET, 43 (23%) PV, and 37 (20%) MF. The median age was 33 years [range, 16-39], and median follow-up time 3 years [range, 0.04-25]. JAK2 allele burdens were significantly lower among AYA JAK2V617F-mutated patients in both PV (p = 0.001) and MF (p = 0.005). Seven percent of MPN AYA patients were diagnosed with a thrombotic event at, or prior to, diagnosis. Over the short median follow-up, 4 thrombotic (PV = 1, MF = 3) and 3 leukemia (ET = 2, MF = 1) events occurred. In multivariate analysis, AYA did not predict for thrombotic or transformational events across three cohorts. In the MF cohort, there was a reduced frequency of negative prognostic variables of anemia (p = 0.011) and leukocytosis (p = 0.048) in AYA when compared with non-AYA. Overall survival was significantly superior in the AYA cohorts in all three MPN groups, namely MF (p < 0.001), PV (p < 0.001), and ET (p = 0.002). Our findings suggest that MPN AYA patients exhibit an indolent clinical phenotype characterized by favorable survival outcomes.

Protein kinase Cɛ inhibition restores megakaryocytic differentiation of hematopoietic progenitors from primary myelofibrosis patients.

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Masselli, E; Carubbi, C; Gobbi, G; Mirandola, P; Galli, D; Martini, S; Bonomini, S; Crugnola, M; Craviotto, L; Aversa, F; Vitale, M

2015-11-01

Among the three classic Philadelphia chromosome-negative myeloproliferative neoplasms, primary myelofibrosis (PMF) is the most severe in terms of disease biology, survival and quality of life. Abnormalities in the process of differentiation of PMF megakaryocytes (MKs) are a hallmark of the disease. Nevertheless, the molecular events that lead to aberrant megakaryocytopoiesis have yet to be clarified. Protein kinase Cɛ (PKCɛ) is a novel serine/threonine kinase that is overexpressed in a variety of cancers, promoting aggressive phenotype, invasiveness and drug resistance. Our previous findings on the role of PKCɛ in normal (erythroid and megakaryocytic commitment) and malignant (acute myeloid leukemia) hematopoiesis prompted us to investigate whether it could be involved in the pathogenesis of PMF MK-impaired differentiation. We demonstrate that PMF megakaryocytic cultures express higher levels of PKCɛ than healthy donors, which correlate with higher disease burden but not with JAK2V617F mutation. Inhibition of PKCɛ function (by a negative regulator of PKCɛ translocation) or translation (by target small hairpin RNA) leads to reduction in PMF cell growth, restoration of PMF MK differentiation and inhibition of PKCɛ-related anti-apoptotic signaling (Bcl-xL). Our data suggest that targeting PKCɛ directly affects the PMF neoplastic clone and represent a proof-of-concept for PKCɛ inhibition as a novel therapeutic strategy in PMF.

Physiopathology, Etiologic Factors, Diagnosis, and Course of Polycythemia Vera as Related to Therapy According to William Dameshek, 1940-1950

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Jan Jacques Michiels

2013-06-01

Full Text Available According to Dameshek, true polycythemia (polycythemia vera: PV is a chronic myeloproliferative disorder of the total bone marrow without any evidence of invasiveness, in which erythrocytosis, leukocytosis, and thrombocytosis are all simultaneously present. A possible hereditary or transmitted tendency may be present, but actual familial polycythemia is rare. As to the etiology, Dameshek proposed 2 highly speculative possibilities in 1950: the presence of excessive bone marrow stimulation by an unknown factor or factors, and a lack or a diminution in the normal inhibitory factor or factors. Dameshek’s hypothesis was confirmed in 2005 by Vainchenker in France by the discovery of the acquired JAK2V617F mutation as the cause of 3 phenotypes of classical myeloproliferative neoplasms: essential thrombocythemia, PV, and myelofibrosis. The JAK2V617F mutation induces a loss of inhibitory activity of the JH2 pseudokinase part on the JH1 kinase part of Janus kinase 2 (JAK2. This leads to enhanced activity of the normal JH1 kinase activity of JAK2, which makes the mutated hematopoietic stem cells hypersensitive to the hematopoietic growth factors thrombopoietin, erythropoietin, insulin-like growth factor-1, stem cell factor, and granulocyte colony-stimulating factor, resulting in trilinear myeloproliferation. In retrospect, the situation observed by Dameshek where all “stops” to blood production in the bone marrow are pulled in PV is caused by the JAK2V617F mutation. Dameshek considered PV patients as fundamentally normal and therefore the treatment should be as physiologic as possible. For this reason, a systematic phlebotomy/iron deficiency method of treatment was recommended; the use of radioactive phosphorus is reserved for refractory cases and cases of major thrombosis. If the patient lives long enough and does not succumb to the effects of thrombosis or other complications, the marrow will gradually show signs of diminished activity. The blood

Concomitant BCR-ABL1 positive chronic myelogenous leukemia emerging in a patient with MPL W515L associated primary myelofibrosis

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Juan C. Gomez-Gelvez, MD

2016-03-01

Full Text Available Myeloproliferative neoplasms (MPNs are clonal hematopoietic stem cell disorders characterized by proliferation of one or more cell lineages in the bone marrow. At present, the main criterion in the 2008 World Health Organization classification of MPNs is the presence of an underlying genetic abnormality. These mutations are generally mutually exclusive except for rare reports in the literature. We report for the first time a detailed analysis of the clinical, histologic and cytogenetic/molecular features of a patient who initially presented with MPL W515L positive primary myelofibrosis and over the course of five years developed an MPN associated with both BCR-ABL1 and MPL W515L mutation. We discuss the diagnostic challenges and therapeutic implications of concomitant BCR-ABL1 translocation with MPL W515L mutation. Multiple genetic alterations may simultaneously coexist in patients exhibiting features of myeloproliferative disorders.

Endogenous retrovirus induces leukemia in a xenograft mouse model for primary myelofibrosis.

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Triviai, Ioanna; Ziegler, Marion; Bergholz, Ulla; Oler, Andrew J; Stübig, Thomas; Prassolov, Vladimir; Fehse, Boris; Kozak, Christine A; Kröger, Nicolaus; Stocking, Carol

2014-06-10

The compound immunodeficiencies in nonobese diabetic (NOD) inbred mice homozygous for the Prkdc(scid) and Il2rg(null) alleles (NSG mice) permit engraftment of a wide-range of primary human cells, enabling sophisticated modeling of human disease. In studies designed to define neoplastic stem cells of primary myelofibrosis (PMF), a myeloproliferative neoplasm characterized by profound disruption of the hematopoietic microenvironment, we observed a high frequency of acute myeloid leukemia (AML) in NSG mice. AML was of mouse origin, confined to PMF-xenografted mice, and contained multiple clonal integrations of ecotropic murine leukemia virus (E-MuLV). Significantly, MuLV replication was not only observed in diseased mice, but also in nontreated NSG controls. Furthermore, in addition to the single ecotropic endogenous retrovirus (eERV) located on chromosome 11 (Emv30) in the NOD genome, multiple de novo germ-line eERV integrations were observed in mice from each of four independent NSG mouse colonies. Analysis confirmed that E-MuLV originated from the Emv30 provirus and that recombination events were not necessary for virus replication or AML induction. Pathogenicity is thus likely attributable to PMF-mediated paracrine stimulation of mouse myeloid cells, which serve as targets for retroviral infection and transformation, as evidenced by integration into the Evi1 locus, a hotspot for retroviral-induced myeloid leukemia. This study thus corroborates a role of paracrine stimulation in PMF disease progression, underlines the importance of target cell type and numbers in MuLV-induced disease, and mandates awareness of replicating MuLV in NOD immunodeficient mice, which can significantly influence experimental results and their interpretation.

Concurrent MPL515 and JAK2V617F mutations in myelofibrosis: chronology of clonal emergence and changes in mutant allele burden over time.

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Lasho, Terra L; Pardanani, Animesh; McClure, Rebecca F; Mesa, Ruben A; Levine, Ross L; Gilliland, D Gary; Tefferi, Ayalew

2006-12-01

MPLW515L/K and JAK2V617F can co-exist in myelofibrosis with myeloid metaplasia (MMM). The chronology of clonal emergence was studied in three such cases using serially stored bone marrow. At diagnosis, a major MPL515 mutant clone was accompanied by a minor JAK2V617F clone in all three instances. At 25 time points over a period of 4-8 years, allele burden fluctuated but remained high for MPLW515L/K and low for JAK2V617F. We conclude that MPLW515L/K and JAK2V617F are both early events in MMM and allele burden, rather than the mere presence of these mutations, might be relevant to phenotypic variation in myeloproliferative disorders.

Polycythemia and Thrombocytosis.

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Parnes, Aric; Ravi, Arvind

2016-12-01

Myeloproliferative neoplasms (MPNs) are diseases of excess cell proliferation from bone marrow precursors. Two classic MPNs, polycythemia vera (PV) and essential thrombocytosis (ET), are conditions of excess proliferation of red blood cells and platelets, respectively. Although PV and ET involve different cells in the myeloid lineage, their clinical presentations have shared features, consistent with overlapping mutations in growth factor signaling. The management of both diseases involves minimizing the risk of thrombotic and hemorrhagic complications. Both PV and ET can progress to myelofibrosis or acute myeloid leukemia, portending a poor prognosis. MPNs can also present as primary myelofibrosis. Copyright © 2016 Elsevier Inc. All rights reserved.

Myeloproliferative neoplasms: JAK2 signaling pathway as a central target for therapy.

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Pasquier, Florence; Cabagnols, Xenia; Secardin, Lise; Plo, Isabelle; Vainchenker, William

2014-09-01

The discovery of the JAK2V617F mutation followed by the discovery of other genetic abnormalities allowed important progress in the understanding of the pathogenesis and management of myeloproliferative neoplasms (MPN)s. Classical Breakpoint cluster region-Abelson (BCR-ABL)-negative neoplasms include 3 main disorders: essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Genomic studies have shown that these disorders are more heterogeneous than previously thought with 3 main entities corresponding to different gene mutations: the JAK2 disorder, essentially due to JAK2V617F mutation, which includes nearly all PVs and a majority of ETs and PMFs with a continuum between these diseases and the myeloproliferative leukemia (MPL) and calreticulin (CALR) disorders, which include a fraction of ET and PMF. All of these mutations lead to a JAK2 constitutive activation. Murine models either with JAK2V617F or MPLW515L, but also with JAK2 or MPL germ line mutations found in hereditary thrombocytosis, have demonstrated that they are drivers of myeloproliferation. However, the myeloproliferative driver mutation is still unknown in approximately 15% of ET and PMF, but appears to also target the JAK/Signal Transducer and Activator of Transcription (STAT) pathway. However, other mutations in genes involved in epigenetics or splicing also can be present and can predate or follow mutations in signaling. They are involved either in clonal dominance or in phenotypic changes, more particularly in PMF. They can be associated with leukemic progression and might have an important prognostic value such as additional sex comb-like 1 mutations. Despite this heterogeneity, it is tempting to target JAK2 and its signaling for therapy. However in PMF, Adenosine Tri-Phosphate (ATP)-competitive JAK2 inhibitors have shown their interest, but also their important limitations. Thus, other approaches are required, which are discussed in this review. Copyright © 2014

Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis.

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Rumi, Elisa; Pietra, Daniela; Pascutto, Cristiana; Guglielmelli, Paola; Martínez-Trillos, Alejandra; Casetti, Ilaria; Colomer, Dolors; Pieri, Lisa; Pratcorona, Marta; Rotunno, Giada; Sant'Antonio, Emanuela; Bellini, Marta; Cavalloni, Chiara; Mannarelli, Carmela; Milanesi, Chiara; Boveri, Emanuela; Ferretti, Virginia; Astori, Cesare; Rosti, Vittorio; Cervantes, Francisco; Barosi, Giovanni; Vannucchi, Alessandro M; Cazzola, Mario

2014-08-14

We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials. © 2014 by The American Society of Hematology.

Interagency Transition Team Development and Facilitation. Essential Tools.

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Stodden, Robert A.; Brown, Steven E.; Galloway, L. M.; Mrazek, Susan; Noy, Liora

2005-01-01

The purpose of this Essential Tool is to assist state-level transition coordinators and others responsible for forming, conducting, and evaluating the performance of interagency transition teams that are focused upon the school and post-school needs of youth with disabilities. This Essential Tool is designed to guide the coordination efforts of…

JAK2V617F mutation in a patient with B-cell chronic lymphocytic leukemia and prefibrotic primary myelofibrosis

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Ristić Slobodan

2015-01-01

Full Text Available Introduction. Secondary malignancies, particularly solid tumors, are common in patients with chronic lymphocytic leukemia (CLL, but association of myeloproliferative neoplasms and chronic lymphocytic leukemia in the same patient is very rare. Case Outline. We report of a 67-year-old man with B-cell chronic lymphoid leukemia (B-CLL who developed primary myelofibrosis (PMF nine years after initial diagnosis. Patient received alkylation agents and purine analogue, which can be a predisposing factor for the development of myeloproliferative neoplasms. JAK2V617F mutation was not present initially at the time of CLL diagnosis, but was found after nine years when PMF occurred, which indicates that B-CLL and PMF represent two separate clonal origin neoplasms. Conclusion. Pathogenic mechanisms for the development of myeloproliferative and lymphoproliferative neoplasms in the same patient are unknown. Further research is needed to determine whether these malignancies originate from two different cell clones or arise from the same pluripotent hematopoietic stem cell. [Projekat Ministarstva nauke Republike Srbije, br. III 41004

Tie2 Expressing Monocytes in the Spleen of Patients with Primary Myelofibrosis.

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Rita Campanelli

Full Text Available Primary myelofibrosis (PMF is a Philadelphia-negative (Ph- myeloproliferative disorder, showing abnormal CD34+ progenitor cell trafficking, splenomegaly, marrow fibrosis leading to extensive extramedullary haematopoiesis, and abnormal neoangiogenesis in either the bone marrow or the spleen. Monocytes expressing the angiopoietin-2 receptor (Tie2 have been shown to support abnormal angiogenic processes in solid tumors through a paracrine action that takes place in proximity to the vessels. In this study we investigated the frequency of Tie2 expressing monocytes in the spleen tissue samples of patients with PMF, and healthy subjects (CTRLs, and evaluated their possible role in favouring spleen angiogenesis. We show by confocal microscopy that in the spleen tissue of patients with PMF, but not of CTRLs, the most of the CD14+ cells are Tie2+ and are close to vessels; by flow cytometry, we found that Tie2 expressing monocytes were Tie2+CD14lowCD16brightCDL62-CCR2- (TEMs and their frequency was higher (p = 0.008 in spleen tissue-derived mononuclear cells (MNCs of patients with PMF than in spleen tissue-derived MNCs from CTRLs undergoing splenectomy for abdominal trauma. By in vitro angiogenesis assay we evidenced that conditioned medium of immunomagnetically selected spleen tissue derived CD14+ cells of patients with PMF induced a denser tube like net than that of CTRLs; in addition, CD14+Tie2+ cells sorted from spleen tissue derived single cell suspension of patients with PMF show a higher expression of genes involved in angiogenesis than that found in CTRLs. Our results document the enrichment of Tie2+ monocytes expressing angiogenic genes in the spleen of patients with PMF, suggesting a role for these cells in starting/maintaining the pathological angiogenesis in this organ.

A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia

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Barosi, G; Besses, C; Birgegard, G

2007-01-01

BACKGROUND: Three main problems hamper the identification of wheat food allergens: (1) lack of a standardized procedure for extracting all of the wheat protein fractions; (2) absence of double-blind, placebo-controlled food challenge studies that compare the allergenic profile of Osborne's three ...

JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis

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Scott, Linda M.; Tong, Wei; Levine, Ross L.; Scott, Mike A.; Beer, Philip A.; Stratton, Michael R.; Futreal, P. Andrew; Erber, Wendy N.; McMullin, Mary Frances; Harrison, Claire N.; Warren, Alan J.; Gilliland, D. Gary; Lodish, Harvey F.; Green, Anthony R.

2010-01-01

BACKGROUND The V617F mutation, which causes the substitution of phenylalanine for valine at position 617 of the Janus kinase (JAK) 2 gene (JAK2), is often present in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis. However, the molecular basis of these myeloproliferative disorders in patients without the V617F mutation is unclear. METHODS We searched for new mutations in members of the JAK and signal transducer and activator of transcription (STAT) gene families in patients with V617F-negative polycythemia vera or idiopathic erythrocytosis. The mutations were characterized biochemically and in a murine model of bone marrow transplantation. RESULTS We identified four somatic gain-of-function mutations affecting JAK2 exon 12 in 10 V617F-negative patients. Those with a JAK2 exon 12 mutation presented with an isolated erythrocytosis and distinctive bone marrow morphology, and several also had reduced serum erythropoietin levels. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin. All such erythroid colonies were heterozygous for the mutation, whereas colonies homozygous for the mutation occur in most patients with V617F-positive polycythemia vera. BaF3 cells expressing the murine erythropoietin receptor and also carrying exon 12 mutations could proliferate without added interleukin-3. They also exhibited increased phosphorylation of JAK2 and extracellular regulated kinase 1 and 2, as compared with cells transduced by wild-type JAK2 or V617F JAK2. Three of the exon 12 mutations included a substitution of leucine for lysine at position 539 of JAK2. This mutation resulted in a myeloproliferative phenotype, including erythrocytosis, in a murine model of retroviral bone marrow transplantation. CONCLUSIONS JAK2 exon 12 mutations define a distinctive myeloproliferative syndrome that affects patients who currently receive a diagnosis of polycythemia vera or idiopathic erythrocytosis

Improved diagnosis of the transition to JAK2 (V⁶¹⁷F homozygosity: the key feature for predicting the evolution of myeloproliferative neoplasms.

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Mariana Selena Gonzalez

Full Text Available Most cases of BCR-ABL1-negative myeloproliferative neoplasms (MPNs, essential thrombocythemia, polycythemia vera and primary myelofibrosis are associated with JAK2 (V617F mutations. The outcomes of these cases are critically influenced by the transition from JAK2 (V617F heterozygosity to homozygosity. Therefore, a technique providing an unbiased assessment of the critical allele burden, 50% JAK2 (V617F, is highly desirable. In this study, we present an approach to assess the JAK2 (V617F burden from genomic DNA (gDNA and complementary DNA (cDNA using one-plus-one template references for allele-specific quantitative-real-time-PCR (qPCR. Plasmidic gDNA and cDNA constructs encompassing one PCR template for JAK2 (V617F spaced from one template for JAK2(Wild Type were constructed by multiple fusion PCR amplifications. Repeated assessments of the 50% JAK2(V617F burden within the dynamic range of serial dilutions of gDNA and cDNA constructs resulted in 52.53 ± 4.2% and 51.46 ± 4.21%, respectively. The mutation-positive cutoff was estimated to be 3.65% (mean +2 standard deviation using 20 samples from a healthy population. This qPCR approach was compared with the qualitative ARMS-PCR technique and with two standard methods based on qPCR, and highly significant correlations were obtained in all cases. qPCR assays were performed on paired gDNA/cDNA samples from 20 MPN patients, and the JAK2 (V617F expression showed a significant correlation with the allele burden. Our data demonstrate that the qPCR method using one-plus-one template references provides an improved assessment of the clinically relevant transition of JAK2 (V617F from heterozygosity to homozygosity.

Renal extramedullary hematopoiesis: interstitial and glomerular pathology.

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Alexander, Mariam P; Nasr, Samih H; Kurtin, Paul J; Casey, Edward T; Hernandez, Loren P Herrera; Fidler, Mary E; Sethi, Sanjeev; Cornell, Lynn D

2015-12-01

Renal extramedullary hematopoiesis is rarely recognized in the antemortem setting. We identified 14 patients with renal extramedullary hematopoiesis on antemortem specimens from 1994 to 2015. The mean age was 68 years (range 47-87 years); males predominated (M:F=9:5). All presented with renal insufficiency, including five (36%) with acute kidney injury. The mean serum creatinine at biopsy was 2.9 mg/dl (range 1.2-7.3 mg/dl). All had proteinuria (mean 7.9 g/24 h; range 0.5-28; n=13), including 9 with ≥3 g/24 h. Renal extramedullary hematopoiesis appeared histologically as an interstitial infiltrate (n=12) and/or a perirenal infiltrate (n=3) or mass-like lesion (n=1). Five were misdiagnosed as interstitial nephritis. Concurrent glomerular disease was prevalent and included fibrillary-like glomerulonephritis (n=3), chronic thrombotic microangiopathy (n=5), focal segmental glomerulosclerosis (n=6), and diabetic glomerulosclerosis (n=2). All patients had an underlying hematologic malignancy: primary myelofibrosis in 9, myeloproliferative neoplasm not otherwise specified in 1, essential thrombocythemia in 1, polycythemia vera in 1, and plasma cell myeloma in 2. Clinical follow-up was available in 12 patients, mean of 29 months (range 4-120 months). In 10 patients for whom treatment history could be obtained, 9 were treated with chemotherapy, and 1 was treated with steroids. The mean creatinine at last follow-up was 2 mg/dl (range 1.2-3.9 mg/dl) (n=9). Ten patients died in the follow-up period from their underlying hematological disease and had persistent renal disease. The two remaining patients had persistent chronic kidney disease. Renal extramedullary hematopoiesis should be considered in the differential diagnosis of interstitial infiltrates, particularly in the presence of a glomerulopathy and a hematologic malignancy.

Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms.

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Milosevic Feenstra, Jelena D; Nivarthi, Harini; Gisslinger, Heinz; Leroy, Emilie; Rumi, Elisa; Chachoua, Ilyas; Bagienski, Klaudia; Kubesova, Blanka; Pietra, Daniela; Gisslinger, Bettina; Milanesi, Chiara; Jäger, Roland; Chen, Doris; Berg, Tiina; Schalling, Martin; Schuster, Michael; Bock, Christoph; Constantinescu, Stefan N; Cazzola, Mario; Kralovics, Robert

2016-01-21

Essential thrombocythemia (ET) and primary myelofibrosis (PMF) are chronic diseases characterized by clonal hematopoiesis and hyperproliferation of terminally differentiated myeloid cells. The disease is driven by somatic mutations in exon 9 of CALR or exon 10 of MPL or JAK2-V617F in >90% of the cases, whereas the remaining cases are termed "triple negative." We aimed to identify the disease-causing mutations in the triple-negative cases of ET and PMF by applying whole-exome sequencing (WES) on paired tumor and control samples from 8 patients. We found evidence of clonal hematopoiesis in 5 of 8 studied cases based on clonality analysis and presence of somatic genetic aberrations. WES identified somatic mutations in 3 of 8 cases. We did not detect any novel recurrent somatic mutations. In 3 patients with clonal hematopoiesis analyzed by WES, we identified a somatic MPL-S204P, a germline MPL-V285E mutation, and a germline JAK2-G571S variant. We performed Sanger sequencing of the entire coding region of MPL in 62, and of JAK2 in 49 additional triple-negative cases of ET or PMF. New somatic (T119I, S204F, E230G, Y591D) and 1 germline (R321W) MPL mutation were detected. All of the identified MPL mutations were gain-of-function when analyzed in functional assays. JAK2 variants were identified in 5 of 57 triple-negative cases analyzed by WES and Sanger sequencing combined. We could demonstrate that JAK2-V625F and JAK2-F556V are gain-of-function mutations. Our results suggest that triple-negative cases of ET and PMF do not represent a homogenous disease entity. Cases with polyclonal hematopoiesis might represent hereditary disorders. © 2016 by The American Society of Hematology.

MPL W515L/K Mutations in Chronic Myeloproliferative Neoplasms.

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Akpınar, Timur Selçuk; Hançer, Veysel Sabri; Nalçacı, Meliha; Diz-Küçükkaya, Reyhan

2013-03-01

The MPL gene encodes the thrombopoietin receptor. Recently MPL mutations (MPL W515L or MPL W515K) were described in patients with essential thrombocythemia (ET) and primary (idiopathic) myelofibrosis (PMF). The prevalence and the clinical importance of these mutations are not clear. In the present study, we aimed to investigate the frequency and clinical significance of MPL W515L/K mutations in our patients with ET and PMF. A total of 77 patients (66 were diagnosed with ET and 11 with PMF) and 42 healthy controls were included in the study. Using peripheral blood samples, the presence of MPL W515L/K mutations and JAK-2 V617F mutation were analyzed by real-time polymerase chain reaction. In our study, MPL W515L/K or JAK-2 V617F mutations were not observed in healthy controls. JAK-2 V617F mutation was present in 35 patients, of whom 29 had ET (43.9%, 29/66) and 6 had PMF (54.5%, 6/11). In the patient group, MPL W515L/K mutations were found in only 2 PMF cases, and these cases were negative for JAK-2 V617F mutation. The prevalence of MPL W515L/K mutations in the patient group was 2.6%, and the prevalence of MPL W515L/K mutations among the cases negative for the JAK-2 V617F mutation was found to be 4.8%. The 2 cases with MPL W515L/K mutations had long follow-up times (124 months and 71 months, respectively), had no thrombotic or hemorrhagic complications, and had no additional cytogenetic anomalies. MPL W515L/K mutations may be helpful for identifying clonal disease in MPN patients with no established Ph chromosome or JAK-2 V617F mutation. None declared.

Characterization and Prognosis Significance of JAK2 (V617F), MPL, and CALR Mutations in Philadelphia-Negative Myeloproliferative Neoplasms

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Singdong, Roongrudee; Siriboonpiputtana, Teerapong; Chareonsirisuthigul, Takol; Kongruang, Adcharee; Limsuwanachot, Nittaya; Sirirat, Tanasan; Chuncharunee, Suporn; Rerkamnuaychoke, Budsaba

2016-10-01

Background: The discovery of somatic acquired mutations of JAK2 (V617F) in Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) has not only improved rational disease classification and prognostication but also brings new understanding insight into the pathogenesis of diseases. Dosage effects of the JAK2 (V617F) allelic burden in Ph-negative MPNs may partially influence clinical presentation, disease progression, and treatment outcome. Material and Methods: Pyrosequencing was performed to detect JAK2 (V617F) and MPL (W515K/L) and capillary electrophoresis to identify CALR exon 9.0 mutations in 100.0 samples of Ph-negative MPNs (38.0 PV, 55 ET, 4 PMF, and 3 MPN-U). Results: The results showed somatic mutations of JAK2 (V617F) in 94.7% of PV, 74.5% of ET, 25.0% of PMF, and all MPN-U. A high proportion of JAK2 (V617F) mutant allele burden (mutational load > 50.0%) was predominantly observed in PV when compared with ET. Although a high level of JAK2 (V617F) allele burden was strongly associated with high WBC counts in both PV and ET, several hematological parameters (hemoglobin, hematocrit, and platelet count) were independent of JAK2 (V617F) mutational load. MPL (W515K/L) mutations could not be detected whereas CALR exon 9.0 mutations were identified in 35.7% of patients with JAK2 negative ET and 33.3% with JAK2 negative PMF. Conclusions: The JAK2 (V617F) allele burden may be involved in progression of MPNs. Furthermore, a high level of JAK2 (V617F) mutant allele appears strongly associated with leukocytosis in both PV and ET. Creative Commons Attribution License

Real-World Assessment of Clinical Outcomes in Patients with Lower-Risk Myelofibrosis Receiving Treatment with Ruxolitinib

Directory of Open Access Journals (Sweden)

Keith L. Davis

2015-01-01

Full Text Available Few trial-based assessments of ruxolitinib in patients with lower-risk myelofibrosis (MF have been conducted, and no studies have made such assessments in a real-world population. We assessed changes in spleen size and constitutional symptoms during ruxolitinib treatment using a retrospective, observational review of anonymized US medical record data of patients diagnosed with IPSS low-risk (n=25 or intermediate-1-risk (n=83 MF. The majority of patients were male (low risk, 60%; intermediate-1 risk, 69%. Most patients (92% and 77% were still receiving ruxolitinib at the medical record abstraction date (median observation/exposure time, 8 months. The proportion of patients with moderate or severe palpable splenomegaly (≥10 cm decreased from diagnosis (56% to best response (12%. Fatigue was reported in 47% of patients and was the most common constitutional symptom. For most symptoms in both risk groups, shifts in the distribution of severity from more to less severe from diagnosis to best response were observed. Both patients with low-risk and intermediate-1-risk MF experienced a substantial decrease in spleen size with ruxolitinib treatment in real-world settings. For most symptoms examined, there were distinct improvements in the distribution of severity during ruxolitinib treatment. These findings suggest that patients with lower-risk MF may benefit clinically from ruxolitinib treatment.

Integrative analysis of copy number and gene expression data suggests novel pathogenetic mechanisms in primary myelofibrosis.

Science.gov (United States)

Salati, Simona; Zini, Roberta; Nuzzo, Simona; Guglielmelli, Paola; Pennucci, Valentina; Prudente, Zelia; Ruberti, Samantha; Rontauroli, Sebastiano; Norfo, Ruggiero; Bianchi, Elisa; Bogani, Costanza; Rotunno, Giada; Fanelli, Tiziana; Mannarelli, Carmela; Rosti, Vittorio; Salmoiraghi, Silvia; Pietra, Daniela; Ferrari, Sergio; Barosi, Giovanni; Rambaldi, Alessandro; Cazzola, Mario; Bicciato, Silvio; Tagliafico, Enrico; Vannucchi, Alessandro M; Manfredini, Rossella

2016-04-01

Primary myelofibrosis (PMF) is a Myeloproliferative Neoplasm (MPN) characterized by megakaryocyte hyperplasia, progressive bone marrow fibrosis, extramedullary hematopoiesis and transformation to Acute Myeloid Leukemia (AML). A number of phenotypic driver (JAK2, CALR, MPL) and additional subclonal mutations have been described in PMF, pointing to a complex genomic landscape. To discover novel genomic lesions that can contribute to disease phenotype and/or development, gene expression and copy number signals were integrated and several genomic abnormalities leading to a concordant alteration in gene expression levels were identified. In particular, copy number gain in the polyamine oxidase (PAOX) gene locus was accompanied by a coordinated transcriptional up-regulation in PMF patients. PAOX inhibition resulted in rapid cell death of PMF progenitor cells, while sparing normal cells, suggesting that PAOX inhibition could represent a therapeutic strategy to selectively target PMF cells without affecting normal hematopoietic cells' survival. Moreover, copy number loss in the chromatin modifier HMGXB4 gene correlates with a concomitant transcriptional down-regulation in PMF patients. Interestingly, silencing of HMGXB4 induces megakaryocyte differentiation, while inhibiting erythroid development, in human hematopoietic stem/progenitor cells. These results highlight a previously un-reported, yet potentially interesting role of HMGXB4 in the hematopoietic system and suggest that genomic and transcriptional imbalances of HMGXB4 could contribute to the aberrant expansion of the megakaryocytic lineage that characterizes PMF patients. © 2015 UICC.

Post-quantum cryptography

Science.gov (United States)

Bernstein, Daniel J.; Lange, Tanja

2017-09-01

Cryptography is essential for the security of online communication, cars and implanted medical devices. However, many commonly used cryptosystems will be completely broken once large quantum computers exist. Post-quantum cryptography is cryptography under the assumption that the attacker has a large quantum computer; post-quantum cryptosystems strive to remain secure even in this scenario. This relatively young research area has seen some successes in identifying mathematical operations for which quantum algorithms offer little advantage in speed, and then building cryptographic systems around those. The central challenge in post-quantum cryptography is to meet demands for cryptographic usability and flexibility without sacrificing confidence.

Post-quantum cryptography.

Science.gov (United States)

Bernstein, Daniel J; Lange, Tanja

2017-09-13

Cryptography is essential for the security of online communication, cars and implanted medical devices. However, many commonly used cryptosystems will be completely broken once large quantum computers exist. Post-quantum cryptography is cryptography under the assumption that the attacker has a large quantum computer; post-quantum cryptosystems strive to remain secure even in this scenario. This relatively young research area has seen some successes in identifying mathematical operations for which quantum algorithms offer little advantage in speed, and then building cryptographic systems around those. The central challenge in post-quantum cryptography is to meet demands for cryptographic usability and flexibility without sacrificing confidence.

Nye sygdomsmarkører ved de kroniske myeloproliferative neoplasier

DEFF Research Database (Denmark)

Holmström, Morten Orebo; Ocias, Lukas Frans; Kallenbach, Klaus

2015-01-01

The chaperone and calcium storing protein calreticulin is coded by CALR, and newly identified mutations in CALR are found in respectively 49-70% and 56-88% of JAK2- and MPL-negative patients with essential thrombocytaemia (ET) and primary myelofibrosis (PMF). A total of 41 mutations have been...

Dualism of mixed chimerism between hematopoiesis and stroma in chronic idiopathic myelofibrosis after allogeneic stem cell transplantation.

Science.gov (United States)

Thiele, J; Varus, E; Siebolts, U; Kvasnicka, H M; Wickenhauser, C; Metz, K A; Beelen, D W; Ditschkowski, M; Zander, A; Kröger, N

2007-04-01

Scant knowledge exists concerning lineage-restricted mixed chimerism (mCh) after allogeneic peripheral blood stem cell transplantation (PSCT) in patients with chronic idiopathic myelofibrosis (CIMF). Following a sex-mismatched PSCT, a combined immunopheno- and genotyping by fluorescence in-situ hybridization (FISH) was performed on sequential bone marrow (BM) biopsies at standardized intervals. Results were compared with PCR analysis of corresponding peripheral blood samples in five patients. According to FISH, pretransplant specimens revealed a gender congruence of more than 99%, while in the first three months the total BM exhibited a persistent fraction of host cells (30% to 40%) with a tendency to decline after about one year. It is noteworthy that the majority of endothelial cells maintained a recipient origin, whereas CD34+ progenitors and especially CD61+ megakaryocytes exhibited only very few host-derived cells. In keeping with the prevalence of donor cells in the hematopoietic compartment, PCR analysis of peripheral blood cells displayed a non-significant degree of mCh. In conclusion, according to FISH and PCR analysis, successful PSCT in CIMF results in an almost complete chimeric (donor-derived) state of the hematopoietic cell population. The non-transplantable stromal compartment includes the vascular endothelium with a predominance of recipient cells. The minimal mCh of this population implies probably a donor-derived origin (endothelial progenitor cells).

Screening and monitoring of MPL W515L mutation with real-time PCR in patients with myelofibrosis undergoing allogeneic-SCT.

Science.gov (United States)

Alchalby, H; Badbaran, A; Bock, O; Fehse, B; Bacher, U; Zander, A R; Kröger, N

2010-09-01

Monitoring of minimal residual disease (MRD) after allogeneic (allo)-SCT for myelofibrosis (MF) allows recognizing the depth of remission and thus guides application of appropriate therapeutic interventions. MPL W515L/K mutations, which are detected in 5-10% of JAK2V617F-negative patients, may be useful for this purpose. Using a highly sensitive quantitative PCR method, we tested 90 patients with MF who underwent allo-SCT for the presence of MPL W515L/K mutations. Two patients with primary MF were found to harbor MPLW515L while no patient was positive for MPLW515K mutation. Both patients were JAK2V617F negative and cleared the mutation rapidly after allo-SCT and remained negative for a median follow-up of 19 months. The results of molecular monitoring correlated well with other remission parameters such as normalization of peripheral blood counts and morphology and complete donor chimerism. We conclude that MPLW515L can be cleared after allo-SCT and hence may be used as an MRD marker in a proportion of JAK2V617F-negative MF patients.

Essentials of forensic post-mortem MR imaging in adults

Science.gov (United States)

Ruder, T D; Thali, M J; Hatch, G M

2014-01-01

Post-mortem MR (PMMR) imaging is a powerful diagnostic tool with a wide scope in forensic radiology. In the past 20 years, PMMR has been used as both an adjunct and an alternative to autopsy. The role of PMMR in forensic death investigations largely depends on the rules and habits of local jurisdictions, availability of experts, financial resources, and individual case circumstances. PMMR images are affected by post-mortem changes, including position-dependent sedimentation, variable body temperature and decomposition. Investigators must be familiar with the appearance of normal findings on PMMR to distinguish them from disease or injury. Coronal whole-body images provide a comprehensive overview. Notably, short tau inversion–recovery (STIR) images enable investigators to screen for pathological fluid accumulation, to which we refer as “forensic sentinel sign”. If scan time is short, subsequent PMMR imaging may be focussed on regions with a positive forensic sentinel sign. PMMR offers excellent anatomical detail and is especially useful to visualize pathologies of the brain, heart, subcutaneous fat tissue and abdominal organs. PMMR may also be used to document skeletal injury. Cardiovascular imaging is a core area of PMMR imaging and growing evidence indicates that PMMR is able to detect ischaemic injury at an earlier stage than traditional autopsy and routine histology. The aim of this review is to present an overview of normal findings on forensic PMMR, provide general advice on the application of PMMR and summarise the current literature on PMMR imaging of the head and neck, cardiovascular system, abdomen and musculoskeletal system. PMID:24191122

Concerns and evidence for ex-post hold-up with essential patents

NARCIS (Netherlands)

Bekkers, R.N.A.

2015-01-01

Patented technologies may add significant value to technical standards. But the owners of patents that are necessary required in order to implement a standard (“essential patents”) obtain a particularly powerful position. One of the widely recognized risks here is patent holdup, where the patent

Symptom burden and splenomegaly in patients with myelofibrosis in the United States: a retrospective medical record review

International Nuclear Information System (INIS)

Mitra, Debanjali; Kaye, James A; Piecoro, Lance T; Brown, Jennifer; Reith, Kelly; Mughal, Tariq I; Sarlis, Nicholas J

2013-01-01

Myelofibrosis (MF) is a clonal hematopoietic malignancy characterized by constitutional and localized symptoms, progressive splenomegaly, bone marrow fibrosis, and cytopenias. Although MF is well studied, few studies exist regarding its symptomatic burden in routine clinical practice. This study aimed to characterize symptoms and other clinical features of MF among patients in the United States. We conducted a retrospective medical record review of adult patients with an MF diagnosis between 1 January 2005 and 31 March 2010, stratified by the presence of palpable splenomegaly. Eligible patients had 12 months or more of follow-up after diagnosis (or after detection of splenomegaly, if present) unless death occurred. Demographic and clinical characteristics, MF-related symptoms, and treatments were reported by treating physicians. We report on 180 MF patients: 102 with splenomegaly, 78 without. Median age was 66 years, 63% were male, and 82% had intermediate-2 or high-risk MF (International Prognostic Scoring System). Fatigue was reported by ∼85% of patients; weight loss, night sweats, and fever (any grade) were each reported by 50% or more of patients. Generalized abdominal pain, left subcostal pain, and early satiety occurred more frequently among patients with splenomegaly. Multiple symptoms were reported by 95% of patients. Common comorbidities were hypertension, diabetes, and chronic pulmonary disease. Symptoms are common in MF patients, regardless of the presence of palpable splenomegaly. Careful assessment of symptom burden is an important aspect of the clinical evaluation of patients with MF

Nephrotic syndrome in primary myelofibrosis with renal extramedullary hematopoiesis and glomerulopathy in the JAK inhibitor era.

Science.gov (United States)

Del Sordo, Rachele; Brugnano, Rachele; Covarelli, Carla; Fiorucci, Gioia; Falzetti, Franca; Barbatelli, Giorgio; Nunzi, Emidio; Sidoni, Angelo

2017-01-01

Primary myelofibrosis (PMF) is an uncommon form of myeloproliferative neoplasm (MPN) characterized by a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow that, in fully-developed disease, is associated with reactive deposition of fibrous connective tissue, extramedullary hematopoiesis (EMH), and splenomegaly. Kidney involvement is rare and clinically presents with proteinuria, nephrotic syndrome, and renal insufficiency. Renal damage can be due to EMH and glomerulopathy. Renal EMH presents three patterns: infiltration of the interstitium with possible renal failure caused by functional damage of parenchyma and vessels, infiltration of capsule and pericapsular adipose tissue, and sclerosing mass-like lesions that can cause hydronephrosis and hydroureter with obstructive uropathy and renal failure. Glomerulopathy associated with PMF is rarely described, ranging from 1 month to 18 years from diagnosis of the neoplasm to renal biopsy. It is characterized by expansion and hypercellularity mesangial, segmental sclerosis, features of chronic thrombotic microangiopathy (TMA), and intracapillary hematopoietic cells infiltrating in absence of immune-mediated glomerulonephritis. We present a nephrotic syndrome in PMF-related glomerulopathy, associated with EMH, without renal failure, in a patient under treatment for 2 years with JAK2 inhibitor ruxolitinib. Despite treatment, the patient died 7 months after renal biopsy. Nephrologists still know very little about this topic and there is no homogeneous data about incidence, pathogenesis, and optimal treatment of this poor prognostic PMF-associated nephrotic syndrome. We focus on data in the literature in the hope of stimulating hematologists, nephrologists, pathologists to future studies about the natural history of renal involvement, useful for optimal management of this rare pathology.

JAK2 V617F, MPL W515L and JAK2 Exon 12 Mutations in Chinese Patients with Primary Myelofibrosis.

Science.gov (United States)

Xia, Jun; Lu, Mi-Ze; Jiang, Yuan-Qiang; Yang, Guo-Hua; Zhuang, Yun; Sun, Hong-Li; Shen, Yun-Feng

2012-03-01

JAK2 V617F, MPL W515L and JAK2 exon 12 mutations are novel acquired mutations that induce constitutive cytokine-independent activation of the JAK-STAT pathway in myeloproliferative disorders (MPD). The discovery of these mutations provides novel mechanism for activation of signal transduction in hematopoietic malignancies. This research was to investigate their prevalence in Chinese patients with primary myelofibrosis (PMF). We introduced allele-specific PCR (AS-PCR) combined with sequence analysis to simultaneously screen JAK2 V617F, MPL W515L and JAK2 exon 12 mutations in 30 patients with PMF. Fifteen PMF patients (50.0%) carried JAK2 V617F mutation, and only two JAK2 V617F-negative patients (6.7%) harbored MPL W515L mutation. None had JAK2 exon 12 mutations. Furthermore, these three mutations were not detected in 50 healthy controls. MPL W515L and JAK2 V617F mutations existed in PMF patients but JAK2 exon 12 mutations not. JAK2 V617F and MPL W515L and mutations might contribute to the primary molecular pathogenesis in patients with PMF.

Study on the relationship between serum sex hormones levels and essential hypertension

International Nuclear Information System (INIS)

Song Qingzhang; Yang Xiuhong; Di Fang

2006-01-01

Objective: To investigate the possible relationship existing between serum sex hormones levels and development of essential hypertension. Methods: Serum sex hormones (LH, FSH, E 2 , P, T) levels were determined with RIA in 87 males and 81 post-menopausal women with essential hypertension as well as in 44 normotensive males and 40 normotensive post-menopausal women serving as controls. Results: The serum E 2 , progesterone and testosterone levels in the hypertensives were significantly higher than those in the respective controls (P 0.05). Sex hormones levels were not much different among hypertensives of various stages (I , II, III). The serum E 2 levels in male hypertensives and progesterone levels in female hypertensives were not correlated with the respective FSH and LH levels. Conclusion: The authors suggested that the changes of serum sex hormones levels might be a risk factor rather than a consequence of the development of essential hypertension. (authors)

Prioritizing essential surgery and safe anesthesia for the Post-2015 Development Agenda: operative capacities of 78 district hospitals in 7 low- and middle-income countries.

Science.gov (United States)

LeBrun, Drake G; Chackungal, Smita; Chao, Tiffany E; Knowlton, Lisa M; Linden, Allison F; Notrica, Michelle R; Solis, Carolina V; McQueen, K A Kelly

2014-03-01

Surgery has been neglected in low- and middle-income countries for decades. It is vital that the Post-2015 Development Agenda reflect that surgery is an important part of a comprehensive global health care delivery model. We compare the operative capacities of multiple low- and middle-income countries and identify critical gaps in surgical infrastructure. The Harvard Humanitarian Initiative survey tool was used to assess the operative capacities of 78 government district hospitals in Bangladesh (n = 7), Bolivia (n = 11), Ethiopia (n = 6), Liberia (n = 11), Nicaragua (n = 10), Rwanda (n = 21), and Uganda (n = 12) from 2011 to 2012. Key outcome measures included infrastructure, equipment availability, physician and nonphysician surgical providers, operative volume, and pharmaceutical capacity. Seventy of 78 district hospitals performed operations. There was fewer than one surgeon or anesthesiologist per 100,000 catchment population in all countries except Bolivia. There were no physician anesthesiologists in any surveyed hospitals in Rwanda, Liberia, Uganda, or in the majority of hospitals in Ethiopia. Mean annual operations per hospital ranged from 374 in Nicaragua to 3,215 in Bangladesh. Emergency operations and obstetric operations constituted 57.5% and 40% of all operations performed, respectively. Availability of pulse oximetry, essential medicines, and key infrastructure (water, electricity, oxygen) varied widely between and within countries. The need for operative procedures is not being met by the limited operative capacity in numerous low- and middle-income countries. It is of paramount importance that this gap be addressed by prioritizing essential surgery and safe anesthesia in the Post-2015 Development Agenda. Copyright © 2014 Mosby, Inc. All rights reserved.

Resolution of bone marrow fibrosis in a patient receiving JAK1/JAK2 inhibitor treatment with ruxolitinib.

Science.gov (United States)

Wilkins, Bridget S; Radia, Deepti; Woodley, Claire; Farhi, Sarah El; Keohane, Clodagh; Harrison, Claire N

2013-12-01

Ruxolitinib, a JAK1/JAK2 inhibitor, is currently the only pharmacological agent approved for the treatment of myelofibrosis. Approval was based on findings from two phase 3 trials comparing ruxolitinib with placebo (COMFORT-I) and with best available therapy (COMFORT-II) for the treatment of primary or secondary myelofibrosis. In those pivotal trials, ruxolitinib rapidly improved splenomegaly, disease-related symptoms, and quality of life and prolonged survival compared with both placebo and conventional treatments. However, for reasons that are currently unclear, there were only modest histomorphological changes in the bone marrow, and only a subset of patients had significant reductions in JAK2 V617F clonal burden. Here we describe a patient with post-polycythemia vera myelofibrosis who received ruxolitinib at our institution (Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom) as part of the COMFORT-II study. While on treatment, the patient had dramatic improvements in splenomegaly and symptoms shortly after starting ruxolitinib. With longer treatment, the patient had marked reductions in JAK2 V617F allele burden, and fibrosis of the bone marrow resolved after approximately 3 years of ruxolitinib treatment. To our knowledge, this is the first detailed case report of resolution of fibrosis with a JAK1/JAK2 inhibitor. ClinicalTrials.gov Identifier: NCT00934544.

Identifying the Essential Elements of Effective Science Communication: What Do the Experts Say?

Science.gov (United States)

Bray, Belinda; France, Bev; Gilbert, John K.

2012-01-01

Experts in science communication were asked to identify the essential elements of a science communication course for post-graduate students. A Delphi methodology provided a framework for a research design that accessed their opinions and allowed them to contribute to, reflect on and identify 10 essential elements. There was a high level of…

MPL W515L/K Mutations in Chronic Myeloproliferative Neoplasms

Directory of Open Access Journals (Sweden)

Timur Selçuk Akpınar

2013-03-01

Full Text Available OBJECTIVE: The MPL gene encodes the thrombopoietin receptor. Recently MPL mutations (MPL W515L or MPL W515K were described in patients with essential thrombocythemia (ET and primary (idiopathic myelofibrosis (PMF. The prevalence and the clinical importance of these mutations are not clear. In the present study, we aimed to investigate the frequency and clinical significance of MPL W515L/K mutations in our patients with ET and PMF. METHODS: A total of 77 patients (66 were diagnosed with ET and 11 with PMF and 42 healthy controls were included in the study. Using peripheral blood samples, the presence of MPL W515L/K mutations and JAK-2 V617F mutation were analyzed by real-time polymerase chain reaction. RESULTS: In our study, MPL W515L/K or JAK-2 V617F mutations were not observed in healthy controls. JAK-2 V617F mutation was present in 35 patients, of whom 29 had ET (43.9%, 29/66 and 6 had PMF (54.5%, 6/11. In the patient group, MPL W515L/K mutations were found in only 2 PMF cases, and these cases were negative for JAK-2 V617F mutation. The prevalence of MPL W515L/K mutations in the patient group was 2.6%, and the prevalence of MPL W515L/K mutations among the cases negative for the JAK-2 V617F mutation was found to be 4.8%. The 2 cases with MPL W515L/K mutations had long follow-up times (124 months and 71 months, respectively, had no thrombotic or hemorrhagic complications, and had no additional cytogenetic anomalies. CONCLUSION: MPL W515L/K mutations may be helpful for identifying clonal disease in MPN patients with no established Ph chromosome or JAK-2 V617F mutation.

The JAK2V617 mutation induces constitutive activation and agonist hypersensitivity in basophils from patients with polycythemia vera

Science.gov (United States)

Pieri, Lisa; Bogani, Costanza; Guglielmelli, Paola; Zingariello, Maria; Rana, Rosa Alba; Bartalucci, Niccolò; Bosi, Alberto; Vannucchi, Alessandro M.

2009-01-01

Background The JAK2V617F mutation has been associated with constitutive and enhanced activation of neutrophils, while no information is available concerning other leukocyte subtypes. Design and Methods We evaluated correlations between JAK2V617F mutation and the count of circulating basophils, the number of activated CD63+ basophils, their response in vitro to agonists as well as the effects of a JAK2 inhibitor. Results We found that basophil count was increased in patients with JAK2V617F -positive myeloproliferative neoplasms, particularly in those with polycythemia vera, and was correlated with the V617F burden. The burden of V617F allele was similar in neutrophils and basophils from patients with polycythemia vera, while total JAK2 mRNA content was remarkably greater in the basophils; however, the content of JAK2 protein in basophils was not increased. The number of CD63+ basophils was higher in patients with polycythemia vera than in healthy subjects or patients with essential thrombocythemia or primary myelofibrosis and was correlated with the V617F burden. Ultrastructurally, basophils from patients with polycythemia vera contained an increased number of granules, most of which were empty suggesting cell degranulation in vivo. Ex vivo experiments revealed that basophils from patients with polycythemia vera were hypersensitive to the priming effect of interleukin-3 and to f-MLP-induced activation; pre-treatment with a JAK2 inhibitor reduced polycythemia vera basophil activation. Finally, we found that the number of circulating CD63+ basophils was significantly greater in patients suffering from aquagenic pruritus, who also showed a higher V617F allele burden. Conclusions These data indicate that the number of constitutively activated and hypersensitive circulating basophils is increased in polycythemia vera, underscoring a role of JAK2V617F in these cells’ abnormal function and, putatively, in the pathogenesis of pruritus. PMID:19608683

[JAK2 V617F and exon 12 genetic variations in Korean patients with BCR/ABL1-negative myeloproliferative neoplasms].

Science.gov (United States)

Kim, Jeong Tae; Cho, Yong Gon; Choi, Sam Im; Lee, Young Jin; Kim, Hye Ran; Jang, Sook Jin; Moon, Dae Soo; Park, Young Jin; Park, Geon

2010-12-01

JAK2 genetic variations have been described in a high proportion of patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN). This study was designed to analyze the frequencies of JAK2 V617F and exon 12 variations, and their correlations with clinical characteristics of Korean patients with BCR/ABL1-negative MPN. We examined a total of 154 patients with BCR/ABL1-negative MPN that included 24, 26, 89, and 15 patients with polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), and unclassified myeloproliferative neoplasms (MPNU), respectively. We performed allele-specific PCR to detect V617F in all BCR/ABL1-negative patients, and performed direct sequencing to detect exon 12 variations in 47 V617F-negative MPN patients. JAK2 c.1641+179_183del5 variation was detected by restriction fragment length polymorphism assay in 176 healthy subjects. JAK2 V617F was detected in 91 patients (59.1%): PV (91.6%), PMF (46.2%), ET (52.8%), and MPNU (66.7%). In V617F-negative MPN patients, no mutations were found in exon 12. The c.1641+179_183del5 was detected in 68.1% of V617F-negative MPN patients and 45.4% of healthy subjects (P=0.008). JAK2 V617F was closely correlated with age and leukocytosis in BCR/ABL1-negative MPN patients (P<0.05). However, c.1641+179_183del5 was not related to age, sex, or complete blood cell count parameters in V617F-negative MPN patients and healthy subjects. The c.1641+179_183del5 was associated with an increased odds ratio for MPN (odds ratio, 2.6; 95% confidences interval, 1.3-5.1; P=0.007). Frequencies of V617F are similar to reported results. JAK2 exon 12 mutations may be rare and c.1641+179_183del5 may influence the occurrence of MPN in Korean patients with V6 17F-negative MPN.

Myeloproliferative neoplasms (MPNs) have a significant impact on patients’ overall health and productivity: the MPN Landmark survey

International Nuclear Information System (INIS)

Mesa, Ruben; Miller, Carole B.; Thyne, Maureen; Mangan, James; Goldberger, Sara; Fazal, Salman; Ma, Xiaomei; Wilson, Wendy; Paranagama, Dilan C.; Dubinski, David G.; Boyle, John; Mascarenhas, John O.

2016-01-01

The Philadelphia chromosome−negative myeloproliferative neoplasms (MPN) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) negatively affect patient quality of life (QoL) and are associated with increased risk of mortality. The MPN Landmark survey was conducted from May to July 2014 in patients with MF, PV, or ET under active management in the United States. The survey assessed respondent perceptions of disease burden and treatment management and included questions on overall disease burden, QoL, activities of daily living, and work productivity. Outcomes were further analyzed by calculated (ie, not respondent-reported) prognostic risk score and symptom severity quartile. The survey was completed by 813 respondents (MF, n = 207; PV, n = 380; ET, n = 226). The median respondent age in each of the 3 MPN subtypes ranged from 62 to 66 years; median disease duration was 4 to 7 years. Many respondents reported that they had experienced MPN-related symptoms ≥1 year before diagnosis (MF, 49 %; PV, 61 %; ET, 58 %). Respondents also reported that MPN-related symptoms reduced their QoL, including respondents with low prognostic risk scores (MF, 67 %; PV, 62 %; ET, 57 %) and low symptom severity (MF, 51 %; PV, 33 %; ET, 15 %). Many respondents, including those with a low prognostic risk score, reported that their MPN had caused them to cancel planned activities or call in sick to work at least once in the preceding 30 days (cancel planned activities: MF, 56 %; PV, 35 %; ET, 35 %; call in sick: MF, 40 %; PV, 21 %; ET, 23 %). These findings of the MPN Landmark survey support previous research about the symptom burden experienced by patients with MPNs and are the first to detail the challenges that patients with MPNs experience related to reductions in activities of daily living and work productivity. The online version of this article (doi:10.1186/s12885-016-2208-2) contains supplementary material, which is available to authorized users

Prognostic significance of ASXL1, JAK2V617F mutations and JAK2V617F allele burden in Philadelphia-negative myeloproliferative neoplasms

Directory of Open Access Journals (Sweden)

Yonal-Hindilerden I

2015-06-01

Full Text Available Ipek Yonal-Hindilerden, Aynur Daglar-Aday, Basak Akadam-Teker, Ceylan Yilmaz, Meliha Nalcaci, Akif Selim Yavuz, Deniz SarginDivision of Hematology, Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University, Fatih-Istanbul, Turkey Background: Despite insights into the genetic basis of Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs, a significant proportion of essential thrombocythemia (ET and primary myelofibrosis (PMF patients present with no known MPN disease alleles. There were no previous studies investigating the impact of ASXL1 mutations in Ph-negative MPNs in Turkey. In the current study, we investigated the prognostic significance of ASXL1 mutations in Turkish MPN patients. We also aimed to determine the prognostic significance of JAK2V617F allele burden and the relationship of JAK2V617F mutation with ASXL1 mutations in Ph-negative MPNs. Methods: About 184 patients from a single center diagnosed with Ph-negative MPNs were screened for ASXL1, JAK2V617F mutations, and JAK2V617F allele burden: 107 ET and 77 PMF. Results: A total of 29 ASXL1 mutations were detected in 24.7% of PMF and 8.4% of ET patients. ASXL1-mutated ET patients showed a trend toward an increase in the incidence of cerebrovascular events and higher total leukocyte counts. ASXL1-mutation in PMF was associated with older age and a higher prevalence of bleeding complications. In univariate analysis, overall survival (OS was significantly reduced in ASXL1-mutated PMF patients. In multivariate analysis, Dynamic International Prognostic Scoring System-plus high-risk category and ASXL1 mutation status were independently associated with shorter survival in PMF. In PMF, mutational status and allele burden of JAK2V617F showed no difference in terms of OS and leukemia-free survival. Conclusion: We conclude that ASXL1 mutations are molecular predictors of short OS in PMF. Keywords: Philadelphia-negative myeloproliferative neoplasms (Ph

Postharvest quality of essential oil treated roses

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Guilherme Mariano Manfredini

2017-07-01

Full Text Available The loss of commercial quality during storage and transportation of roses is one of the factors that reflect on production costs, leading producers to preventively apply harmful chemicals, mainly to hamper Botrytis cinerea development and reduce further losses. An alternative to increase flower longevity without contaminating the environment with harmful chemicals is the use of natural products, such as essential oils, which have fungistatic and insecticide properties, as well as low toxicity. The objective of this study was to evaluate the effect of essential oils on the vase life of Rosa cv. Avalanche: 12 treatments were tested, resulting from the combination of 5 types of essential oils plus the control in two cold storage periods (2 to 6 days at 1 °C, 90-95% RH. The essential oils tested were eucalyptus, cinnamon, lemongrass and peppermint (1%, clove (0.1%, plus a control with distilled water. Application was made by spraying the flower buds. After storage at low temperatures, the flower stems were kept in a room (16 °C, 70% RH during 10 days for evaluation. Flower stems stored for 2 days in a cold chamber showed better means for darkening, turgor and bent neck, as well as a lower weight loss by the stems. The application of lemongrass essential oil at 1% caused burns on the petals, compromising quality and pot life. The essential oils of peppermint and eucalyptus allowed flower quality maintenance until the 10th day of evaluation. It is possible to conclude that post-harvest spraying with peppermint or eucalyptus essential oil at 1%, combined with cold storage for 2 days, provided greater longevity and quality for cv. Avalanche roses.

Massage Therapy Given by Caregiver in Treating Quality of Life of Young Patients Undergoing Treatment for Cancer

Science.gov (United States)

2018-05-24

Accelerated Phase Chronic Myelogenous Leukemia; Acute Undifferentiated Leukemia; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Burkitt Lymphoma; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Acute Myeloid Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Grade III Lymphomatoid Granulomatosis; Childhood Immunoblastic Large Cell Lymphoma; Childhood Myelodysplastic Syndromes; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Contiguous Stage II Mantle Cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Essential Thrombocythemia; Extramedullary Plasmacytoma; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Juvenile Myelomonocytic Leukemia; Mast Cell Leukemia; Meningeal Chronic Myelogenous Leukemia; Noncontiguous Stage II Mantle Cell Lymphoma; Polycythemia Vera; Post-transplant Lymphoproliferative Disorder; Primary Myelofibrosis; Primary Systemic Amyloidosis; Progressive Hairy Cell Leukemia, Initial Treatment; Prolymphocytic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Stage 0 Chronic Lymphocytic Leukemia; Stage I Childhood Anaplastic Large Cell

Sunitinib Malate in Treating HIV-Positive Patients With Cancer Receiving Antiretroviral Therapy

Science.gov (United States)

2014-03-14

Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Acute Undifferentiated Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Grade III Lymphomatoid Granulomatosis; Adult Langerhans Cell Histiocytosis; Adult Nasal Type Extranodal NK/T-cell Lymphoma; Aggressive NK-cell Leukemia; AIDS-related Diffuse Large Cell Lymphoma; AIDS-related Diffuse Mixed Cell Lymphoma; AIDS-related Diffuse Small Cleaved Cell Lymphoma; AIDS-related Immunoblastic Large Cell Lymphoma; AIDS-related Lymphoblastic Lymphoma; AIDS-related Malignancies; AIDS-related Small Noncleaved Cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Chronic Phase Chronic Myelogenous Leukemia; Clear Cell Renal Cell Carcinoma; Cutaneous B-cell Non-Hodgkin Lymphoma; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Extramedullary Plasmacytoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; HIV Infection; HIV-associated Hodgkin Lymphoma; Intraocular Lymphoma; Isolated Plasmacytoma of Bone; Light Chain Deposition Disease; Mast Cell Leukemia; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid/NK-cell Acute Leukemia; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Osteolytic Lesions of Multiple Myeloma; Peripheral T-cell Lymphoma; Plasma Cell Neoplasm; Polycythemia Vera; Post

Frequency of janus associated kinase 2 (jak2) mutation in patients of bcr-abl negative myeloproliferative neoplasms

International Nuclear Information System (INIS)

Sadiq, M.A.; Ahmed, S.; Ali, N.

2013-01-01

To determine the frequency of Janus associated kinase 2 mutation in the patients of BCR-ABL negative classical myeloproliferative neoplasms. Study Design: Cross-sectional descriptive study Place and Duration of Study: Molecular Department of Haematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi from Jul 2011 to Jul 2012. Patients and Methods: Ninety three consecutive patients of Polycythaemia vera (PV), Essential thrombocythaemia (ET) and Idiopathic myelofibrosis (IMF) diagnosed by the conventional haematological criteria were included in the study. All patients were screened for G-T point mutation (V617F) in the JAK2 gene on chromosome 9 by an allele specific PCR. Results: Out of the 93 myeloproliferative neoplasm (MPN) patients, 33(35%) had polycythaemia vera, 36(39%) had essential thrombocythaemia and 24(26%) had idiopathic myelofibrosis. JAK2 mutation was seen in 64/93 (69%) patients including 33/33(100%) in PV, 19/36(52.6%) in ET and 12/24(50%) in IMF. Conclusion: Classical myeloproliferative neoplasms are an important group of heamatological disorder in our country. JAK2 gene mutation is seen in significant proportion of these disorders (69%). JAK2 mutation analysis can be used to differentiate between polycythemia vera and secondary polycythemia in most cases with near certainty, where it was found in 100% of the cases. (author)

Post-transcriptional trafficking and regulation of neuronal gene expression.

Science.gov (United States)

Goldie, Belinda J; Cairns, Murray J

2012-02-01

Intracellular messenger RNA (mRNA) traffic and translation must be highly regulated, both temporally and spatially, within eukaryotic cells to support the complex functional partitioning. This capacity is essential in neurons because it provides a mechanism for rapid input-restricted activity-dependent protein synthesis in individual dendritic spines. While this feature is thought to be important for synaptic plasticity, the structures and mechanisms that support this capability are largely unknown. Certainly specialized RNA binding proteins and binding elements in the 3' untranslated region (UTR) of translationally regulated mRNA are important, but the subtlety and complexity of this system suggests that an intermediate "specificity" component is also involved. Small non-coding microRNA (miRNA) are essential for CNS development and may fulfill this role by acting as the guide strand for mediating complex patterns of post-transcriptional regulation. In this review we examine post-synaptic gene regulation, mRNA trafficking and the emerging role of post-transcriptional gene silencing in synaptic plasticity.

Gestational Diabetes Mellitus: Post-partum Risk and Follow Up.

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Poola-Kella, Silpa; Steinman, Rachel A; Mesmar, Bayan; Malek, Rana

2018-01-31

Women with gestational diabetes mellitus (GDM) are at an increased risk for developing metabolic syndrome, type 2 diabetes mellitus (T2DM), and cardiovascular disease. In this review, we will discuss postpartum cardiovascular and diabetes risk in women with a history of GDM and different ways to improve postpartum screening. This review involves a comprehensive literature review on gestational diabetes and postpartum risk for cardiovascular disease and diabetes mellitus as well as post-partum screening methods. Cardiovascular risk post-partum is potentiated by increased inflammatory markers leading to worsening atherosclerosis and cardiovascular events downstream. Decreased insulin sensitivity and β cell compensation, recurrent GDM, maternal factors such as pre and post-partum weight gain and lactation may contribute to T2DM risk. Postpartum glucose testing is essential in screening women as hyperglycemia in pregnancy has long term effects on both cardiovascular disease and diabetes risk on the mother. Long and short term improvement to post-partum glucose testing is essential to decreasing cardiometabolic and diabetes risk in women with gestational diabetes mellitus. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

C-X-C motif chemokine 12 influences the development of extramedullary hematopoiesis in the spleens of myelofibrosis patients.

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Wang, Xiaoli; Cho, Sool Yeon; Hu, Cing Siang; Chen, Daniel; Roboz, John; Hoffman, Ronald

2015-02-01

Myelofibrosis (MF) is characterized by the constitutive mobilization of hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) and the establishment of extramedullary hematopoiesis. The mechanisms underlying this abnormal HSC/HPC trafficking pattern remain poorly understood. We demonstrated that both splenic and peripheral blood (PB) MF CD34(+) cells equally share a defective ability to home to the marrow, but not to the spleens, of NOD/LtSz-Prkdc(scid) mice. This trafficking pattern could not be attributed to discordant expression of integrins or chemokine receptors other than the downregulation of C-X-C chemokine receptor type 4 by both PB and splenic MF CD34(+) cells. The number of both splenic MF CD34(+) cells and HPCs that migrated toward splenic MF plasma was, however, significantly greater than the number that migrated toward PB MF plasma. The concentration of the intact HSC/HPC chemoattractant C-X-C motif chemokine 12 (CXCL12) was greater in splenic MF plasma than PB MF plasma, as quantified using mass spectrometry. Functionally inactive truncated products of CXCL12, which are the product of proteolytic degradation by serine proteases, were detected at similar levels in both splenic and PB MF plasma. Treatment with an anti-CXCL12 neutralizing antibody resulted in a reduction in the degree of migration of splenic MF CD34(+) cells toward both PB and splenic MF plasma, validating the role of CXCL12 as a functional chemoattractant. Our data indicate that the MF splenic microenvironment is characterized by increased levels of intact, functional CXCL12, which contributes to the localization of MF CD34(+) cells to the spleen and the establishment of extramedullary hematopoiesis. Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

Ireland – a test case of Post-colonialism / Post colonialism

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Brenda Murray

2006-05-01

Full Text Available Contextualisation This review attempts to set the stage for post-colonial theorising, in the light of alternative representations of ‘whiteness’, on issues of gender, race and language within the discourse of equality. In this paper Ireland and the Irish provide a backdrop against which the nature and impact of colonialism on the colonised and the coloniser are explored. Many challenging questions emerge about the ideological basis of post colonial theory, not least when traditional paradigms of racism, as conveyed by the black / white dichotomy, are examined: Ireland presents a context, it is argued, where subjugation is of white on white. Linked to this is the language of the coloniser, a powerful hegemonic force which, in some situations, has been nurtured by the colonised and later developed into a text which is unique, producing a new literature which, it is asserted, truly invokes the ‘post colonial’. Abstract: Post-colonialism – essentially a critique of colonialism, is characterised by a process of disengagement from the colonial epoch and has taken many forms. In this article a set of phenomena are examined that have become inscribed in the cultures of the colonised with a view to identifying alternative cultural origins and dispositions recovered in this post-colonial era. Ireland and the Irish provide the background context of this exploration into perspectives generated by the peripheral or post-colonial nations. Globalisation, too, has had a role to play in the increasing de-territorialisation of communities as a result of cross-frontier mobility, increased intra-community mobility and new communication technologies. A critical reflection on the process of disengagement leads the author to conclude that we must come to recognise new cultural forms which are accepting of a heterogeneous and inclusive society: one which is not characterised by difference.

Insecticidal effects of Ocimum sanctum var. cubensis essential oil on the diseases vector Chrysomya putoria

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Idelsy Chil-Núñez

2018-05-01

Full Text Available Context: The blowfly Chrysomya putoria is widely distributed throughout the Neotropical region and, besides transmitting pathogens; they could cause secondary myiasis. Botanical insecticides provide an alternative to synthetic pesticides because the excessive use of synthetic insecticides resulted in a progressive resistance of the pests to these chemicals, diminishing their effectiveness and generating consequences with negative environmental impact. The essential oil extracted from Ocimum sanctum (basil has showed insecticidal activity against some insects but has no reported studies on the activity of this plant against flies. Aims: To evaluate the insecticidal effects of Ocimum sanctum var. cubensis Gomes essential oil on the post embryonic development of Chrysomya putoria. Methods: The colonies of Chrysomya putoria were established and maintained at the Laboratório de Entomologia Médica e Forense (FIOCRUZ, Rio de Janeiro, Brazil. The basil essential oil was tested in six concentrations (4.13, 8.25, 20.63, 41.25, 61.87 and 80,25 mg/mL. Mortality and changes in life cycle were recorded daily. Results: β-caryophyllene, β-selinene and eugenol, were the main constituents of the basil essential oil. The experiments demonstrated that in all concentrations tested, this essential oil shortening the duration of all post embryonic stages having a direct impact in the viability of this fly estimating the LC50 in 7.47 mg/mL of concentration. In addition, the essential oil caused morphological alterations in abdomen, wings and ptilinum at lower concentrations. Conclusions: This essential oil emerge as a good option for the control of the disease vector blowfly Chrysomya putoria.

JAK2 V617F, MPL, and CALR mutations in essential thrombocythaemia and major thrombotic complications: a single-institute retrospective analysis.

Science.gov (United States)

Pósfai, Éva; Marton, Imelda; Király, Péter Attila; Kotosz, Balázs; Kiss-László, Zsuzsanna; Széll, Márta; Borbényi, Zita

2015-07-01

Thrombo-haemorrhagic events are the main cause of morbidity and mortality in essential thrombocythemia. The aim of this study was to estimate the incidence of thrombotic events and the impact of the JAK2V617F, MPL (W515L, W515K, W515R, W515A and S505N) and CALR (type-1, type-2) mutations on 101 essential thrombocythaemia patients (72 females and 29 males with a mean age of 61 years) diagnosed in a Southern Hungarian regional academic centre. The incidence of major thrombosis was 13.86 %. Sixty percent of the patients carried the JAK2V617F mutation. The MPL mutations were analysed by sequencing and the W515L was the only one we could identify with an incidence of 3.96 %. Type-2 CALR mutation could be identified in 3 cases among the patients who had JAK2/MPL-unmutated ET. Statistical analyses revealed that the JAK2V617F mutation was associated with significantly increased levels of platelet (p = 0.042), haemoglobin (p = 0.000), red blood cell (p = 0.000) and haematocrit (p = 0.000) and hepatomegaly (p = 0.045) at diagnosis compared to JAK2V617F negative counterparts, however there was no significant association between the JAK2V617F mutation status (relative risk: 1.297, 95 % CI 0.395-4.258; p = 0.668) and subsequent thrombotic complications. The impact of JAK2V617F, MPL W515L and CALR mutations on the clinical findings at the diagnosis of ET was obvious, but their statistically significant role in the prediction of thrombotic events could not be proven in this study. Our results indirectly support the concept that, besides the quantitative and qualitative changes in the platelets, the mechanisms leading to thrombosis are more complex and multifactorial.

Fungicidal activity of essential oils of Cinnamomum zeylanicum (L.) and Syzygium aromaticum (L.) Merr et L.M. Perry against crown rot and anthracnose pathogens isolated from banana.

Science.gov (United States)

Ranasinghe, L; Jayawardena, B; Abeywickrama, K

2002-01-01

To develop a post-harvest treatment system against post-harvest fungal pathogens of banana using natural products. Colletotrichum musae was isolated and identified as the causative agent responsible for anthracnose peel blemishes while three fungi, namely Lasiodiplodia theobromae, C. musae and Fusarium proliferatum, were identified as causative agents responsible for crown rot. During the liquid bioassay, cinnamon [Cinnamomum zeylanicum (L.)] leaf, bark and clove [Syzygium aromaticum (L.)] oils were tested against the anthracnose and crown rot pathogens. The test oils were fungistatic and fungicidal against the test pathogens within a range of 0.03-0.11% (v/v). Cinnamon and clove essential oils could be used as antifungal agents to manage post harvest fungal diseases of banana. Cinnamon and clove essential oil could be used as alternative post-harvest treatments on banana. Banana treated with essential oil is chemically safe and acceptable to consumers. Benomyl (Benlate), which is currently used to manage fungal pathogens, can cause adverse health effects and could be replaced with volatile essential oils.

Splenic irradiation in the treatment of patients with chronic myelogenous leukemia or myelofibrosis with myeloid metaplasia. Results of daily and intermittent fractionation with and without concomitant hydroxyurea

International Nuclear Information System (INIS)

Wagner, H. Jr.; McKeough, P.G.; Desforges, J.; Madoc-Jones, H.

1986-01-01

Seventeen patients with either chronic myelogenous leukemia (CML) or myelofibrosis with myeloid metaplasia (MMM) received 24 courses of splenic irradiation at this institution from 1973 to 1982. Eleven of the 17 patients had received prior chemotherapy. Patients were treated with 60 Co gamma rays or 6 MV photons. The fraction size ranged from 15 to 100 rad and the total dose per treatment course from 15 to 650 rad, with the exception of one patient who received 1650 rad. Fourteen of 19 courses (71%) given for splenic pain yielded significant subjective relief while 17 of 26 courses given for splenomegaly obtained at least 50% regression of splenic size. Blood counts were carefully monitored before each treatment to limit hematologic toxicity. From this experience, the authors conclude that splenic irradiation effectively palliates splenic pain and reverses splenomegaly in the majority of patients with CML and MMM. Intermittent fractionation (twice or thrice weekly) is more convenient for the patient, appears to be as effective as daily treatment, and may be associated with less hematologic toxicity. Preliminary results of concurrent treatment with splenic irradiation and oral hydroxyurea show promise and warrant further study

[Legal aspects of post-mortem radiology in the Netherlands].

Science.gov (United States)

Venderink, W; Dute, J C J

2016-01-01

In the Netherlands, the application of post-mortem radiology (virtual autopsy) is on the rise. Contrary to conventional autopsy, with post-mortem radiology the body remains intact. There is uncertainty concerning the legal admissibility of post-mortem radiology, since the Dutch Corpse Disposal Act does not contain any specific regulations for this technique. Autopsy and post-mortem radiology differ significantly from a technical aspect, but these differences do not have far-reaching legal consequences from a legal perspective. Even though the body remains intact during post-mortem radiology, the bodily integrity of a deceased person is breached if it would be applied without previously obtained consent. This permission can only be obtained after the relatives are fully informed about the proposed activity. In this respect, it is not relevant which technique is used, be it post-mortem radiology or autopsy. Therefore, the other legal conditions for post-mortem radiology are essentially identical to those for autopsy.

Deformation mechanism under essential work of fracture process in polycyclo-olefin materials

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2008-06-01

Full Text Available The fracture toughness of a glassy polycyclo-olefin (PCO was investigated by the essential work of fracture (EWF method using a double-edge notched specimens. It was shown that the PCO follows the EWF concept in the temperature range between room temperature and glass transition temperature Tg where the ligament yielding appear at a maximum point on the stress-displacement curves and subsequently the necking and tearing processes take place in the post yielding region. The essential work of fracture required for the ligament yielding drops as the temperature approaches Tg. The non-essential work of fracture attributed to tearing process after yielding is consumed to expand the plastic region and causes molecular chains to orient to the stretching direction.

Valorisation of post-sorption materials: Opportunities, strategies, and challenges.

Science.gov (United States)

Harikishore Kumar Reddy, D; Vijayaraghavan, K; Kim, Jeong Ae; Yun, Yeoung-Sang

2017-04-01

Adsorption is a facile, economic, eco-friendly and low-energy requiring technology that aims to separate diverse compounds (ions and molecules) from one phase to another using a wide variety of adsorbent materials. To date, this technology has been used most often for removal/recovery of pollutants from aqueous solutions; however, emerging post-sorption technologies are now enabling the manufacture of value-added key adsorption products that can subsequently be used for (i) fertilizers, (ii) catalysis, (iii) carbonaceous metal nanoparticle synthesis, (iv) feed additives, and (v) biologically active compounds. These new strategies ensure the sustainable valorisation of post-sorption materials as an economically viable alternative to the engineering of other green chemical products because of the ecological affability, biocompatibility, and widespread accessibility of post-sorption materials. Fertilizers and feed additives manufactured using sorption technology contain elements such as N, P, Cu, Mn, and Zn, which improve soil fertility and provide essential nutrients to animals and humans. This green and effective approach to managing post-sorption materials is an important step in reaching the global goals of sustainability and healthy human nutrition. Post-sorbents have also been utilized for the harvesting of metal nanoparticles via modern catalytic pyrolysis techniques. The resulting materials exhibited a high surface area (>1000m 2 /g) and are further used as catalysts and adsorbents. Together with the above possibilities, energy production from post-sorbents is under exploration. Many of the vital 3E (energy, environment, and economy) problems can be addressed using post-sorption materials. In this review, we summarize a new generation of applications of post-adsorbents as value-added green chemical products. At the end of each section, scientific challenges, further opportunities, and issues related to toxicity are discussed. We believe this critical

Determinants of post-partum anaemia – a cross sectional study ...

African Journals Online (AJOL)

Prevention and treatment of anaemia in post-natal women is essential in reducing maternal ... (WHO) criteria had further investigations done to determine the cause. ... Intermittent Preventive Therapy (IPT) administration during pregnancy were ...

Control of Colletotrichum gloeosporioides (penz.) Sacc. In yellow passion fruit using Cymbopogon citratus essential oil

Science.gov (United States)

Anaruma, Nina Duarte; Schmidt, Flávio Luís; Duarte, Marta Cristina Teixeira; Figueira, Glyn Mara; Delarmelina, Camila; Benato, liane Aparecida; Sartoratto, Adilson

2010-01-01

The use of antibiotics in agriculture is limited when compared to their applications in human and veterinary medicine. On the other hand, the use of antimicrobials in agriculture contributes to the drug resistance of human pathogens and has stimulated the search for new antibiotics from natural products. Essential oils have been shown to exert several biological activities including antibacterial and antifungal actions. The aim of this study was to determine the activity of 28 essential oils from medicinal plants cultivated at CPMA (Medicinal and Aromatic Plants Collection), CPQBA/UNICAMP, against Colletotrichum gloeosporioides (Penz.) Sacc., the anthracnose agent in yellow passion fruit (Passiflora edulis Sims f. flavicarpa Deg), as well as evaluating their effect in the control of post-harvest decay. The oils were obtained by water-distillation using a Clevenger-type system and their minimal inhibitory concentrations (MIC) determined by the micro-dilution method. According to the results, 15 of the 28 essential oils presented activity against Colletotrichum gloeosporioides, and the following four oils presented MIC values between 0.25 and 0.3 mg/mL: Coriandrum sativum, Cymbopogon citratus, Cymbopogon flexuosus and Lippia alba. The evaluation of Cymbopogon citratus essential oil in the control of post-harvest decay in yellow passion fruit showed that the disease index of the samples treated with the essential oil did not differ (P ≤ 0.05) from that of the samples treated with fungicide. The present study shows the potential of Cymbopogon citratus essential oil in the control of the anthracnose agent in yellow passion fruit. PMID:24031465

Control of Colletotrichum gloeosporioides (penz. Sacc. In yellow passion fruit using Cymbopogon citratus essential oil

Directory of Open Access Journals (Sweden)

Nina Duarte Anaruma

2010-03-01

Full Text Available The use of antibiotics in agriculture is limited when compared to their applications in human and veterinary medicine. On the other hand, the use of antimicrobials in agriculture contributes to the drug resistance of human pathogens and has stimulated the search for new antibiotics from natural products. Essential oils have been shown to exert several biological activities including antibacterial and antifungal actions. The aim of this study was to determine the activity of 28 essential oils from medicinal plants cultivated at CPMA (Medicinal and Aromatic Plants Collection, CPQBA/UNICAMP, against Colletotrichum gloeosporioides (Penz. Sacc., the anthracnose agent in yellow passion fruit (Passiflora edulis Sims f. flavicarpa Deg, as well as evaluating their effect in the control of post-harvest decay. The oils were obtained by water-distillation using a Clevenger-type system and their minimal inhibitory concentrations (MIC determined by the micro-dilution method. According to the results, 15 of the 28 essential oils presented activity against Colletotrichum gloeosporioides, and the following four oils presented MIC values between 0.25 and 0.3 mg/mL: Coriandrum sativum, Cymbopogon citratus, Cymbopogon flexuosus and Lippia alba. The evaluation of Cymbopogon citratus essential oil in the control of post-harvest decay in yellow passion fruit showed that the disease index of the samples treated with the essential oil did not differ (P < 0.05 from that of the samples treated with fungicide. The present study shows the potential of Cymbopogon citratus essential oil in the control of the anthracnose agent in yellow passion fruit.

Essential oil composition and antifungal activity of Melissa officinalis originating from north-Est Morocco, against postharvest phytopathogenic fungi in apples.

Science.gov (United States)

El Ouadi, Y; Manssouri, M; Bouyanzer, A; Majidi, L; Bendaif, H; Elmsellem, H; Shariati, M A; Melhaoui, A; Hammouti, B

2017-06-01

To investigate biological control methods against post-harvest phytopathogenic fungi in apples, tests on the antifungal activity of essential oil of Melissa officinalis were carried out. The essential oil, obtained by hydrodistillation, was analyzed by gas chromatography coupled with mass spectrometry (GC-MS). Analysis of the essential oil was able to detect 88.7% of the components. The main components are P-mentha-1,2,3-triol (13.1%), P-menth-3-en-8-ol (8.8%), pulegone (8.8%), piperitynone oxide (8.4%) and 2-piperitone oxide (7.3%). The determination of the antifungal activity of the essential oil of M. officinalisis carried out in vitro using the technique of poison food (PF) and the volatile activity test (VA). To carry out these two tests, three phytopathogens that cause the deterioration of apples have been selected: Botrytis cinerea, Penicillium expansum and Rhizopus stolonifer. The overall results of this study suggest that M. officinalis essential oil has potential as a bio-antifungal preservative for the control of post-harvest diseases of apple. Copyright © 2017 Elsevier Ltd. All rights reserved.

Loudspeaker Equalization with Post-Processing

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Ser Wee

2002-01-01

Full Text Available Loudspeaker equalization is an essential technique in audio system design. A well-known equalization scheme is based on the deconvolution of the desired equalized response with the measured impulse response of the loudspeaker. In this paper, a post-processing scheme is combined with the deconvolution-based algorithm to provide a better equalization effect. Computer simulation results are given to demonstrate the significant improvement that can be achieved using this method.

miRNA-mRNA integrative analysis in primary myelofibrosis CD34+ cells: role of miR-155/JARID2 axis in abnormal megakaryopoiesis

Science.gov (United States)

Norfo, Ruggiero; Zini, Roberta; Pennucci, Valentina; Bianchi, Elisa; Salati, Simona; Guglielmelli, Paola; Bogani, Costanza; Fanelli, Tiziana; Mannarelli, Carmela; Rosti, Vittorio; Pietra, Daniela; Salmoiraghi, Silvia; Bisognin, Andrea; Ruberti, Samantha; Rontauroli, Sebastiano; Sacchi, Giorgia; Prudente, Zelia; Barosi, Giovanni; Cazzola, Mario; Rambaldi, Alessandro; Bortoluzzi, Stefania; Ferrari, Sergio; Tagliafico, Enrico; Vannucchi, Alessandro M.

2014-01-01

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by megakaryocyte (MK) hyperplasia, bone marrow fibrosis, and abnormal stem cell trafficking. PMF may be associated with somatic mutations in JAK2, MPL, or CALR. Previous studies have shown that abnormal MKs play a central role in the pathophysiology of PMF. In this work, we studied both gene and microRNA (miRNA) expression profiles in CD34+ cells from PMF patients. We identified several biomarkers and putative molecular targets such as FGR, LCN2, and OLFM4. By means of miRNA-gene expression integrative analysis, we found different regulatory networks involved in the dysregulation of transcriptional control and chromatin remodeling. In particular, we identified a network gathering several miRNAs with oncogenic potential (eg, miR-155-5p) and targeted genes whose abnormal function has been previously associated with myeloid neoplasms, including JARID2, NR4A3, CDC42, and HMGB3. Because the validation of miRNA-target interactions unveiled JARID2/miR-155-5p as the strongest relationship in the network, we studied the function of this axis in normal and PMF CD34+ cells. We showed that JARID2 downregulation mediated by miR-155-5p overexpression leads to increased in vitro formation of CD41+ MK precursors. These findings suggest that overexpression of miR-155-5p and the resulting downregulation of JARID2 may contribute to MK hyperplasia in PMF. PMID:25097177

[Prognostic value of JAK2, MPL and CALR mutations in Chinese patients with primary myelofibrosis].

Science.gov (United States)

Xu, Z F; Li, B; Liu, J Q; Li, Y; Ai, X F; Zhang, P H; Qin, T J; Zhang, Y; Wang, J Y; Xu, J Q; Zhang, H L; Fang, L W; Pan, L J; Hu, N B; Qu, S Q; Xiao, Z J

2016-07-01

To evaluate the prognostic value of JAK2, MPL and CALR mutations in Chinese patients with primary myelofibrosis (PMF). Four hundred and two Chinese patients with PMF were retrospectively analyzed. The Kaplan-Meier method, the Log-rank test, the likelihood ratio test and the Cox proportional hazards regression model were used to evaluate the prognostic scoring system. This cohort of patients included 209 males and 193 females with a median age of 55 years (range: 15- 89). JAK2V617F mutations were detected in 189 subjects (47.0% ), MPLW515 mutations in 13 (3.2%) and CALR mutations in 81 (20.1%) [There were 30 (37.0%) type-1, 48 (59.3%) type-2 and 3 (3.7%) less common CALR mutations], respectively. 119 subjects (29.6%) had no detectable mutation in JAK2, MPL or CALR. Univariate analysis indicated that patients with CALR type-2 mutations or no detectable mutations had inferior survival compared to those with JAK2, MPL or CALR type- 1 or other less common CALR mutations (the median survival was 74vs 168 months, respectively [HR 2.990 (95% CI 1.935-4.619),P<0.001]. Therefore, patients were categorized into the high-risk with CALR type- 2 mutations or no detectable driver mutations and the low- risk without aforementioned mutations status. The DIPSS-Chinese molecular prognostic model was proposed by adopting mutation categories and DIPSS-Chinese risk group. The median survival of patients classified in low risk (132 subjects, 32.8% ), intermediate- 1 risk (143 subjects, 35.6%), intermediate- 2 risk (106 subjects, 26.4%) and high risk (21 subjects, 5.2%) were not reached, 156 (95% CI 117- 194), 60 (95% CI 28- 91) and 22 (95% CI 10- 33) months, respectively, and there was a statistically significant difference in overall survival among the four risk groups (P<0.001). There was significantly higher predictive power for survival according to the DIPSS-Chinese molecular prognostic model compared with the DIPSS-Chinese model (P=0.005, -2 log-likelihood ratios of 855.6 and 869

Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival

International Nuclear Information System (INIS)

Rubert, Joëlle; Qian, Zhiyan; Andraos, Rita; Guthy, Daniel A; Radimerski, Thomas

2011-01-01

The JAK2 V617F mutation plays a major role in the pathogenesis of myeloproliferative neoplasms and is found in the vast majority of patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia or from primary myelofibrosis. The V617F mutation is thought to provide hematopoietic stem cells and myeloid progenitors with a survival and proliferation advantage. It has previously been shown that activated JAK2 promotes cell survival by upregulating the anti-apoptotic STAT5 target gene Bcl-xL. In this study, we have investigated the role of additional apoptotic players, the pro-apoptotic protein Bim as well as the anti-apoptotic protein Mcl-1. Pharmacological inhibition of JAK2/STAT5 signaling in JAK2 V617F mutant SET-2 and MB-02 cells was used to study effects on signaling, cell proliferation and apoptosis by Western blot analysis, WST-1 proliferation assays and flow cytometry. Cells were transfected with siRNA oligos to deplete candidate pro- and anti-apoptotic proteins. Co-immunoprecipitation assays were performed to assess the impact of JAK2 inhibition on complexes of pro- and anti-apoptotic proteins. Treatment of JAK2 V617F mutant cell lines with a JAK2 inhibitor was found to trigger Bim activation. Furthermore, Bim depletion by RNAi suppressed JAK2 inhibitor-induced cell death. Bim activation following JAK2 inhibition led to enhanced sequestration of Mcl-1, besides Bcl-xL. Importantly, Mcl-1 depletion by RNAi was sufficient to compromise JAK2 V617F mutant cell viability and sensitized the cells to JAK2 inhibition. We conclude that Bim and Mcl-1 have key opposing roles in regulating JAK2 V617F cell survival and propose that inactivation of aberrant JAK2 signaling leads to changes in Bim complexes that trigger cell death. Thus, further preclinical evaluation of combinations of JAK2 inhibitors with Bcl-2 family antagonists that also tackle Mcl-1, besides Bcl-xL, is warranted to assess the therapeutic potential

Clinical Characteristics of Cerebrovascular Pathology with Patients Suffering from Ph-Negative Myeloproliferative Disease

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Marine M. Tanashyan

2016-09-01

Full Text Available Background: Disturbances of microcirculation play a significant role in the development and progression of both acute and chronic cerebrovascular diseases (CVD and may be associated with different hemogram abnormalities. One of the reasons of the prothrombogenic state of the endothelium is the increase in the number of blood corpuscles leading to (non-Ph myeloproliferative disorders (MPD including essential thrombocythemia (ET, polycythemia vera (PV, and primary myelofibrosis (PM. Materials and Methods: The study included 167 patients: 102 patients with Ph-MPD and the control group comprising 65 patients with CVD. According to MPD subtype, the patients were divided into three groups: patients with ET (37%, n = 38, male/female 7/31, age 52 ± 7 years, those with PV (40%, n = 41, male/female 20/21, age 50 ± 6 years and those with PM (23%, n = 23, male/female 5/18, age 54 ± 4 years. Results: In 79% (n = 81 of cases in the study group (with Ph-MPD, patients had chronic CVD, with the most frequently identified symptoms being asthenia (92% and headache (72%. Headache in Ph-MPD patients was more frequently (86% associated with PM, while in patients with PV and ET it was equally distributed (70%. Neurological symptoms in 53% of cases were associated with focal changes of the brain on MRI localized in the subcortical area of the frontal and parietal lobes. Twenty-one (21% patients suffered an acute cerebrovascular accident, 8 of them had thrombotic occlusion of one of the internal carotid arteries leading to hemispheric infarcts. Endothelial function (as measured by flow-dependent dilation of the brachial artery was severely impaired in all study groups (median 5% with normal cut-off at 10%, the lowest degree of vasodilator activity being specific for patients with a history of stroke (p = 0.011. Conclusion: Patients suffering from MPD had asymptomatic focal changes in the brain in the absence of concomitant vascular disease (hypertension

Burned bodies: post-mortem computed tomography, an essential tool for modern forensic medicine.

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Coty, J-B; Nedelcu, C; Yahya, S; Dupont, V; Rougé-Maillart, C; Verschoore, M; Ridereau Zins, C; Aubé, C

2018-06-07

Currently, post-mortem computed tomography (PMCT) has become an accessible and contemporary tool for forensic investigations. In the case of burn victims, it provides specific semiologies requiring a prudent understanding to differentiate between the normal post-mortem changes from heat-related changes. The aim of this pictorial essay is to provide to the radiologist the keys to establish complete and focused reports in cases of PMCT of burn victims. Thus, the radiologist must discern all the contextual divergences with the forensic history, and must be able to report all the relevant elements to answer to the forensic pathologist the following questions: Are there tomographic features that could help to identify the victim? Is there evidence of remains of biological fluids in liquid form available for toxicological analysis and DNA sampling? Is there another obvious cause of death than heat-related lesions, especially metallic foreign bodies of ballistic origin? Finally, what are the characteristic burn-related injuries seen on the corpse that should be sought during the autopsy? • CT is highly useful to find features permitting the identification of a severely burned body. • PMCT is a major asset in gunshot injuries to depict ballistic foreign bodies in the burned cadavers. • CT is able to recognise accessible blood for tests versus heat clot (air-crescent sign). • Heat-related fractures are easily differentiated from traumatic fractures. • Epidural collections with a subdural appearance are typical heat-related head lesions.

Survey of the capacity for essential surgery and anaesthesia services in Papua New Guinea

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Martin, Janet; Tau, Goa; Cherian, Meena Nathan; Vergel de Dios, Jennifer; Mills, David; Fitzpatrick, Jane; Adu-Krow, William; Cheng, Davy

2015-01-01

Objective To assess capacity to provide essential surgical services including emergency, obstetric and anaesthesia care in Papua New Guinea (PNG) in order to support planning for relevant post-2015 sustainable development goals for PNG. Design Cross-sectional survey. Setting Hospitals and health facilities in PNG. Participants 21 facilities including 3 national/provincial hospitals, 11 district/rural hospitals, and 7 health centres. Outcome measures The WHO Situational Analysis Tool to Assess Emergency and Essential Surgical Care (WHO-SAT) was used to measure each participating facility's capacity to deliver essential surgery and anaesthesia services, including 108 items related to relevant infrastructure, human resources, interventions and equipment. Results While major surgical procedures were provided at each hospital, fewer than 30% had uninterrupted access to oxygen, and 57% had uninterrupted access to resuscitation bag and mask. Most hospitals reported capacity to provide general anaesthesia, though few hospitals reported having at least one certified surgeon, obstetrician and anaesthesiologist. Access to anaesthetic machines, pulse oximetry and blood bank was severely limited. Many non-hospital health centres providing basic surgical procedures, but almost none had uninterrupted access to electricity, running water, oxygen and basic supplies for resuscitation, airway management and obstetric services. Conclusions Capacity for essential surgery and anaesthesia services is severely limited in PNG due to shortfalls in physical infrastructure, human resources, and basic equipment and supplies. Achieving post-2015 sustainable development goals, including universal healthcare, will require significant investment in surgery and anaesthesia capacity in PNG. PMID:26674504

MPLW515L mutation in acute megakaryoblastic leukaemia.

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Hussein, K; Bock, O; Theophile, K; Schulz-Bischof, K; Porwit, A; Schlue, J; Jonigk, D; Kreipe, H

2009-05-01

The thrombopoietin receptor gene (MPL) is expressed in megakaryocytes and exhibits the gain of function point mutation W515K/L in approximately 5% of patients with primary myelofibrosis/idiopathic myelofibrosis (PMF) representing one subtype of the chronic myeloproliferative disorders (myeloproliferative neoplasm). A series of primary and secondary acute myeloid leukaemias (AML) with megakaryoblastic phenotype and myelofibrosis unrelated to PMF (n=12) was analysed for the MPL(W515K/L) mutation by pyrosequencing. In three cases (25%), MPL(W515L) was found and in two of these a combination with trisomy 21 or the Philadelphia chromosome occurred. None of the secondary AML cases evolving from pre-existing PMF showed MPL(W515K/L) (n=4). We conclude that MPL(W515L) occurs in a considerable proportion of acute megakaryoblastic leukaemias with myelofibrosis unrelated to PMF.

Leaf elemental analysis in mycorrhizal post oak seedlings

Energy Technology Data Exchange (ETDEWEB)

Boling, B.C. [Department of Biology, University of North Texas, P.O. Box 305220, Denton, TX 76203-5220 (United States); Naab, F.U. [Ion Beam Modification and Analysis Laboratory, Department of Physics, University of North Texas, P.O. Box 311427, Denton, TX 76203-1427 (United States)]. E-mail: fun001@unt.edu; Smith, D. [Department of Biology, University of North Texas, P.O. Box 305220, Denton, TX 76203-5220 (United States); Duggan, J.L. [Ion Beam Modification and Analysis Laboratory, Department of Physics, University of North Texas, P.O. Box 311427, Denton, TX 76203-1427 (United States); McDaniel, F.D. [Ion Beam Modification and Analysis Laboratory, Department of Physics, University of North Texas, P.O. Box 311427, Denton, TX 76203-1427 (United States)

2006-09-15

Growth and element assimilation was investigated in the leaves of post oak seedlings exposed to four different treatment combinations of fertilization and ectomycorrhizal inoculation. Element concentration was analyzed via particle-induced X-ray emission spectrometry (PIXE). PIXE detected 10 of the 13 essential macro and micronutrients: P, S, Mg, Ca, K, Cu, Zn, Mn, Fe and Cl. Mean growth and dry weight was significantly different across the treatment groups as well as the mean concentration of Mg, Al, S, K, Ca, Fe, Cu and Zn. The data suggest that fertilization rather than mycorrhizal inoculation had a stronger influence on nutrient uptake. This study is the first to analyze element concentration in post oak and to investigate the potential benefits of mycorrhizal symbiosis in post oak seedlings in terms of nutrient uptake.

Training traditional birth attendants on the WHO Essential Newborn Care reduces perinatal mortality.

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Garcés, Ana; McClure, Elizabeth M; Hambidge, Michael; Krebs, Nancy F; Mazariegos, Manolo; Wright, Linda L; Moore, Janet; Carlo, Waldemar A

2012-05-01

To evaluate the impact of birth attendant training using the World Health Organization Essential Newborn Care (ENC) course among traditional birth attendants, with a particular emphasis on the effect of acquisition of skills on perinatal outcomes. Population-based, prospective, interventional pre-post design study. 11 rural clusters in Chimaltenango, Guatemala. Health care providers. This study analyzed the effect of training and implementation of the ENC health care provider training course between September 2005 and December 2006. The primary outcome measure was the rate of death from all causes in the first seven days after birth in fetuses/infants ≥1500g. Secondary outcome measures were overall rate of stillbirth, rate of perinatal death, which included stillbirths plus neonatal deaths in the first seven days in fetuses/infants ≥1500g. Perinatal mortality decreased from 39.5/1000 pre-ENC to 26.4 post-ENC (RR 0.72; 95%CI 0.54-0.97). This reduction was attributable almost entirely to a decrease in the stillbirth rate of 21.4/1000 pre-Essential Newborn Care to 7.9/1000 post-ENC (RR 0.40; 95%CI 0.25-0.64). Seven-day neonatal mortality did not decrease (18.3/1000 to 18.6/1000; RR 1.05; 95%CI 0.70-1.57). Essential Newborn Care training reduced stillbirths in a population-based controlled study with deliveries conducted almost exclusively by traditional birth attendants. Scale-up of this intervention in other settings might help assess reproducibility and sustainability. © Published [2012]. This article is a U.S. Government work and is in the public domain in the USA. Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.

"Where Is the Post-Modern Truth We Have Lost in Reductionist Knowledge?" A Curriculum's Epitaph

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Slabbert, Johannes A.; Hattingh, Annemarie

2006-01-01

This essay suggests a way for creating a curriculum for the future amidst the challenges of post-modern uncertainty. Curriculum discourse in the past has been dominated by widely-accepted key questions, which produce and maintain curricula that are essentially fragmented and reductionistic, and directly opposed to the essential demands of the…

Reconstruction versus Transformation: Post-War Education and the Struggle for Gender Equity in Sierra Leone

Science.gov (United States)

Maclure, Richard; Denov, Myriam

2009-01-01

In post-war contexts, education is widely regarded as essential not only for civic reconciliation, but also as a key force for gender equity. In Sierra Leone, however, despite enhanced educational opportunities for girls, much of the emphasis on post-war educational reconstruction is unlikely to rectify gender inequities that remain entrenched…

Tuberculosis post-liver transplantation: a rare but complicated disease.

Science.gov (United States)

Lu, W; Wai, C T; Da Costa, M; Tambyah, P A; Prabhakaran, K; Lee, K H

2005-03-01

Tuberculosis is a rare but serious complication after transplantation. We report a case and discuss its presentation and management. A 60-year-old Indonesian male presented initially with fever, acute confusion and rapidly progressive right upper lobe pneumonia 3.5 months post-liver transplant, and was diagnosed with pulmonary tuberculosis by positive sputum smear for acid-fast bacilli and tuberculosis culture. Standard anti-tuberculosis therapy was administered but was complicated by interaction with cyclosporine and drug-induced cholestasis. A high level of suspicion, prompt antituberculosis treatment and close follow-up are essential in management of post-transplant tuberculosis.

Pre-, intra- and post-operative imaging of cochlear implants

Energy Technology Data Exchange (ETDEWEB)

Vogl, T.J.; Naguib, N.N.N.; Burck, I. [University Hospital Frankfurt (Germany). Inst. of Diagnostic and Interventional Radiology; Tawfik, A. [Mansoura Univ. (Egypt). Dept. of Diagnostic and Interventional Radiology; Emam, A. [University Hospital Alexandria (Egypt). Dept. of Diagnostic and Interventional Radiology; Nour-Eldin, A. [University Hospital Cairo (Egypt). Dept. of Radiology; Stoever, T. [University Hospital of Frankfurt (Germany). Dept. of Otolaryngology

2015-11-15

The purpose of this review is to present essential imaging aspects in patients who are candidates for a possible cochlear implant as well as in postsurgical follow-up. Imaging plays a major role in providing information on preinterventional topography, variations and possible infections. Preoperative imaging using DVT, CT, MRI or CT and MRI together is essential for candidate selection, planning of surgical approach and exclusion of contraindications like the complete absence of the cochlea or cochlear nerve, or infection. Relative contraindications are variations of the cochlea and vestibulum. Intraoperative imaging can be performed by fluoroscopy, mobile radiography or DVT. Postoperative imaging is regularly performed by conventional X-ray, DVT, or CT. In summary, radiological imaging has its essential role in the pre- and post-interventional period for patients who are candidates for cochlear implants.

The role of post accident chemistry data in nuclear safety

International Nuclear Information System (INIS)

Bradshaw, R.W.; Caruthers, G.F.

1982-01-01

The NRC instituted the NUREG-0737 requirements as implementation of the Post-TMI Action Plan in October, 1980. Among these requirements was the capability to obtain chemistry samples of the reactor coolant and containment building atmosphere under post accident conditions. The quantitative criteria were, in general, beyond the capabilities of existing plant systems. As a consequence the nuclear industry expended substantial efforts to design and install the post-accident sampling systems necessary to comply with these criteria. With such efforts essentially complete, the task remains to establish the role that data provided by these systems would play in mitigating the consequences of a nuclear plant accident. This role definition must include a characterization of the timing and priority for the post accident chemistry data. This paper defines that role using the Safety Level and Safety Function concepts as a matrix

Systematic identification of novel, essential host genes affecting bromovirus RNA replication.

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Brandi L Gancarz

Full Text Available Positive-strand RNA virus replication involves viral proteins and cellular proteins at nearly every replication step. Brome mosaic virus (BMV is a well-established model for dissecting virus-host interactions and is one of very few viruses whose RNA replication, gene expression and encapsidation have been reproduced in the yeast Saccharomyces cerevisiae. Previously, our laboratory identified ∼100 non-essential host genes whose loss inhibited or enhanced BMV replication at least 3-fold. However, our isolation of additional BMV-modulating host genes by classical genetics and other results underscore that genes essential for cell growth also contribute to BMV RNA replication at a frequency that may be greater than that of non-essential genes. To systematically identify novel, essential host genes affecting BMV RNA replication, we tested a collection of ∼900 yeast strains, each with a single essential gene promoter replaced by a doxycycline-repressible promoter, allowing repression of gene expression by adding doxycycline to the growth medium. Using this strain array of ∼81% of essential yeast genes, we identified 24 essential host genes whose depleted expression reproducibly inhibited or enhanced BMV RNA replication. Relevant host genes are involved in ribosome biosynthesis, cell cycle regulation and protein homeostasis, among other cellular processes. BMV 2a(Pol levels were significantly increased in strains depleted for a heat shock protein (HSF1 or proteasome components (PRE1 and RPT6, suggesting these genes may affect BMV RNA replication by directly or indirectly modulating 2a(Pol localization, post-translational modification or interacting partners. Investigating the diverse functions of these newly identified essential host genes should advance our understanding of BMV-host interactions and normal cellular pathways, and suggest new modes of virus control.

Change in Caco-2 cells following treatment with various lavender essential oils.

Science.gov (United States)

Donadu, M G; Usai, D; Mazzarello, V; Molicotti, P; Cannas, S; Bellardi, M G; Zanetti, S

2017-09-01

Lavender is an aromatic evergreen shrub diffused in the Mediterranean basin appreciated since antiquity. The genus Lavandula is part of Lamiaceae family and includes more than 20 species, among which true lavender (L. vera D.C. or L. angustifolia Miller.) and spike lavender (L. latifolia Medikus); there are also numerous hybrids known as lavandins (L. hybrida Rev.). L. vera, spike lavender and several hybrids are the most intensely used breeding species for the production of essential oils. Lavender and lavandin essential oils have been applied in food, pharmaceutical and other agro industries as biological products. In their chemical composition, terpenes linalool and linalyl acetate along with terpenoids such as 1,8-cineole are mostly responsible for biological and therapeutic activities. This study evaluates cytotoxic activity of essential oils derived from four lavender species on human epithelial colorectal adenocarcinoma cells. Analysis of pre- and post-treatment cell morphology has been performed using scanning electron microscope.

Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen

DEFF Research Database (Denmark)

Nieswandt, B; Brakebusch, C; Bergmeier, W

2001-01-01

Platelet adhesion on and activation by components of the extracellular matrix are crucial to arrest post-traumatic bleeding, but can also harm tissue by occluding diseased vessels. Integrin alpha2beta1 is thought to be essential for platelet adhesion to subendothelial collagens, facilitating subs...

Clinical features and outcomes of patients with primary myelofibrosis in Japan: report of a 17-year nationwide survey by the Idiopathic Disorders of Hematopoietic Organs Research Committee of Japan.

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Takenaka, Katsuto; Shimoda, Kazuya; Uchida, Naoyuki; Shimomura, Taizo; Nagafuji, Koji; Kondo, Tadakazu; Shibayama, Hirohiko; Mori, Takehiko; Usuki, Kensuke; Azuma, Taichi; Tsutsumi, Yutaka; Tanaka, Junji; Dairaku, Hitomi; Matsuo, Keitaro; Ozawa, Keiya; Kurokawa, Mineo; Arai, Shunya; Akashi, Koichi

2017-01-01

We conducted a 17-year nationwide survey (1999-2015) to elucidate the clinical outcomes of patients with primary myelofibrosis (PMF) in Japan. Questionnaires were sent annually to approximately 500 hematology departments. Newly diagnosed patients with PMF were enrolled in this study, and were followed up annually to collect prognostic information. Approximately 50 patients were enrolled per year, yielding a total of 780 patients with PMF included in this study. The median age at diagnosis was 66 years. At the time of analysis, the median survival duration was 47 months, and the 3-year overall survival rate was 59 %. Infection and disease transformation into acute leukemia were the most frequent causes of death. Of the proposed prognostic models for predicting the outcomes of PMF patients in Japan, the Dynamic International Prognostic Scoring System of PMF plus model was the most feasible. Forty-three patients received allogeneic hematopoietic stem cell transplantation (alloSCT) at a median of 343 days after diagnosis. This treatment significantly prolonged the survival of PMF patients, and the 3-year overall survival rate after first alloSCT was 84 %. A long-term registration study is required for further evaluation of prognosis and the impact of treatments on survival.

Pre-operative assessment and post-operative care in elective shoulder surgery.

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Akhtar, Ahsan; Macfarlane, Robert J; Waseem, Mohammad

2013-01-01

Pre-operative assessment is required prior to the majority of elective surgical procedures, primarily to ensure that the patient is fit to undergo surgery, whilst identifying issues that may need to be dealt with by the surgical or anaesthetic teams. The post-operative management of elective surgical patients begins during the peri-operative period and involves several health professionals. Appropriate monitoring and repeated clinical assessments are required in order for the signs of surgical complications to be recognised swiftly and adequately. This article examines the literature regarding pre-operative assessment in elective orthopaedic surgery and shoulder surgery, whilst also reviewing the essentials of peri- and post-operative care. The need to recognise common post-operative complications early and promptly is also evaluated, along with discussing thromboprophylaxis and post-operative analgesia following shoulder surgery.

Enfartes Esplénicos – quando a etiologia é multifactorial: Mutação do gene MTHFR e Trombocitose Essencial

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Marta Pereira

2016-06-01

Full Text Available INTRODUCTION: Essential thrombocythemia (ET is a rare chronic myeloproliferative disease associated with an increased risk of thrombotic events in up to 50% of all patients. In patients with hyperhomocysteinemia associated with MTHFR mutation in homozigozity, the risk for thrombotic events is increased in 1-2%. Therefore, the coexistence of these two clinical entities causes an exponential rise in the risk for ischemic phenomena. CASE REPORT: A 56-year-old male, a smoker with previously known dyslipidemia and cerebrovascular disease was admitted to our hospital for epigastric and left hypochondrium pain for two months. Imagiological studies showed splenomegaly and several lesions suggestive of splenic infarction. Laboratory studies revealed leukocytosis (12900/μL, thrombocythemia (570x103/μL, reduced folic acid levels (0.90 ng/mL and hyperhomocysteinemia (42.5 μmol/L. MTHFR c.677C>T mutation was positive (homozygous. His bone marrow showed characteristics suggestive of ET and JAK2 V612F was positive (heterozygous with bcr-abl mutation negative. Aspirine and hydroxyurea were started as well as vitaminic supplementation, with good response. DISCUSSION: The present case reflects the association between two unusual clinical entities, in which thrombotic phenomena are very common, particularly in the vascular territorries involved in this patient. We highlight the importance of a quick diagnosis and treatment, the main keys for a survival rate similar to the general population.

USP7 is a SUMO deubiquitinase essential for DNA replication

DEFF Research Database (Denmark)

Lecona, Emilio; Rodriguez-Acebes, Sara; Specks, Julia

2016-01-01

Post-translational modification of proteins by ubiquitin (Ub) and Ub-like modifiers regulates DNA replication. We have previously shown that chromatin around replisomes is rich in SUMO and poor in Ub, whereas mature chromatin exhibits an opposite pattern. How this SUMO-rich, Ub-poor environment...... is maintained at sites of DNA replication in mammalian cells remains unexplored. Here we identify USP7 as a replisome-enriched SUMO deubiquitinase that is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 counteracts their ubiquitination. Inhibition or genetic deletion of USP7 leads...... to the accumulation of Ub on SUMOylated proteins, which are displaced away from replisomes. Our findings provide a model explaining the differential accumulation of SUMO and Ub at replication forks and identify an essential role of USP7 in DNA replication that should be considered in the development of USP7...

An attempt of postharvest orange fruit rot control using essential oils from Mediterranean plants.

Science.gov (United States)

Camele, Ippolito; De Feo, Vincenzo; Altieri, Luciana; Mancini, Emilia; De Martino, Laura; Luigi Rana, Gian

2010-12-01

Twelve essential oils from Mediterranean aromatic plants were tested at different doses against four fungi known as causal agents of post-harvest orange fruit rot: Botrytis cinerea, Penicillium italicum, Phytophthora citrophthora, and Rhizopus stolonifer. Essential oils were obtained from Hyssopus officinalis, Lavandula angustifolia, Majorana hortensis, Melissa officinalis, Ocimum basilicum, Origanum vulgare, Salvia officinalis, and Thymus vulgaris (Family Lamiaceae), Verbena officinalis (Family Verbenaceae), and Pimpinella anisum, Foeniculum vulgare, and Carum carvi (Family Apiaceae). Because preliminary in vitro experiments showed that only the oils from V. officinalis, T. vulgaris, and O. vulgare exhibited some fungistatic activity against the above-named fungi, these three essential oils were used in successive in vivo tests carried out to protect healthy "Washington navel" orange fruits from artificial infection by the same micromycetes. The essential oil of T. vulgaris, at a 2,000 ppm dose, controlled fruit rot by B. cinerea, P. citrophthora, and R. stolonifer but was ineffective against P. italicum. Essential oils of V. officinalis and O. vulgare inhibited infection by the first two fungi and only by P. citrophthora, respectively. This finding represents an important result, with the goal of using the essential oils as natural preservatives for food products, due to their positive effect on their safety and shelf life.

Combined effect of ultrasound and essential oils to reduce Listeria monocytogenes on fresh produce.

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Özcan, Gülçin; Demirel Zorba, Nükhet Nilüfer

2016-06-01

Salads prepared from contaminated fresh produce have a high risk of causing food-borne illnesses. Essential oils obtained from plants have antimicrobial activity and may provide a natural approach to reduce the pathogens on fresh produce. Additionally, ultrasound treatments have been shown to reduce the microbial counts on different foods. The objective of this study was to investigate the antimicrobial activities of cinnamon and lemon essential oils in vitro and in food applications. Mixtures of lettuce, parsley and dill were inoculated with Listeria monocytogenes and then dip-treated for 5 min in one of the following treatments: sterile tap water, chlorinated water, 1% lemon essential oil, 2% cinnamon essential oil or 2% cinnamon essential oil + ultrasound. The samples were stored at 4 ℃ and collected at d 0, 1, 3, 5, 7 and 9 post inoculation. The 1% lemon (4 log) and 2% cinnamon (2 log) essential oil washes provided partial inhibition against L. monocytogenes by d 1. The combined application of 2% cinnamon oil and ultrasound resulted in only 0.85 log inhibition by d 1; however, the number of L. monocytogenes increased during storage and became nearly equal to the control at d 9. Therefore, different combinations of essential oils with other antimicrobials or novel technologies are required. © The Author(s) 2015.

Linguistic Culture and Essentialism in South Africa

Directory of Open Access Journals (Sweden)

Stephanie Rudwick

2008-10-01

Full Text Available This paper explores how language and culture are intertwined and often regarded as “invariable fixed properties” in contemporary South Africa by focusing on one particular indigenous African language group, i.e. isiZulu-speakers. Drawing from general theoretical sociolinguistic approaches to language and culture and considering South Africa’s socio-political history, the paper demonstrates the significance and saliency of Zulu linguistic culture to Zulu people in the post-apartheid state. It is examined, how Zulu linguistic culture is regarded a resource in the isiZulu-speaking community and as one of the most salient tools of in-group identification in the larger contemporary South African society. Zulu people’s culture is profoundly language-embedded and Zulu linguistic culture often based on essentialism.

Functional Integrity of the Retrosplenial Cortex Is Essential for Rapid Consolidation and Recall of Fear Memory

Science.gov (United States)

Katche, Cynthia; Dorman, Guido; Slipczuk, Leandro; Cammarota, Martin; Medina, Jorge H.

2013-01-01

Memory storage is a temporally graded process involving different phases and different structures in the mammalian brain. Cortical plasticity is essential to store stable memories, but little is known regarding its involvement in memory processing. Here we show that fear memory consolidation requires early post-training macromolecular synthesis in…

USP7 is a SUMO deubiquitinase essential for DNA replication

Science.gov (United States)

Lecona, Emilio; Rodriguez-Acebes, Sara; Specks, Julia; Lopez-Contreras, Andres J; Ruppen, Isabel; Murga, Matilde; Muñoz, Javier; Mendez, Juan; Fernandez-Capetillo, Oscar

2016-01-01

Post-translational modification of proteins by ubiquitin (Ub) and Ub-like modifiers regulates various aspects of DNA replication. We previously showed that the chromatin around replisomes is rich in SUMO and depleted in Ub, whereas an opposite pattern is observed in mature chromatin. How this SUMO-rich/Ub-low environment is maintained at sites of DNA replication is not known. Here we identify USP7 as a replisome-enriched SUMO deubiquitinase that is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 counteracts their ubiquitination. Chemical inhibition or genetic deletion of USP7 leads to the accumulation of Ub on SUMOylated proteins, which are displaced to chromatin away from replisomes. Our findings provide a model to explain the differential accumulation of SUMO and Ub at replication forks, and identify an essential role of USP7 in DNA replication that should be taken into account for the use of USP7 inhibitors as anticancer agents. PMID:26950370

Astronomy essentials

CERN Document Server

Brass, Charles O

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Astronomy includes the historical perspective of astronomy, sky basics and the celestial coordinate systems, a model and the origin of the solar system, the sun, the planets, Kepler'

Essential health benefits and the Affordable Care Act: law and process.

Science.gov (United States)

Bagley, Nicholas; Levy, Helen

2014-04-01

Starting in 2014, the Affordable Care Act (ACA) will require private insurance plans sold in the individual and small-group markets to cover a roster of "essential health benefits." Precisely which benefits should count as essential, however, was left to the discretion of the Department of Health and Human Services (HHS). The matter was both important and controversial. Nonetheless, HHS announced its policy by posting on the Internet a thirteen-page bulletin stating that it would allow each state to define essential benefits for itself. On both substance and procedure, the move was surprising. The state-by-state approach departed from the uniform, federal standard that the ACA appears to anticipate and that informed observers expected HHS to adopt. And announcing the policy through an Internet bulletin appeared to allow HHS to sidestep traditional administrative procedures, including notice and comment, immediate review in the courts, and White House oversight. This article explores two questions. First, is the state-by-state approach a lawful exercise of HHS's authority? Second, did HHS in fact evade the procedural obligations that are meant to shape the exercise of its discretion?

Class Room Seminar and Journal Club (CRSJC) as an Effective Teaching Learning Tool: Perception to Post Graduation Pharmacy Students

Science.gov (United States)

Dahiya, Sunita; Dahiya, Rajiv

2015-01-01

Theory and practicals are two essential components of pharmacy course curriculum; but in addition to appearing and passing examination with good score grades, pharmacy post graduation (PG) pursuing students are essentially required to develop some professional skills which might not be attained solely by conventional class room programs. This…

Dual extraction of essential oil and podophyllotoxin from creeping juniper (Juniperus horizontalis.

Directory of Open Access Journals (Sweden)

Charles L Cantrell

Full Text Available Juniperus horizontalis Moench (Family Cupressaceae, commonly called creeping juniper, is a widely distributed species in the United States and much of Canada. It is potentially a source for two important chemical products, the anticancer drug synthetic precursor, podophyllotoxin and essential oils. The objectives of this study were to ascertain the likelihood of utilizing J. horizontalis needles for the simultaneous production of both (--podophyllotoxin and essential oil components and to determine the optimum distillation time (DT needed for the production of essential oil containing a specific ratio of constituents. Eleven different distillation times were tested in this study: 20, 40, 80, 160, 180, 240, 480, 600, 720, 840, and 960 min. Total essential oil content increased with increasing distillation time from a minimum of 0.023% at 20 min to a maximum of 1.098% at 960 min. The major constituents present in the oil were alpha-pinene, sabinene, and limonene. The percent concentration of sabinene in the essential oil varied from a high of 46.6% at 80 min to a low of 30.2% at 960 min, that of limonene changed very little as a result of distillation time and remained near 30% for all distillation times, whereas the concentration of alpha-pinene was 9.6% at 20 min DT and decreased to 4.2% at 960 min. Post distillation analysis of needles revealed elevated amounts of (--podophyllotoxin remaining in the tissue varied in the amount of podophyllotoxin present, from a low of 0.281% to a high of 0.364% as compared to undistilled needles which gave 0.217% podophyllotoxin. As a result of this study, specific essential oil components can now be targeted in J. horizontalis by varying the distillation time. Furthermore, needles can be successfully utilized as a source of both essential oil and podophyllotoxin, consecutively.

A Framework for ERP Post-Implementation Amendments: A Literature Analysis

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Taiwo Oseni

2017-06-01

Full Text Available Post-implementation amendments to ERP systems (ERP-PIA are of importance for advancing ERP research, but more importantly essential if ERP systems are to be used as a strategic and competitive business tool. For ease of clarity, we have adopted the term “amendments” to encompass the main forms of post implementation activities: maintenance, enhancements and upgrades. The term ‘amendments’ is used to counteract one of the major findings from this research - the inconsistency of terms used by many authors to explain post implementation activities. This paper presents a review of the ERP post-implementation amendment literature in order to provide answers to two specific questions: first, what is the current state of research in the field of ERP-PIA; and second, what are the future research directions that need to be explored in the field of ERP-PIA. From the review, we develop a framework to identify: (a major themes concerning ERP post-implementation amendments, (b inherent gaps in the post-implementation amendments literature, and (c specific areas that require further research attention influencing the uptake of amendments. Suggestions on empirical evaluation of research directions and their relevance in the extension of existing literature is presented.

Development of a provisional essential medicines list for children in Canada: consensus process.

Science.gov (United States)

Woods, Hannah; Oronsaye, Efosa; Bali, Anjli; Rajakulasingam, Yathavan; Lee, Taehoon; Umali, Norman; Cohen, Eyal; Finkelstein, Yaron; Offringa, Martin; Persaud, Nav

2018-03-26

Worldwide, many countries have developed a list of essential medicines for children to improve prescribing. We aimed to create an essential medicines list for children in Canada. We adapted the previously created preliminary list of essential medicines for adults in Canada and the WHO Model List of Essential Medicines for Children to create a provisional list of essential medicines for children in Canada. Canadian clinicians made suggestions for changes. Literature relevant to each suggestion was presented to clinician-scientists, who used a modified nominal group technique to make recommendations on the suggestions. Ontario Public Drug Programs prescription data were reviewed to identify commonly prescribed medications missing from the list. Literature relevant to these medications was shared with a clinician-scientist review panel to determine which should be added, and a revised list was developed. A total of 76 items were removed from the list of essential medicines for adults in Canada because they were not indicated for use in children or were not relevant in the Canadian health care context; 7 medications were added to the child list based on Ontario Public Drugs Programs prescribing data and clinician-scientist review. Suggestions to add, remove or substitute medications were made by peer-reviewers and resulted in removal of 1 medication and replacement of 1 medication. The process produced a provisional list of 67 essential medications for children. A provisional list of 67 essential medicines for children was created through a peer-reviewed, multistep process based on current clinical evidence, Canadian clinical practice guidelines and historical prescribing data. It is publicly posted at http://cleanmeds.ca/. The list should be further developed based on wider input and should be continuously revised based on emerging evidence of the safety and effectiveness of these medicines in all pediatric age groups. Copyright 2018, Joule Inc. or its licensors.

KNIME essentials

CERN Document Server

Bakos, Gábor

2013-01-01

KNIME Essentials is a practical guide aimed at getting the results you want, as quickly as possible.""Knime Essentials"" is written for data analysts looking to quickly get up to speed using the market leader in data processing tools, KNIME. No knowledge of KNIME is required, but we will assume that you have some background in data processing.

A Contemporary Introduction to Essential Oils: Chemistry, Bioactivity and Prospects for Australian Agriculture

Directory of Open Access Journals (Sweden)

Nicholas Sadgrove

2015-03-01

Full Text Available This review is a comprehensive introduction to pertinent aspects of the extraction methodology, chemistry, analysis and pharmacology of essential oils, whilst providing a background of general organic chemistry concepts to readers from non-chemistry oriented backgrounds. Furthermore, it describes the historical aspects of essential oil research whilst exploring contentious issues of terminology. This follows with an examination of essential oil producing plants in the Australian context with particular attention to Aboriginal custom use, historical successes and contemporary commercial prospects. Due to the harsh dry environment of the Australian landmass, particularly to the cyclical climatic variation attendant upon repeated glaciation/post-glaciation cycles, the arid regions have evolved a rich assortment of unique endemic essential oil yielding plants. Though some of these aromatic plants (particularly myrtaceous species have given birth to commercially valuable industries, much remains to be discovered. Given the market potential, it is likely that recent discoveries in our laboratory and elsewhere will lead to new product development. This review concludes with an emphasis on the use of chemotaxonomy in selection of commercially viable cultivar chemotypes from the Australian continent. Finally, drawing largely from our own results we propose a list of Australian endemic species with novel commercial potential.

Plant essential oils and potassium metabisulfite as repellents for Drosophila suzukii (Diptera: Drosophilidae)

Science.gov (United States)

Renkema, Justin M.; Wright, Derek; Buitenhuis, Rose; Hallett, Rebecca H.

2016-01-01

Spotted wing drosophila, Drosophila suzukii, is a globally invasive pest of soft-skinned fruit. Females oviposit into ripening fruit and larvae cause direct destruction of tissues. As many plant essential oils are permitted food additives, they may provide a safe means of protecting fruit from D. suzukii infestation in both conventional and organic production systems. Twelve oils and potassium metabisulfite (KMS) were screened in the laboratory as repellents for D. suzukii flies. Most essential oils deterred D. suzukii flies from cotton wicks containing attractive raspberry juice. Peppermint oil was particularly effective, preventing almost all flies from contacting treated wicks and remaining 100% repellent for 6 d post-application. Thyme oil was unique because it caused high male mortality and reduced the number of responding flies compared to other oils. KMS was not found to be repellent to D. suzukii, but may have fumigant properties, particularly at high concentrations. Peppermint oil appears to be the best candidate for field testing to determine the effectiveness and feasibility of using essential oils as part of a push-pull management strategy against D. suzukii. This is the first time that essential oils have been evaluated and proven effective in preventing fruit-infesting flies from contacting attractive stimuli. PMID:26893197

Carbon Dioxide Reduction Post-Processing Sub-System Development

Science.gov (United States)

Abney, Morgan B.; Miller, Lee A.; Greenwood, Zachary; Barton, Katherine

2012-01-01

The state-of-the-art Carbon Dioxide (CO2) Reduction Assembly (CRA) on the International Space Station (ISS) facilitates the recovery of oxygen from metabolic CO2. The CRA utilizes the Sabatier process to produce water with methane as a byproduct. The methane is currently vented overboard as a waste product. Because the CRA relies on hydrogen for oxygen recovery, the loss of methane ultimately results in a loss of oxygen. For missions beyond low earth orbit, it will prove essential to maximize oxygen recovery. For this purpose, NASA is exploring an integrated post-processor system to recover hydrogen from CRA methane. The post-processor, called a Plasma Pyrolysis Assembly (PPA) partially pyrolyzes methane to recover hydrogen with acetylene as a byproduct. In-flight operation of post-processor will require a Methane Purification Assembly (MePA) and an Acetylene Separation Assembly (ASepA). Recent efforts have focused on the design, fabrication, and testing of these components. The results and conclusions of these efforts will be discussed as well as future plans.

Effect of edible coatings with essential oils on the quality of red raspberries over shelf-life.

Science.gov (United States)

Gomes, Marcos de Souza; Cardoso, Maria das Graças; Guimarães, Ana Clara Garcia; Guerreiro, Adriana Cavaco; Gago, Custódia Maria Luís; Vilas Boas, Eduardo Valério de Barros; Dias, Cristina Maria Barrocas; Manhita, Ana Cristina Cabaça; Faleiro, Maria Leonor; Miguel, Maria Graça Costa; Antunes, Maria Dulce Carlos

2017-02-01

The objective of the present work was to develop strategies for increasing the shelf-life of red raspberries (Rubus idaeus L.), by preventing microorganism growth. Fruits coated with alginate plus lemon essential oil (0.2%) or orange essential oil (0.1%) after 15 days of storage had less red skin than the remaining samples. The less red color verified in these samples was also coincident with the lower concentration of anthocyanins at the end of the experiment as well as the lower capacity for scavenging ABTS free radicals or quenching singlet oxygen. Cyanidin and pelargonidin glucosides were found in raspberries fruits. The edible coatings supplemented with the essential oil of orange either at 0.1% or 0.2% were very efficient for controlling yeast and mold growth after 15 days of storage. To control the development of aerobic mesophilic bacteria the use of essential oil of lemon 0.2% and essential oil of orange 0.1% were the most efficient. The application of the film improved post-harvest quality of raspberry, since the addition of essential oils of citrus films promoted to the inhibitory effect of fungi and bacteria growth after 15 days of storage, without changing quality parameters. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

The Effect of Mechanical Wounding on the Composition of Essential Oil from Ocimum Minimum L. Leaves

Directory of Open Access Journals (Sweden)

S. Grant Wyllie

2001-01-01

Full Text Available The effect of mechanical damage on the composition of the essential oil obtained from eugenol-rich Ocimum minimum leaves was determined over 48 hours. Changes in the levels of five oil-constituents were detected in the first post-wounding day but only one of those components (camphor exhibited the same behaviour the day after. The levels of eugenol (-4.8% and linalool (+2.5% were affected the most by the wounding process. Principal component analysis (PCA showed the post-wounding response to be independent from the pre-wounding levels of the particular compounds expressing the response and from the overall leaf oil-composition.

Should I Take Further Mathematics? Physics Undergraduates' Experiences of Post-Compulsory Mathematics

Science.gov (United States)

Bowyer, Jessica; Darlington, Ellie

2017-01-01

It is essential that physics undergraduates are appropriately prepared for the mathematical demands of their course. This study investigated physics students' perceptions of post-compulsory mathematics as preparation for their degree course. 494 physics undergraduates responded to an online questionnaire about their experiences of A-level…

Modern algebra essentials

CERN Document Server

Lutfiyya, Lutfi A

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Modern Algebra includes set theory, operations, relations, basic properties of the integers, group theory, and ring theory.

Calculus III essentials

CERN Document Server

REA, Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Calculus III includes vector analysis, real valued functions, partial differentiation, multiple integrations, vector fields, and infinite series.

The Danish National Chronic Myeloid Neoplasia Registry

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Bak M

2016-10-01

Full Text Available Marie Bak,1 Else Helene Ibfelt,2 Thomas Stauffer Larsen,3 Dorthe Rønnov-Jessen,4 Niels Pallisgaard,5 Ann Madelung,6 Lene Udby,1 Hans Carl Hasselbalch,1 Ole Weis Bjerrum,7 Christen Lykkegaard Andersen1,7 1Department of Hematology, Zealand University Hospital, University of Copenhagen, Roskilde, 2Research Centre for Prevention and Health, Rigshospitalet Glostrup, University of Copenhagen, Glostrup, 3Department of Hematology, Odense University Hospital, Odense, 4Department of Hematology, Vejle Hospital, Vejle, 5Department of Surgical Pathology, Zealand University Hospital, University of Copenhagen, Roskilde, 6Department of Surgical Pathology, Zealand University Hospital, University of Copenhagen, Næstved, 7Department of Hematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Aim: The Danish National Chronic Myeloid Neoplasia Registry (DCMR is a population-based clinical quality database, introduced to evaluate diagnosis and treatment of patients with chronic myeloid malignancies. The aim is to monitor the clinical quality at the national, regional, and hospital departmental levels and serve as a platform for research. Study population: The DCMR has nationwide coverage and contains information on patients diagnosed at hematology departments from January 2010 onward, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, unclassifiable myeloproliferative neoplasms, chronic myelomonocytic leukemia, and chronic myeloid leukemia. Main variables: Data are collected using standardized registration forms (so far up to four forms per patient, which are consecutively filled out online at time of diagnosis, after 2-year and 5-year follow-ups, and at end of follow-up. The forms include variables that describe clinical/paraclinical assessments, treatment, disease progression, and survival – disease-specific variables – as well as variables that are identical for all chronic myeloid malignancies. Descriptive

Enhanced expression of Stim, Orai, and TRPC transcripts and proteins in endothelial progenitor cells isolated from patients with primary myelofibrosis.

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Silvia Dragoni

Full Text Available BACKGROUND: An increase in the frequency of circulating endothelial colony forming cells (ECFCs, the only subset of endothelial progenitor cells (EPCs truly belonging to the endothelial phenotype, occurs in patients affected by primary myelofibrosis (PMF. Herein, they might contribute to the enhanced neovascularisation of fibrotic bone marrow and spleen. Store-operated Ca2+ entry (SOCE activated by the depletion of the inositol-1,4,5-trisphosphate (InsP3-sensitive Ca2+ store drives proliferation in ECFCs isolated from both healthy donors (N-ECFCs and subjects suffering from renal cellular carcinoma (RCC-ECFCs. SOCE is up-regulated in RCC-ECFCs due to the over-expression of its underlying molecular components, namely Stim1, Orai1, and TRPC1. METHODOLOGY/PRINCIPAL FINDINGS: We utilized Ca2+ imaging, real-time polymerase chain reaction, western blot analysis and functional assays to evaluate molecular structure and the functional role of SOCE in ECFCs derived from PMF patients (PMF-ECFCs. SOCE, induced by either pharmacological (i.e. cyclopiazonic acid or CPA or physiological (i.e. ATP stimulation, was significantly higher in PMF-ECFCs. ATP-induced SOCE was inhibited upon blockade of the phospholipase C/InsP3 signalling pathway with U73111 and 2-APB. The higher amplitude of SOCE was associated to the over-expression of the transcripts encoding for Stim2, Orai2-3, and TRPC1. Conversely, immunoblotting revealed that Stim2 levels remained constant as compared to N-ECFCs, while Stim1, Orai1, Orai3, TRPC1 and TRPC4 proteins were over-expressed in PMF-ECFCs. ATP-induced SOCE was inhibited by BTP-2 and low micromolar La3+ and Gd3+, while CPA-elicited SOCE was insensitive to Gd3+. Finally, BTP-2 and La3+ weakly blocked PMF-ECFC proliferation, while Gd3+ was ineffective. CONCLUSIONS: Two distinct signalling pathways mediate SOCE in PMF-ECFCs; one is activated by passive store depletion and is Gd3+-resistant, while the other one is regulated by the InsP3

Essential medicine policy in China: pros and cons.

Science.gov (United States)

Hu, Shanlian

2013-01-01

To analyze the achievements, issues and policy recommendations for implementing essential medicine system in China after a 3-year effort. Policy documents analysis and Literature reviews are conducted. From 2009-2011, a series of national essential medicine (EM) policies has been established which contain EM list, organizing production, quality assurance, pricing, tendering and procurement, distribution, rational use, monitoring and evaluation, etc. About 98.8% government-run primary healthcare institutions and 41.5% village health posts are conducting zero-mark-up policy while buying EMs. The average cost per visit, per admission, and per description in outpatient and inpatient departments has declined. The issues with the national EM list cannot meet the requirements of clinical practice at the local level, all provinces have to increase additional 64-455 EMs in their local supplementary list; the limitation of EML in primary healthcare institutions causes patients to transfer directly to secondary or tertiary hospitals to search appropriate treatment; there is no defined regulation or legislation regarding the responsibility and accountability of government to compensate for the financial loss after implementing a zero mark-up policy in primary healthcare institutions. In the future, some innovative reform should be taken into account, such as revising EML, quality assurance, control margins within the distribution system, differential pricing and internal reference-based pricing, waive taxes and import duties of EMs, and separation between prescribing and dispensing in public hospital reform. Establishing a national essential medicine system is a difficult task to accomplish. The role of the zero-mark-up policy of EMs is to cut off the economic profit chain among different stakeholders. Using pharmaceutical profit to subsidize hospital revenue will be gradually eliminated in China.

Statistics I essentials

CERN Document Server

Milewski, Emil G

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Statistics I covers include frequency distributions, numerical methods of describing data, measures of variability, parameters of distributions, probability theory, and distributions.

Electric circuits essentials

CERN Document Server

REA, Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Electric Circuits I includes units, notation, resistive circuits, experimental laws, transient circuits, network theorems, techniques of circuit analysis, sinusoidal analysis, polyph

Pre-calculus essentials

CERN Document Server

Woodward, Ernest

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Pre-Calculus reviews sets, numbers, operations and properties, coordinate geometry, fundamental algebraic topics, solving equations and inequalities, functions, trigonometry, exponents

Electronics I essentials

CERN Document Server

REA, The Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Electronics I covers fundamentals of semiconductor devices, junction diodes, bipolar junction transistors, power supplies, multitransistor circuits, small signals, low-frequency anal

Post-error adjustments and ADHD symptoms in adults : The effect of laterality and state regulation

NARCIS (Netherlands)

Mohamed, Saleh M.H.; Borger, Norbert A.; Geuze, Reint H.; van der Meere, Jaap J.

2016-01-01

Evidence is accumulating that individuals with Attention-Deficit/Hyperactivity Disorder (ADHD) do not adjust their responses after committing errors. Post-error response adjustments are taken to reflect, among others, error monitoring that is essential for learning, flexible behavioural adaptation,

The influence of sun drying process and prolonged storage on composition of essential oil from clove buds (Syzygium aromaticum)

Science.gov (United States)

Hastuti, L. T.; Saepudin, E.; Cahyana, A. H.; Rahayu, D. U. C.; Murni, V. W.; Haib, J.

2017-07-01

Clove (Syzygium aromaticum) is native to Indonesia and used as a spice in virtually all of the world's cuisine. Clove bud oil, a yellow liquid, is obtained from distillation of buds. The quality of oil is influenced by origin, post-harvest processing, pre-treatment before distillation, the distillation method, and post-distillation treatment. The objective of this study is to investigate the effect of drying process and prolonged storage on essential oil composition of clove bud from the Tolitoli, Indonesia. To determine the effect of drying, fresh clove bud was dried under sunlight until it reached moisture content 13±1 %. The effect of storage was studied in the oil extracted from clove bud that was stored in laboratory at 25 °C for 4 months. The essential oil of each treatment was obtained by steam distillation and its chemical composition was analyzed by GC/MS. The major components found in fresh and dried clove are as follows: eugenol, eugenyl acetate, and caryophyllene. Percentage of caryophyllene was slightly increase after drying but decrease during storage. While the content of eugenyl acetate decreased during drying and storage, the content of eugenol increased. The drying and storage also affect to the change on minor compounds of essential oil of clove.

Thermodynamics II essentials

CERN Document Server

REA, The Editors of

2013-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Thermodynamics II includes review of thermodynamic relations, power and refrigeration cycles, mixtures and solutions, chemical reactions, chemical equilibrium, and flow through nozzl

Electronics II essentials

CERN Document Server

REA, The Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Electronics II covers operational amplifiers, feedback and frequency compensation of OP amps, multivibrators, logic gates and families, Boolean algebra, registers, counters, arithmet

Laplace transforms essentials

CERN Document Server

Shafii-Mousavi, Morteza

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Laplace Transforms includes the Laplace transform, the inverse Laplace transform, special functions and properties, applications to ordinary linear differential equations, Fourier tr

Statistics II essentials

CERN Document Server

Milewski, Emil G

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Statistics II discusses sampling theory, statistical inference, independent and dependent variables, correlation theory, experimental design, count data, chi-square test, and time se

Boolean algebra essentials

CERN Document Server

Solomon, Alan D

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Boolean Algebra includes set theory, sentential calculus, fundamental ideas of Boolean algebras, lattices, rings and Boolean algebras, the structure of a Boolean algebra, and Boolean

Set theory essentials

CERN Document Server

Milewski, Emil G

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Set Theory includes elementary logic, sets, relations, functions, denumerable and non-denumerable sets, cardinal numbers, Cantor's theorem, axiom of choice, and order relations.

Geometry I essentials

CERN Document Server

REA, The Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Geometry I includes methods of proof, points, lines, planes, angles, congruent angles and line segments, triangles, parallelism, quadrilaterals, geometric inequalities, and geometric

Post-processing computational fluid dynamic simulations of gas turbine combustor

International Nuclear Information System (INIS)

Sturgess, G.J.; Inko-Tariah, W.P.C.; James, R.H.

1986-01-01

The flowfield in combustors for gas turbine engines is extremely complex. Numerical simulation of such flowfields using computational fluid dynamics techniques has much to offer the design and development engineer. It is a difficult task, but it is one which is now being attempted routinely in the industry. The results of such simulations yield enormous amounts of information from which the responsible engineer has to synthesize a comprehensive understanding of the complete flowfield and the processes contained therein. The complex picture so constructed must be distilled down to the essential information upon which rational development decisions can be made. The only way this can be accomplished successfully is by extensive post-processing of the calculation. Post processing of a simulation relies heavily on computer graphics, and requires the enhancement provided by color. The application of one such post-processor is presented, and the strengths and weaknesses of various display techniques are illustrated

Thermodynamics I essentials

CERN Document Server

REA, The Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Thermodynamics I includes review of properties and states of a pure substance, work and heat, energy and the first law of thermodynamics, entropy and the second law of thermodynamics

Physics I essentials

CERN Document Server

REA, The Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Physics I includes vectors and scalars, one-dimensional motion, plane motion, dynamics of a particle, work and energy, conservation of energy, dynamics of systems of particles, rotation

levels of essential and non-essential metals in ethiopian ouzo

African Journals Online (AJOL)

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Key words/phrases: Alcoholic beverage, Ethiopia, essential metal, non-essential metal, ouzo. * Author to whom all correspondence should ... ing the attention of scientists and policy makers as a vital part of food security strategies and ... Canadian Government indicated that it had detected ethyl carbamate, C3H7NO2, which ...

Evaluation of a post-fire tree mortality model for western US conifers

Science.gov (United States)

Sharon M. Hood; Charles W McHugh; Kevin C. Ryan; Elizabeth Reinhardt; Sheri L. Smith

2007-01-01

Accurately predicting fire-caused mortality is essential to developing prescribed fire burn plans and post-fire salvage marking guidelines. The mortality model included in the commonly used USA fire behaviour and effects models, the First Order Fire Effects Model (FOFEM), BehavePlus, and the Fire and Fuels Extension to the Forest Vegetation Simulator (FFE-FVS), has not...

Observations on the presence of insulin resistance in patients with essential hypertension and coronary heart disease

International Nuclear Information System (INIS)

Zhu Mei; Wu Guo

2006-01-01

Objective: To investigate the presence of insulin resistance in patients with essential hypertension (EH) and coronary heart disease (CHD). Methods: Fasting and 2h post oral 75g glucose blood sugar (with oxidase method), insulin and C-peptide (with RIA) levels were examined in 52 patients with EH, 40 patients with CHD and 35 controls. Results: The fasting and 2h post o- ral glucose serum levels of glucose, insulin and C-peptide in the patients were significantly higher than those in the controls (P < 0.01), suggesting presence of impaired glucose tolerance and insulin resistance. Conclusion: Impaired glucose tolerance due to insulin resistance was demonstrated in the studied patients with EH or CHD. (authors)

[Pre- and post-surgical orthodontic treatment of mandibular asymmetry and prognathism].

Science.gov (United States)

Chen, Song; Chen, Yang-xi; Hu, Jing

2005-01-01

The purpose of this study was to analyze the pre- and post surgical orthodontic treatment of mandibular asymmetry and prognathism in our hospital, and to summarize some helpful experiences for future clinical work. The data were derived from 21 adults aged from 19 - 28 years who had severe mandibular asymmetry and prognathism. The ANB angle of all patients is from -3 degrees to -8 degrees. The value of wits of all patients is from -7 mm to -14 mm. The deviation of chin point of all patients is from 3 mm to 7 mm. The duration of pre- and post-surgical orthodontic treatment was 10-20 months (mean 18 months) and 5-10 months (mean 7.5 months), respectively. The keys in pre-surgical orthodontic treatment include (1) three dimensional dental decompensation; (2) arch form and transverse discrepancy correction; (3) model surgery and the splint making. The main objective of post surgical orthodontic treatment is to detail the occlusion. Pre- and post surgical orthodontic treatment is essential for the orthognathic treatment of patients with mandibular asymmetry and prognathism.

Post-seismic relaxation from geodetic and seismic data

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Mikhail V. Rodkin

2017-01-01

Full Text Available We have examined the aftershock sequence and the post-seismic deformation process of the Parkfield earthquake (2004, M = 6, California, USA source area using GPS data. This event was chosen because of the possibility of joint analysis of data from the rather dense local GPS network (from SOPAC Internet archive and of the availability of the rather detailed aftershock sequence data (http://www.ncedc.org/ncedc/catalog-search.html. The relaxation process of post-seismic deformation prolongs about the same 400 days as the seismic aftershock process does. Thus, the aftershock process and the relaxation process in deformation could be the different sides of the same process. It should be noted that the ratio of the released seismic energy and of the GPS obtained deformation is quite different for the main shock and for the aftershock stage. The ratio of the released seismic energy to the deformation value decreases essentially for the post-shock process. The similar change in the seismic energy/deformation value ratio is valid in a few other strong earthquakes. Thus, this decrease seems typical of aftershock sequences testifying for decrease of ratio of elastic to inelastic deformation in the process of post-shock relaxation when the source area appears to be mostly fractured after the main shock occurs, but the healing process had no yet sufficient time to develop.

The α-tocopherol transfer protein is essential for vertebrate embryogenesis.

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Galen W Miller

Full Text Available The hepatic α-tocopherol transfer protein (TTP is required for optimal α-tocopherol bioavailability in humans; mutations in the human TTPA gene result in the heritable disorder ataxia with vitamin E deficiency (AVED, OMIM #277460. TTP is also expressed in mammalian uterine and placental cells and in the human embryonic yolk-sac, underscoring TTP's significance during fetal development. TTP and vitamin E are essential for productive pregnancy in rodents, but their precise physiological role in embryogenesis is unknown. We hypothesize that TTP is required to regulate delivery of α-tocopherol to critical target sites in the developing embryo. We tested to find if TTP is essential for proper vertebrate development, utilizing the zebrafish as a non-placental model. We verify that TTP is expressed in the adult zebrafish and its amino acid sequence is homologous to the human ortholog. We show that embryonic transcription of TTP mRNA increases >7-fold during the first 24 hours following fertilization. In situ hybridization demonstrates that Ttpa transcripts are localized in the developing brain, eyes and tail bud at 1-day post fertilization. Inhibiting TTP expression using oligonucleotide morpholinos results in severe malformations of the head and eyes in nearly all morpholino-injected embryos (88% compared with 5.6% in those injected with control morpholinos or 1.7% in non-injected embryos. We conclude that TTP is essential for early development of the vertebrate central nervous system.

Post-operative serious adverse events in a mixed surgical population

DEFF Research Database (Denmark)

Hansen, M S; Petersen, E E; Dahl, J B

2016-01-01

BACKGROUND: The number of surgical procedures is increasing, and knowledge of surgical risk factors, post-operative mortality and serious adverse events (SAE) is essential. The aim with our study was to determine the risk of a composite outcome of post-operative: death; myocardial infarction...... or gynaecological surgery was conducted retrieving data from The Danish Civil Registration System and the National Patient Register. Total observation time was from January 1, 2012 to June 6, 2013. RESULTS: A total7449 adult patients were included in the final analysis. The risk of the composite outcome during...... of 8.3% (7.8-9.0). The results are applicable in estimations of adequate sample sizes in future clinical trials investigating effects of interventions on SAEs....

Post retention and post/core shear bond strength of four post systems.

Science.gov (United States)

Stockton, L W; Williams, P T; Clarke, C T

2000-01-01

As clinicians we continue to search for a post system which will give us maximum retention while maximizing resistance to root fracture. The introduction of several new post systems, with claims of high retentive and resistance to root fracture values, require that independent studies be performed to evaluate these claims. This study tested the tensile and shear dislodgment forces of four post designs that were luted into roots 10 mm apical of the CEJ. The Para Post Plus (P1) is a parallel-sided, passive design; the Para Post XT (P2) is a combination active/passive design; the Flexi-Post (F1) and the Flexi-Flange (F2) are active post designs. All systems tested were stainless steel. This study compared the test results of the four post designs for tensile and shear dislodgment. All mounted samples were loaded in tension until failure occurred. The tensile load was applied parallel to the long axis of the root, while the shear load was applied at 450 to the long axis of the root. The Flexi-Post (F1) was significantly different from the other three in the tensile test, however, the Para Post XT (P2) was significantly different to the other three in the shear test and had a better probability for survival in the Kaplan-Meier survival function test. Based on the results of this study, our recommendation is for the Para Post XT (P2).

Post and core build-ups in crown and bridge abutments: Bio-mechanical advantages and disadvantages.

Science.gov (United States)

Mamoun, John

2017-06-01

Dentists often place post and core buildups on endodontically treated abutments for crown and bridge restorations. This article analyzes the bio-mechanical purposes, advantages and disadvantages of placing a core or a post and core in an endodontically treated tooth and reviews literature on post and core biomechanics. The author assesses the scientific rationale of the claim that the main purpose of a post is to retain a core, or the claim that posts weaken teeth. More likely, the main function of a post is to help prevent the abutment, on which a crown is cemented, from fracturing such that the abutment separates from the tooth root, at a fracture plane that is located approximately and theoretically at the level of the crown (or ferrule) margin. A post essentially improves the ferrule effect that is provided by the partial fixed denture prosthesis. This paper also explores the difference between bio-mechanical failures of crowns caused by lack of retention or excess taper, versus failures due to a sub-optimal ferrule effect in crown and bridge prostheses.

Levels of essential and non-essential metals in Rhamnus prinoides ...

African Journals Online (AJOL)

The objective of this study was to assess the levels of essential and toxic metals in leaf and stem of Rhamnus prinoides which are used for bitterness of local alcoholic beverages in Ethiopia and as traditional medicine in some African countries. Levels of essential metals (Ca, Mg, Cr, Mn, Fe, Co, Ni, Cu and Zn) and toxic ...

Post What? The Liminality of Multi-Racial Identity

Directory of Open Access Journals (Sweden)

Danielle Fuentes Morgan

2016-06-01

Full Text Available This article, “Post What? The Liminality of Multi-Racial Identity,” argues that the successes and failures of 21st-century satire reveal the myth of post-raciality while simultaneously dismissing racial essentialism. I focus on three critical moments: the commercial success of Mat Johnson’s Loving Day, a text and forthcoming television show that examines the shifting self-identities of mixed-race individuals; the inability of a potential love interest on the television series, Louie, to accept a black woman as the ex-wife of the titular protagonist’s phenotypically white daughters; and Barack Obama’s self-designation as “black” on the census shortly after his election. I argue that the widespread reach of these instances, coupled with audience engagement and response, underscores the ways that the public realm frames a contemporary understanding of race as both meaningful and absurd.

Essential Palatal Myoclonus

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Bhuwan Raj Pandey

2017-06-01

Full Text Available Introduction: Palatal myoclonus is a rare condition presenting with clicking sound in ear or muscle tremor in pharynx. There are two varieties: essential and symptomatic. Various treatment options exists ranging from watchful observation to botulinum toxin injection. We have not found any reported case of palatal myoclonus from our country. Here we present a case of essential palatal myoclonus managed with clonazepam. Case report: A young female presented in Ear Nose and Throat clinic with complain of auditory click and spontaneous rhythmic movement of throat muscles for eight months. On examination, there was involuntary, rhythmic contraction of bilateral soft-palate, uvula, and base of tongue. Neurological, eye, and peripheral examination were normal. A diagnosis of essential palatal myoclonus was made. It was managed successfully with clonazepam; patient was still on low dose clonazepam at the time of making this report. Conclusion: Essential palatal myoclonus can be clinically diagnosed and managed even in settings where MRI is not available or affordable.

Academic Freedom in the Post-9/11 Era. Education, Politics and Public Life

Science.gov (United States)

Carvalho, Edward J., Ed.; Downing, David B.

2011-01-01

Academic freedom has been a principle that undergirds the university since 1915. Beyond this, it also protects a spirit of free inquiry essential to a democratic society. But in the post-9/11 present, the basic principles of academic freedom have been deeply challenged. There have been many startling instances where the rhetoric of national…

Essential Bacillus subtilis genes

DEFF Research Database (Denmark)

Kobayashi, K.; Ehrlich, S.D.; Albertini, A.

2003-01-01

To estimate the minimal gene set required to sustain bacterial life in nutritious conditions, we carried out a systematic inactivation of Bacillus subtilis genes. Among approximate to4,100 genes of the organism, only 192 were shown to be indispensable by this or previous work. Another 79 genes were...... predicted to be essential. The vast majority of essential genes were categorized in relatively few domains of cell metabolism, with about half involved in information processing, one-fifth involved in the synthesis of cell envelope and the determination of cell shape and division, and one-tenth related...... to cell energetics. Only 4% of essential genes encode unknown functions. Most essential genes are present throughout a wide range of Bacteria, and almost 70% can also be found in Archaea and Eucarya. However, essential genes related to cell envelope, shape, division, and respiration tend to be lost from...

Differential genetic basis for pre-menopausal and post-menopausal salt-sensitive hypertension.

Science.gov (United States)

Herrera, Victoria L M; Pasion, Khristine A; Moran, Ann Marie; Ruiz-Opazo, Nelson

2012-01-01

Essential hypertension affects 75% of post-menopausal women in the United States causing greater cardiovascular complications compared with age-matched men and pre-menopausal women. Hormone replacement and current anti-hypertensive therapies do not correct this post-menopausal increased risk suggesting a distinct pathogenic framework. We investigated the hypothesis that distinct genetic determinants might underlie susceptibility to salt sensitive hypertension in pre-menopausal and post-menopausal states. To determine whether distinct genetic loci contribute to post-menopausal salt-sensitive hypertension, we performed a genome-wide scan for quantitative trait loci (QTLs) affecting blood pressure (BP) in 16-month old post-menopausal F2 (Dahl S×R)-intercross female rats characterized for blood pressure by radiotelemetry. Given identical environments and high salt challenge, post-menopausal BP levels were significantly higher than observed in pre-menopausal (post-menopausal versus pre-menopausal SBP, P<0.0001) and ovariectomized (post-menopausal versus ovariectomized SBP, P<0.001) F2-intercross female rats. We detected four significant to highly significant BP-QTLs (BP-pm1 on chromosome 13, LOD 3.78; BP-pm2 on chromosome 11, LOD 2.76; BP-pm3 on chromosome 2, LOD 2.61; BP-pm4 on chromosome 4, LOD 2.50) and two suggestive BP-QTLs (BP-pm5 on chromosome 15, LOD 2.37; BP-f1 on chromosome 5, LOD 1.65), four of which (BP-pm2, BP-pm3, BP-pm4, BP-pm5) were unique to this post-menopausal cohort. These data demonstrate distinct polygenic susceptibility underlying post-menopausal salt-sensitive hypertension providing a pathway towards the identification of mechanism-based therapy for post-menopausal hypertension and ensuing target-organ complications.

Crucial factors of the inflammatory microenvironment (IL-1β/TNF-α/TIMP-1) promote the maintenance of the malignant hemopoietic clone of myelofibrosis: an in vitro study.

Science.gov (United States)

Sollazzo, Daria; Forte, Dorian; Polverelli, Nicola; Romano, Marco; Perricone, Margherita; Rossi, Lara; Ottaviani, Emanuela; Luatti, Simona; Martinelli, Giovanni; Vianelli, Nicola; Cavo, Michele; Palandri, Francesca; Catani, Lucia

2016-07-12

Along with molecular abnormalities (mutations in JAK2, Calreticulin (CALR) and MPL genes), chronic inflammation is the major hallmark of Myelofibrosis (MF). Here, we investigated the in vitro effects of crucial factors of the inflammatory microenvironment (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, Tissue Inhibitor of Metalloproteinases (TIMP)-1 and ATP) on the functional behaviour of MF-derived circulating CD34+ cells.We found that, regardless mutation status, IL-1β or TNF-α increases the survival of MF-derived CD34+ cells. In addition, along with stimulation of cell cycle progression to the S-phase, IL-1β or TNF-α ± TIMP-1 significantly stimulate(s) the in vitro clonogenic ability of CD34+ cells from JAK2V617 mutated patients. Whereas in the JAK2V617F mutated group, the addition of IL-1β or TNF-α + TIMP-1 decreased the erythroid compartment of the CALR mutated patients. Megakaryocyte progenitors were stimulated by IL-1β (JAK2V617F mutated patients only) and inhibited by TNF-α. IL-1β + TNF-α + C-X-C motif chemokine 12 (CXCL12) ± TIMP-1 highly stimulates the in vitro migration of MF-derived CD34+ cells. Interestingly, after migration toward IL-1β + TNF-α + CXCL12 ± TIMP-1, CD34+ cells from JAK2V617F mutated patients show increased clonogenic ability.Here we demonstrate that the interplay of these inflammatory factors promotes and selects the circulating MF-derived CD34+ cells with higher proliferative activity, clonogenic potential and migration ability. Targeting these micro-environmental interactions may be a clinically relevant approach.

Genetics Home Reference: essential tremor

Science.gov (United States)

... Facebook Twitter Home Health Conditions Essential tremor Essential tremor Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Essential tremor is a movement disorder that causes involuntary, rhythmic ...

Polycythaemia and myelofibrosis

Energy Technology Data Exchange (ETDEWEB)

Leblond, P.F.; Weed, R.I.

1975-06-01

The peripheral blood picture in early PV, polycythaemia vera, is largely dominated by the presence of quantitative changes involving all three lines of proliferating marrow cells. Of major importance in this disease is the recognition of the existence of an absolute increase in the circulating red cell mass, a phenomenon often leading to a rise in whole blood viscosity due to a greater degree of physical interaction between circulating red cells at haematocrits above 55 to 60 percent. By virtue of its particular ultrastructure, it is thought that the spleen in this disease plays a major role in poikilocyte formation as well as in their subsequent elimination from the circulation because of the mechanical inability of such cells to negotiate the small apertures present in the walls of splenic sinuses. However, the primary site of pathological involvement in MF appears to be the bone marrow where the possible existence of alterations in the fine structure of the sinus walls could be responsible for the premature release into the circulation of morphologically identifiable precursors of all three haematopoietic cell lines. Since an important feature of blood cell maturation is the progressive acquisition of deformability, these immature cells, being still rigid, are highly susceptible to becoming trapped in other organs such as the liver and the spleen. Hence the hypothesis that the myeloid metaplasia commonly found in patients with this disease may result from a ''seeding'' in these organs of immature precursor cells having kept their capacity to establish colonies and to undergo further differentiation. These considerations are expressed as an example of the type of interpretation that can be ascribed to a careful examination of the peripheral blood in PV and MF, by taking into account some of the most recent developments in the field of microrheology.

Chemical composition and insecticidal activity of Cymbopogon citratus essential oil from Cuba and Brazil against housefly

Directory of Open Access Journals (Sweden)

Zeneida Teixeira Pinto

Full Text Available Essential oil of Cymbopogon citratus collected from Brazil and Cuba was tested to a chemical characterization and then was tested on the post-embryonic development of Musca domestica. The chemical composition analysis by GC-MS of the oils from Brazil/Cuba allowed the identification of 13 and 12 major constituents respectively; nine of them common to both. In the both oils, the main components were the isomers geranial and neral, which together form the compound citral. This corresponds to a total of 97.92%/Brazil and 97.69%/Cuba of the compounds identified. The monoterpene myrcene, observed only in the sample of Cuba, presented a large relative abundance (6.52%. The essential oil of C. citratus (Brazil/Cuba was dissolved in DMSO and tested at concentrations of 5, 10, 25, 50, 75 and 100% and citral was prepared by mixing 16.8 mg with 960 µL DMSO. Both essential oils and monoterpene citral were applied topically to newly-hatched larvae (1µL/larva. The results showed a lethal concentration (LC50 of 4.25 and 3.24% for the Brazilian and Cuban essential oils, respectively. Mortalities of larval and newly-hatched larvae to adult periods were dose-dependent for the two both oils as for monoterpene citral, reaching 90%. Both essential oils and citral caused morphological changes in adult specimens.

Chemical composition and insecticidal activity of Cymbopogon citratus essential oil from Cuba and Brazil against housefly.

Science.gov (United States)

Pinto, Zeneida Teixeira; Sánchez, Félix Fernández; dos Santos, Arith Ramos; Amaral, Ana Claudia Fernandes; Ferreira, José Luiz Pinto; Escalona-Arranz, Julio César; Queiroz, Margareth Maria de Carvalho

2015-01-01

Essential oil of Cymbopogon citratus collected from Brazil and Cuba was tested to a chemical characterization and then was tested on the post-embryonic development of Musca domestica. The chemical composition analysis by GC-MS of the oils from Brazil/Cuba allowed the identification of 13 and 12 major constituents respectively; nine of them common to both. In the both oils, the main components were the isomers geranial and neral, which together form the compound citral. This corresponds to a total of 97.92%/Brazil and 97.69%/Cuba of the compounds identified. The monoterpene myrcene, observed only in the sample of Cuba, presented a large relative abundance (6.52%). The essential oil of C. citratus (Brazil/Cuba) was dissolved in DMSO and tested at concentrations of 5, 10, 25, 50, 75 and 100% and citral was prepared by mixing 16.8 mg with 960 µL DMSO. Both essential oils and monoterpene citral were applied topically to newly-hatched larvae (1µL/larva). The results showed a lethal concentration (LC50) of 4.25 and 3.24% for the Brazilian and Cuban essential oils, respectively. Mortalities of larval and newly-hatched larvae to adult periods were dose-dependent for the two both oils as for monoterpene citral, reaching 90%. Both essential oils and citral caused morphological changes in adult specimens.

Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies

Directory of Open Access Journals (Sweden)

Srdan Verstovsek

2016-12-01

Full Text Available Abstract Background Pacritinib (SB1518 is a highly selective kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R. This multicenter phase 1/2 study evaluated the maximum tolerated dose (MTD, safety, and clinical activity of pacritinib in patients with myelofibrosis (MF and other advanced myeloid malignancies. Methods In the phase 1 dose-escalation part of the study, 43 adults with advanced myeloid malignancies received pacritinib 100 to 600 mg once daily (QD. In the phase 2 part of the study, 31 adults with refractory or intermediate- or high-risk newly diagnosed MF and any degree of cytopenia received pacritinib 400 mg QD. The primary endpoint is a ≥35% reduction in spleen volume at week 24 as determined by magnetic resonance imaging. Results Five patients (11.6% experienced a dose-limiting toxicity during cycle 1 of phase 1. The clinical benefit rate was 86.0% (13 patients achieving clinical improvement and 24 patients having stable disease. The MTD was established at 500 mg QD, and the recommended phase 2 dose was 400 mg QD. In phase 2, the primary endpoint was achieved by 23.5% of evaluable patients (4/17, with 47.4% (9/19 achieving a ≥50% spleen length reduction at week 24 as measured by physical examination. At week 24, 38.9% of evaluable patients (7/18 achieved a ≥50% decrease in MF Quality of Life and Symptom Assessment total score. Gastrointestinal toxicities were the most common adverse events and were predominantly grade 1/2 in severity. Grade 3/4 anemia was reported in 5/31 patients and grade 3/4 thrombocytopenia was reported in 3/31 patients. The most frequent AEs considered to be treatment related were diarrhea (28/31, nausea (15/31, vomiting (9/31, and fatigue (4/31. Grade 3 treatment-related AEs were reported in seven patients (22.6%, four of whom had diarrhea. No grade 4/5 treatment-related AEs were reported. No leukopenia, neutropenia, or lymphopenia were reported. Conclusions Pacritinib was well

Chromium supplementation improved post-stroke brain infarction and hyperglycemia.

Science.gov (United States)

Chen, Wen-Ying; Mao, Frank Chiahung; Liu, Chia-Hsin; Kuan, Yu-Hsiang; Lai, Nai-Wei; Wu, Chih-Cheng; Chen, Chun-Jung

2016-04-01

Hyperglycemia is common after acute stroke and is associated with a worse outcome of stroke. Thus, a better understanding of stress hyperglycemia is helpful to the prevention and therapeutic treatment of stroke. Chromium is an essential nutrient required for optimal insulin activity and normal carbohydrate and lipid metabolism. Beyond its nutritional effects, dietary supplement of chromium causes beneficial outcomes against several diseases, in particular diabetes-associated complications. In this study, we investigated whether post-stroke hyperglycemia involved chromium dynamic mobilization in a rat model of permanent focal cerebral ischemia and whether dietary supplement of chromium improved post-stroke injury and alterations. Stroke rats developed brain infarction, hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Post-stroke hyperglycemia was accompanied by elevated secretion of counter-regulatory hormones including glucagon, corticosterone, and norepinephrine, decreased insulin signaling in skeletal muscles, and increased hepatic gluconeogenesis. Correlation studies revealed that counter-regulatory hormone secretion showed a positive correlation with chromium loss and blood glucose increased together with chromium loss. Daily chromium supplementation increased tissue chromium levels, attenuated brain infarction, improved hyperglycemia, and decreased plasma levels of glucagon and corticosterone in stroke rats. Our findings suggest that stroke rats show disturbance of tissue chromium homeostasis with a net loss through urinary excretion and chromium mobilization and loss might be an alternative mechanism responsible for post-stroke hyperglycemia.

Neuregulin-1 signaling is essential for nerve-dependent axolotl limb regeneration.

Science.gov (United States)

Farkas, Johanna E; Freitas, Polina D; Bryant, Donald M; Whited, Jessica L; Monaghan, James R

2016-08-01

The Mexican axolotl (Ambystoma mexicanum) is capable of fully regenerating amputated limbs, but denervation of the limb inhibits the formation of the post-injury proliferative mass called the blastema. The molecular basis behind this phenomenon remains poorly understood, but previous studies have suggested that nerves support regeneration via the secretion of essential growth-promoting factors. An essential nerve-derived factor must be found in the blastema, capable of rescuing regeneration in denervated limbs, and its inhibition must prevent regeneration. Here, we show that the neuronally secreted protein Neuregulin-1 (NRG1) fulfills all these criteria in the axolotl. Immunohistochemistry and in situ hybridization of NRG1 and its active receptor ErbB2 revealed that they are expressed in regenerating blastemas but lost upon denervation. NRG1 was localized to the wound epithelium prior to blastema formation and was later strongly expressed in proliferating blastemal cells. Supplementation by implantation of NRG1-soaked beads rescued regeneration to digits in denervated limbs, and pharmacological inhibition of NRG1 signaling reduced cell proliferation, blocked blastema formation and induced aberrant collagen deposition in fully innervated limbs. Taken together, our results show that nerve-dependent NRG1/ErbB2 signaling promotes blastemal proliferation in the regenerating limb and may play an essential role in blastema formation, thus providing insight into the longstanding question of why nerves are required for axolotl limb regeneration. © 2016. Published by The Company of Biologists Ltd.

Computer science I essentials

CERN Document Server

Raus, Randall

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Computer Science I includes fundamental computer concepts, number representations, Boolean algebra, switching circuits, and computer architecture.

Dietary essentiality of “nutritionally non-essential amino acids” for animals and humans

OpenAIRE

Hou, Yongqing; Yin, Yulong; Wu, Guoyao

2015-01-01

Based on growth or nitrogen balance, amino acids (AA) had traditionally been classified as nutritionally essential (indispensable) or non-essential (dispensable) for animals and humans. Nutritionally essential AA (EAA) are defined as either those AA whose carbon skeletons cannot be synthesized de novo in animal cells or those that normally are insufficiently synthesized de novo by the animal organism relative to its needs for maintenance, growth, development, and health and which must be prov...

Treatment of Essential Tremor

Science.gov (United States)

... for PATIENTS and their FAMILIES TREATMENT OF ESSENTIAL TREMOR This fact sheet is provided to help you understand which therapies help treat essential tremor. Neurologists from the American Academy of Neurology are ...

Differential genetic basis for pre-menopausal and post-menopausal salt-sensitive hypertension.

Directory of Open Access Journals (Sweden)

Victoria L M Herrera

Full Text Available Essential hypertension affects 75% of post-menopausal women in the United States causing greater cardiovascular complications compared with age-matched men and pre-menopausal women. Hormone replacement and current anti-hypertensive therapies do not correct this post-menopausal increased risk suggesting a distinct pathogenic framework. We investigated the hypothesis that distinct genetic determinants might underlie susceptibility to salt sensitive hypertension in pre-menopausal and post-menopausal states. To determine whether distinct genetic loci contribute to post-menopausal salt-sensitive hypertension, we performed a genome-wide scan for quantitative trait loci (QTLs affecting blood pressure (BP in 16-month old post-menopausal F2 (Dahl S×R-intercross female rats characterized for blood pressure by radiotelemetry. Given identical environments and high salt challenge, post-menopausal BP levels were significantly higher than observed in pre-menopausal (post-menopausal versus pre-menopausal SBP, P<0.0001 and ovariectomized (post-menopausal versus ovariectomized SBP, P<0.001 F2-intercross female rats. We detected four significant to highly significant BP-QTLs (BP-pm1 on chromosome 13, LOD 3.78; BP-pm2 on chromosome 11, LOD 2.76; BP-pm3 on chromosome 2, LOD 2.61; BP-pm4 on chromosome 4, LOD 2.50 and two suggestive BP-QTLs (BP-pm5 on chromosome 15, LOD 2.37; BP-f1 on chromosome 5, LOD 1.65, four of which (BP-pm2, BP-pm3, BP-pm4, BP-pm5 were unique to this post-menopausal cohort. These data demonstrate distinct polygenic susceptibility underlying post-menopausal salt-sensitive hypertension providing a pathway towards the identification of mechanism-based therapy for post-menopausal hypertension and ensuing target-organ complications.

Essential Medicines in a High Income Country: Essential to Whom?

Science.gov (United States)

Duong, Mai; Moles, Rebekah J; Chaar, Betty; Chen, Timothy F

2015-01-01

To explore the perspectives of a diverse group of stakeholders engaged in medicines decision making around what constitutes an "essential" medicine, and how the Essential Medicines List (EML) concept functions in a high income country context. In-depth qualitative semi-structured interviews were conducted with 32 Australian stakeholders, recognised as decision makers, leaders or advisors in the area of medicines reimbursement or supply chain management. Participants were recruited from government, pharmaceutical industry, pharmaceutical wholesale/distribution companies, medicines non-profit organisations, academic health disciplines, hospitals, and consumer groups. Perspectives on the definition and application of the EML concept in a high income country context were thematically analysed using grounded theory approach. Stakeholders found it challenging to describe the EML concept in the Australian context because many perceived it was generally used in resource scarce settings. Stakeholders were unable to distinguish whether nationally reimbursed medicines were essential medicines in Australia. Despite frequent generic drug shortages and high prices paid by consumers, many struggled to describe how the EML concept applied to Australia. Instead, broad inclusion of consumer needs, such as rare and high cost medicines, and consumer involvement in the decision making process, has led to expansive lists of nationally subsidised medicines. Therefore, improved communication and coordination is needed around shared interests between stakeholders regarding how medicines are prioritised and guaranteed in the supply chain. This study showed that decision-making in Australia around reimbursement of medicines has strayed from the fundamental utilitarian concept of essential medicines. Many stakeholders involved in medicine reimbursement decisions and management of the supply chain did not consider the EML concept in their approach. The wide range of views of what stakeholders

Essential Medicines in a High Income Country: Essential to Whom?

Directory of Open Access Journals (Sweden)

Mai Duong

Full Text Available To explore the perspectives of a diverse group of stakeholders engaged in medicines decision making around what constitutes an "essential" medicine, and how the Essential Medicines List (EML concept functions in a high income country context.In-depth qualitative semi-structured interviews were conducted with 32 Australian stakeholders, recognised as decision makers, leaders or advisors in the area of medicines reimbursement or supply chain management. Participants were recruited from government, pharmaceutical industry, pharmaceutical wholesale/distribution companies, medicines non-profit organisations, academic health disciplines, hospitals, and consumer groups. Perspectives on the definition and application of the EML concept in a high income country context were thematically analysed using grounded theory approach.Stakeholders found it challenging to describe the EML concept in the Australian context because many perceived it was generally used in resource scarce settings. Stakeholders were unable to distinguish whether nationally reimbursed medicines were essential medicines in Australia. Despite frequent generic drug shortages and high prices paid by consumers, many struggled to describe how the EML concept applied to Australia. Instead, broad inclusion of consumer needs, such as rare and high cost medicines, and consumer involvement in the decision making process, has led to expansive lists of nationally subsidised medicines. Therefore, improved communication and coordination is needed around shared interests between stakeholders regarding how medicines are prioritised and guaranteed in the supply chain.This study showed that decision-making in Australia around reimbursement of medicines has strayed from the fundamental utilitarian concept of essential medicines. Many stakeholders involved in medicine reimbursement decisions and management of the supply chain did not consider the EML concept in their approach. The wide range of views of

Transport phenomena II essentials

CERN Document Server

REA, The Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Transport Phenomena II covers forced convention, temperature distribution, free convection, diffusitivity and the mechanism of mass transfer, convective mass transfer, concentration

Heat transfer II essentials

CERN Document Server

REA, The Editors of

1988-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Heat Transfer II reviews correlations for forced convection, free convection, heat exchangers, radiation heat transfer, and boiling and condensation.

Differential equations I essentials

CERN Document Server

REA, Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Differential Equations I covers first- and second-order equations, series solutions, higher-order linear equations, and the Laplace transform.

Algebra & trigonometry II essentials

CERN Document Server

REA, Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Algebra & Trigonometry II includes logarithms, sequences and series, permutations, combinations and probability, vectors, matrices, determinants and systems of equations, mathematica

Numerical analysis II essentials

CERN Document Server

REA, The Editors of; Staff of Research Education Association

1989-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Numerical Analysis II covers simultaneous linear systems and matrix methods, differential equations, Fourier transformations, partial differential equations, and Monte Carlo methods.

Business statistics I essentials

CERN Document Server

Clark, Louise

2014-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Business Statistics I includes descriptive statistics, introduction to probability, probability distributions, sampling and sampling distributions, interval estimation, and hypothesis t

Rhetoric and Essentially Contested Arguments

Science.gov (United States)

Garver, Eugene

1978-01-01

Draws a connection between Gallie's essentially contested concepts and Aristotle's account of rhetorical argument by presenting a definition of Essentially Contested Argument which is used as the connecting term between rhetoric and essentially contested concepts and by demonstrating the value of making this connection. (JF)

Effect of essential oils of clove and cumin against the growth of Staphylococus Aureus isolated from Denture Stomatitis

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Minasari Minasari

2017-08-01

Full Text Available Background: Essential oils of clove and cumin had an inhibition effect against Staphylococcus aureus. Clove’s essential oils has a compound named eugenol, which can directly damage the membrane cell of bacteria. Thymoquinone, the active ingredient in the black cumin’s essential oils inhibits the protein synthesis and cause malfunction of the bacterial cell. The purpose of this research was to determine the differences of inhibitory effect from essential oils of cloves and cumin to the growth of Staphylococcus aureus. Method: This research was an experimental laboratory with Post-test Only Control Group Design. Sample that being used for this experiment was Staphylococcus aureus that had been isolated from a denture stomatitis patient. This inhibition test was determined using a Disc Diffusion Test’s method with the essential oils of clove and cumin, while distilled water and 96% ethanol as a negative and positive control, respectively. Essential oils were obtained from the distillation method with water and steam and the test was done 7 times repetition with every ingredients. Inhibition zone was measured with a vernier calipers. The data were analyzed by ANOVA One-way test followed by a multiple comparison test. Result:  The average zone of inhibition against Staphylococcus aureus from aquades 0 mm, 96% ethanol 13.894 mm, the essential oils of clove 14.784 mm and black cumin 11.944 mm. The multiple comparison test analysis showed a significant differences (p <0.05 between the average zone of inhibition of the materials tested. Conclusion: Clove essential oil has a greater inhibition against Staphylococcus aureus than the essential oils of cumin.

The Politics of Law in a Post-Conflict UN Protectorate

DEFF Research Database (Denmark)

Grasten, Maj Lervad; J. Uberti, Luca

2017-01-01

rely on semi-structured interviews with international officials and a review of legal documents to argue that the process of institutional change was driven largely by a contest between conflicting legal norms, rather than a contest between politically organised interest-based groups. International...... on the background paradigm ushered in a protracted period of ideational contestation. Privatisation in post-war Kosovo was essentially about the ‘politics of law’, as the legalisation of privatisation policy led inevitably to the contentious politicisation of legal norms....

Group theory I essentials

CERN Document Server

Milewski, Emil G

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Group Theory I includes sets and mapping, groupoids and semi-groups, groups, isomorphisms and homomorphisms, cyclic groups, the Sylow theorems, and finite p-groups.

C programming language essentials

CERN Document Server

Ackermann, Ernest C

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. C Programming Language discusses fundamental notions, data types and objects, expressions, statements, declarations, function and program structure, the preprocessor, and the standar

Algebra & trigonometry I essentials

CERN Document Server

REA, Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Algebra & Trigonometry I includes sets and set operations, number systems and fundamental algebraic laws and operations, exponents and radicals, polynomials and rational expressions, eq

Transport phenomena I essentials

CERN Document Server

REA, The Editors of

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Transport Phenomena I includes viscosity, flow of Newtonian fluids, velocity distribution in laminar flow, velocity distributions with more than one independent variable, thermal con

Data structures II essentials

CERN Document Server

Smolarski, Dennis C

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Data Structures II includes sets, trees, advanced sorting, elementary graph theory, hashing, memory management and garbage collection, and appendices on recursion vs. iteration, alge

Data structures I essentials

CERN Document Server

Smolarski, Dennis C

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Data Structures I includes scalar variables, arrays and records, elementary sorting, searching, linked lists, queues, and appendices of binary notation and subprogram parameter passi

Teores do óleo essencial de cidrão [Aloysia triphylla (L'Hérit Britton (Verbenaceae] em diferentes horários de colheita e processamentos pós-colheita Lemon verbena's [Aloysia triphylla (L'Hérit Britton (Verbenaceae] essential oil content in different harvest periods and post-harvesting process

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Renata da Silva Brant

2009-01-01

Full Text Available Este estudo foi realizado com o objetivo de avaliar o teor do óleo essencial de cidrão [Aloysia triphylla (L´Hérit Britton] em diferentes horários de colheita e processamentos pós-colheita. O delineamento utilizado foi inteiramente casualizado. As colheitas foram realizadas em três horários distintos (8 h, 12 h e 16 h, com três repetições. Os processamentos pós-colheita foram cinco: T1- folhas frescas fragmentadas em 1cm; T2- folhas frescas processadas em liquidificador; T3- folhas frescas inteiras; T4- folhas secas inteiras; T5- folhas secas pulverizadas em moinho, com três repetições. O óleo essencial de cada tratamento foi extraído pela técnica de hidrodestilação, utilizando o aparelho modificado de Clevenger, por uma hora e trinta minutos. Os horários de colheita quando se detectou maior teor de óleo foram 8 h e 16 h. Os maiores teores de óleo essencial foram encontrados em folhas frescas fragmentadas em 1cm, folhas frescas processadas em liquidificador, folhas frescas inteiras e folhas secas inteiras.This study was carried out in order to evaluate the essential oil content of lemon verbena at different harvest times and post-harvest processings. The experimental design used was completely randomized. The harvested material was collected at three different hours (8:00, 12:00 and 16:00 pm, and it was taken three times. In post-harvest processings, three replications and five treatments were us do: 1 cm fresh leaf fragments, blended fresh leaves, whole fresh leaves, whole dry leaves and dry leaves ground in mill. The essential oil was determined in Clevenger's modified apparatus for 1 hour and 30 minutes. The periods of the day that detected high essential oil content were at 8:00 am and 16:00 pm. The high essential oil level was in 1 cm fresh leaf fragments, blender processed fresh leaves, whole fresh leaves and whole dry leaves.

Carbon Monoxide: An Essential Signalling Molecule

Science.gov (United States)

Mann, Brian E.

Carbon monoxide (CO), like nitric oxide (NO), is an essential signalling molecule in humans. It is active in the cardiovascular system as a vasodilator. In addition, CO possesses anti-inflammatory, anti-apoptotic and anti-proliferative properties and protects tissues from hypoxia and reperfusion injury. Some of its applications in animal models include suppression of organ graft rejection and safeguarding the heart during reperfusion after cardiopulmonary bypass surgery. CO also suppresses arteriosclerotic lesions following angioplasty, reverses established pulmonary hypertension and mitigates the development of post-operative ileus in the murine small intestine and the development of cerebral malaria in mice as well as graft-induced intimal hyperplasia in pigs. There have been several clinical trials using air-CO mixtures for the treatment of lung-, heart-, kidney- and abdominal-related diseases. This review examines the research involving the development of classes of compounds (with particular emphasis on metal carbonyls) that release CO, which could be used in clinically relevant conditions. The review is drawn not only from published papers in the chemical literature but also from the extensive biological literature and patents on CO-releasing molecules (CO-RMs).

Computer science II essentials

CERN Document Server

Raus, Randall

2012-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Computer Science II includes organization of a computer, memory and input/output, coding, data structures, and program development. Also included is an overview of the most commonly

Imaging evaluation of post pancreatic surgery

International Nuclear Information System (INIS)

Scialpi, Michele; Scaglione, Mariano; Volterrani, Luca; Lupattelli, Luciano; Ragozzino, Alfonso; Romano, Stefania; Rotondo, Antonio

2005-01-01

The role of several imaging techniques in patients submitted to pancreatic surgery with special emphasis to single-slice helical computed tomography (CT) and multidetector-row CT (MDCT) was reviewed. Several surgical options may be performed such as Whipple procedure, distal pancreatectomy, central pancreatectomy, and total pancreatectomy. Ultrasound examination may be used to detect peritoneal fluid in the early post-operative period as well as lesion recurrence in long-term follow-up. Radiological gastrointestinal studies has a major role in evaluation of intestinal functionality. In spite of the advent of other imaging modalities, CT is the most effective after pancreatic surgery. On post-operative CT, the most common findings were small fluid peritoneal or pancreatic collections, stranding of the mesenteric fat with perivascular cuffing, reactive adenopathy and pneumobilia. In addition, CT may demonstrate early (leakage of anastomosis, pancreatico-jejunal fistula, haemorrage, acute pancreatitis of the remnant pancreas, peritonitis), and late (chronic fistula, abscess, aneurysms, anastomotic bilio-digestive stenosis, perianastomotic ulcers, biloma, and intra-abdominal bleeding) surgical complications. In the follow-up evaluation, CT may show tumor recurrence, liver and lymph nodes metastasis. Magnetic resonance may be used as alternative imaging modality to CT, when renal insufficiency or contrast sensitivity prevents the use of iodinated i.v. contrast material or when the biliary tree study is primarily requested. The knowledge of the type of surgical procedures, the proper identification of the anastomoses as well as the normal post-operative imaging appearances are essential for an accurate detection of the complications and recurrent disease

Imaging evaluation of post pancreatic surgery

Energy Technology Data Exchange (ETDEWEB)

Scialpi, Michele [Department of Radiology, ' Santissima Annunziata' Hospital, Via Bruno 1, I-74100 Taranto (Italy)]. E-mail: michelescialpi@libero.it; Scaglione, Mariano [Department of Radiology, ' A. Cardarelli' Hospital, I-80131 Naples (Italy); Volterrani, Luca [Institute of Radiology, University of Siena, I-53100 Siena (Italy); Lupattelli, Luciano [Institute of Radiology, University of Perugia, I-06122 Perugia (Italy); Ragozzino, Alfonso [Department of Radiology, ' A. Cardarelli' Hospital, I-80131 Naples (Italy); Romano, Stefania [Department of Radiology, ' A. Cardarelli' Hospital, I-80131 Naples (Italy); Rotondo, Antonio [Section of Radiology, Department ' Magrassi-Lanzara' , Second University, I-80138 Naples (Italy)

2005-03-01

The role of several imaging techniques in patients submitted to pancreatic surgery with special emphasis to single-slice helical computed tomography (CT) and multidetector-row CT (MDCT) was reviewed. Several surgical options may be performed such as Whipple procedure, distal pancreatectomy, central pancreatectomy, and total pancreatectomy. Ultrasound examination may be used to detect peritoneal fluid in the early post-operative period as well as lesion recurrence in long-term follow-up. Radiological gastrointestinal studies has a major role in evaluation of intestinal functionality. In spite of the advent of other imaging modalities, CT is the most effective after pancreatic surgery. On post-operative CT, the most common findings were small fluid peritoneal or pancreatic collections, stranding of the mesenteric fat with perivascular cuffing, reactive adenopathy and pneumobilia. In addition, CT may demonstrate early (leakage of anastomosis, pancreatico-jejunal fistula, haemorrage, acute pancreatitis of the remnant pancreas, peritonitis), and late (chronic fistula, abscess, aneurysms, anastomotic bilio-digestive stenosis, perianastomotic ulcers, biloma, and intra-abdominal bleeding) surgical complications. In the follow-up evaluation, CT may show tumor recurrence, liver and lymph nodes metastasis. Magnetic resonance may be used as alternative imaging modality to CT, when renal insufficiency or contrast sensitivity prevents the use of iodinated i.v. contrast material or when the biliary tree study is primarily requested. The knowledge of the type of surgical procedures, the proper identification of the anastomoses as well as the normal post-operative imaging appearances are essential for an accurate detection of the complications and recurrent disease.

Essential role of chromatin remodeling protein Bptf in early mouse embryos and embryonic stem cells.

Directory of Open Access Journals (Sweden)

Joseph Landry

2008-10-01

Full Text Available We have characterized the biological functions of the chromatin remodeling protein Bptf (Bromodomain PHD-finger Transcription Factor, the largest subunit of NURF (Nucleosome Remodeling Factor in a mammal. Bptf mutants manifest growth defects at the post-implantation stage and are reabsorbed by E8.5. Histological analyses of lineage markers show that Bptf(-/- embryos implant but fail to establish a functional distal visceral endoderm. Microarray analysis at early stages of differentiation has identified Bptf-dependent gene targets including homeobox transcriptions factors and genes essential for the development of ectoderm, mesoderm, and both definitive and visceral endoderm. Differentiation of Bptf(-/- embryonic stem cell lines into embryoid bodies revealed its requirement for development of mesoderm, endoderm, and ectoderm tissue lineages, and uncovered many genes whose activation or repression are Bptf-dependent. We also provide functional and physical links between the Bptf-containing NURF complex and the Smad transcription factors. These results suggest that Bptf may co-regulate some gene targets of this pathway, which is essential for establishment of the visceral endoderm. We conclude that Bptf likely regulates genes and signaling pathways essential for the development of key tissues of the early mouse embryo.

Essentialism goes social: belief in social determinism as a component of psychological essentialism.

Science.gov (United States)

Rangel, Ulrike; Keller, Johannes

2011-06-01

Individuals tend to explain the characteristics of others with reference to an underlying essence, a tendency that has been termed psychological essentialism. Drawing on current conceptualizations of essentialism as a fundamental mode of social thinking, and on prior studies investigating belief in genetic determinism (BGD) as a component of essentialism, we argue that BGD cannot constitute the sole basis of individuals' essentialist reasoning. Accordingly, we propose belief in social determinism (BSD) as a complementary component of essentialism, which relies on the belief that a person's essential character is shaped by social factors (e.g., upbringing, social background). We developed a scale to measure this social component of essentialism. Results of five correlational studies indicate that (a) BGD and BSD are largely independent, (b) BGD and BSD are related to important correlates of essentialist thinking (e.g., dispositionism, perceived group homogeneity), (c) BGD and BSD are associated with indicators of fundamental epistemic and ideological motives, and (d) the endorsement of each lay theory is associated with vital social-cognitive consequences (particularly stereotyping and prejudice). Two experimental studies examined the idea that the relationship between BSD and prejudice is bidirectional in nature. Study 6 reveals that rendering social-deterministic explanations salient results in increased levels of ingroup favoritism in individuals who chronically endorse BSD. Results of Study 7 show that priming of prejudice enhances endorsement of social-deterministic explanations particularly in persons habitually endorsing prejudiced attitudes. 2011 APA, all rights reserved

Essential Tremor

Science.gov (United States)

... Treatment There is no definitive cure for essential tremor. Symptomatic drug therapy may include propranolol or other beta blockers and primidone, an anticonvulsant drug. Eliminating tremor "triggers" ...

Robotic colorectal surgery: previous laparoscopic colorectal experience is not essential.

Science.gov (United States)

Sian, Tanvir Singh; Tierney, G M; Park, H; Lund, J N; Speake, W J; Hurst, N G; Al Chalabi, H; Smith, K J; Tou, S

2018-06-01

A background in minimally invasive colorectal surgery (MICS) has been thought to be essential prior to robotic-assisted colorectal surgery (RACS). Our aim was to determine whether MICS is essential prior to starting RACS training based on results from our initial experience with RACS. Two surgeons from our centre received robotic training through the European Academy of Robotic Colorectal Surgery (EARCS). One surgeon had no prior formal MICS training. We reviewed the first 30 consecutive robotic colorectal procedures from a prospectively maintained database between November 2014 and January 2016 at our institution. Fourteen patients were male. Median age was 64.5 years (range 36-82) and BMI was 27.5 (range 20-32.5). Twelve procedures (40%) were performed by the non-MICS-trained surgeon: ten high anterior resections (one conversion), one low anterior resection and one abdomino-perineal resection of rectum (APER). The MICS-trained surgeon performed nine high and four low anterior resections, one APER and in addition three right hemicolectomies and one abdominal suture rectopexy. There were no intra-operative complications and two patients required re-operation. Median post-operative stay was five days (range 1-26). There were two 30-day re-admissions. All oncological resections had clear margins and median node harvest was 18 (range 9-39). Our case series demonstrates that a background in MICS is not essential prior to starting RACS training. Not having prior MICS training should not discourage surgeons from considering applying for a robotic training programme. Safe and successful robotic colorectal services can be established after completing a formal structured robotic training programme.

Python essential reference

CERN Document Server

Beazley, David M

2009-01-01

Python Essential Reference is the definitive reference guide to the Python programming language — the one authoritative handbook that reliably untangles and explains both the core Python language and the most essential parts of the Python library. Designed for the professional programmer, the book is concise, to the point, and highly accessible. It also includes detailed information on the Python library and many advanced subjects that is not available in either the official Python documentation or any other single reference source. Thoroughly updated to reflect the significant new programming language features and library modules that have been introduced in Python 2.6 and Python 3, the fourth edition of Python Essential Reference is the definitive guide for programmers who need to modernize existing Python code or who are planning an eventual migration to Python 3. Programmers starting a new Python project will find detailed coverage of contemporary Python programming idioms.

Socialisation and Economic Alienation in the Post-industrial Society

Directory of Open Access Journals (Sweden)

Tumanyan Vadym E.

2013-11-01

Full Text Available The article offers a theoretical and methodological assessment of modern institutional and technological shifts and changes in the context of their impact on the social status of an economic individual and its ability to effectively appropriate results of socio-economic development under conditions of the post-industrial society and globalisation. The article describes the content of socialisation of economy in the post-industrial society as a process of removal of social and institutional gaps, which arise due to a self-sufficient technological development, and demonstrates the role of value criteria and restrictions in humanisation of social relations and deployment of essential powers of a human being. The article specifies consequences of increase of the gap between the existing potential of human freedom and strengthening of its impersonal regulation with the help of modern technologies. It characterises social risks of re-formatting of the system of values and offers ways for preventive and adaptive socialisation of economic systems under conditions of globalisation.

Predicting post-vaccination autoimmunity: who might be at risk?

Science.gov (United States)

Soriano, Alessandra; Nesher, Gideon; Shoenfeld, Yehuda

2015-02-01

Vaccinations have been used as an essential tool in the fight against infectious diseases, and succeeded in improving public health. However, adverse effects, including autoimmune conditions may occur following vaccinations (autoimmune/inflammatory syndrome induced by adjuvants--ASIA syndrome). It has been postulated that autoimmunity could be triggered or enhanced by the vaccine immunogen contents, as well as by adjuvants, which are used to increase the immune reaction to the immunogen. Fortunately, vaccination-related ASIA is uncommon. Yet, by defining individuals at risk we may further limit the number of individuals developing post-vaccination ASIA. In this perspective we defined four groups of individuals who might be susceptible to develop vaccination-induced ASIA: patients with prior post-vaccination autoimmune phenomena, patients with a medical history of autoimmunity, patients with a history of allergic reactions, and individuals who are prone to develop autoimmunity (having a family history of autoimmune diseases; asymptomatic carriers of autoantibodies; carrying certain genetic profiles, etc.). Copyright © 2014 Elsevier Ltd. All rights reserved.

In Vitro Study of the Antifungal Activity of Essential Oils Obtained from Mentha spicata, Thymus vulgaris, and Laurus nobilis.

Science.gov (United States)

Houicher, Abderrahmane; Hechachna, Hind; Teldji, Hanifa; Ozogul, Fatih

2016-01-01

The aim of this study was to determine the antifungal activity of the essential oils isolated from three aromatic plants against 13 filamentous fungal strains. The major constituents of Mentha spicata, Thymus vulgaris, and Laurus nobilis essential oils were carvone (52.2%), linalool (78.1%), and 1,8-cineole (45.6%), respectively. There are also some patents suggesting the use of essential oils as natural and safe alternatives to fungicides for plant protection. In the present work, M. spicata essential oil exhibited the strongest activity against all tested fungi in which Fusarium graminearum, F.moniliforme, and Penicillium expansum were the most sensitive to mint oil with lower minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values of 2.5 μL mL-1 (v/v). Thymus vulgaris essential oil was less active compared to the oil of M. spicata. Aspergillus ochraceus was the most sensitive strain to thyme oil with MIC and MFC values of 2.5 and 5 μL mL-1, respectively. Thymus vulgaris essential oil also exhibited a moderate fungicidal effect against the tested fungi, except for A. niger (MFC >20 μL-1). L. nobilis essential oil showed a similar antifungal activity with thyme oil in which A. parasiticus was the most resistant strain to this oil (MFC >20 μL mL-1). Our findings suggested the use of these essential oils as alternatives to synthetic fungicides in order to prevent pre-and post-harvest infections and ensure product safety. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Physiological Roles of Plant Post-Golgi Transport Pathways in Membrane Trafficking.

Science.gov (United States)

Uemura, Tomohiro

2016-10-01

Membrane trafficking is the fundamental system through which proteins are sorted to their correct destinations in eukaryotic cells. Key regulators of this system include RAB GTPases and soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs). Interestingly, the numbers of RAB GTPases and SNAREs involved in post-Golgi transport pathways in plant cells are larger than those in animal and yeast cells, suggesting that plants have evolved unique and complex post-Golgi transport pathways. The trans-Golgi network (TGN) is an important organelle that acts as a sorting station in the post-Golgi transport pathways of plant cells. The TGN also functions as the early endosome, which is the first compartment to receive endocytosed proteins. Several endocytosed proteins on the plasma membrane (PM) are initially targeted to the TGN/EE, then recycled back to the PM or transported to the vacuole for degradation. The recycling and degradation of the PM localized proteins is essential for the development and environmental responses in plant. The present review describes the post-Golgi transport pathways that show unique physiological functions in plants. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Minimising post-operative risk using a Post-Anaesthetic Care Tool (PACT): protocol for a prospective observational study and cost-effectiveness analysis.

Science.gov (United States)

Street, Maryann; Phillips, Nicole M; Kent, Bridie; Colgan, Stephen; Mohebbi, Mohammadreza

2015-06-01

While the risk of adverse events following surgery has been identified, the impact of nursing care on early detection of these events is not well established. A systematic review of the evidence and an expert consensus study in post-anaesthetic care identified essential criteria for nursing assessment of patient readiness for discharge from the post-anaesthetic care unit (PACU). These criteria were included in a new nursing assessment tool, the Post-Anaesthetic Care Tool (PACT), and incorporated into the post-anaesthetic documentation at a large health service. The aim of this study is to test the clinical reliability of the PACT and evaluate whether the use of PACT will (1) enhance the recognition and response to patients at risk of deterioration in PACU; (2) improve documentation for handover from PACU nurse to ward nurse; (3) result in improved patient outcomes and (4) reduce healthcare costs. A prospective, non-randomised, pre-implementation and post-implementation design comparing: (1) patients (n=750) who have surgery prior to the implementation of the PACT and (2) patients (n=750) who have surgery after PACT. The study will examine the use of the tool through the observation of patient care and nursing handover. Patient outcomes and cost-effectiveness will be determined from health service data and medical record audit. Descriptive statistics will be used to describe the sample and compare the two patient groups (pre-intervention and post-intervention). Differences in patient outcomes between the two groups will be compared using the Cochran-Mantel-Haenszel test and regression analyses and reported as ORs with the corresponding 95% CIs. This study will test the clinical reliability and cost-effectiveness of the PACT. It is hypothesised that the PACT will enable nurses to recognise and respond to patients at risk of deterioration, improve handover to ward nurses, improve patient outcomes, and reduce healthcare costs. Published by the BMJ Publishing Group

C-Mannosylation of thrombopoietin receptor (c-Mpl) regulates thrombopoietin-dependent JAK-STAT signaling.

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Sasazawa, Yukiko; Sato, Natsumi; Suzuki, Takehiro; Dohmae, Naoshi; Simizu, Siro

The thrombopoietin receptor, also known as c-Mpl, is a member of the cytokine superfamily, which regulates the differentiation of megakaryocytes and formation of platelets by binding to its ligand, thrombopoietin (TPO), through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. The loss-of-function mutations of c-Mpl cause severe thrombocytopenia due to impaired megakaryocytopoiesis, and gain-of-function mutations cause thrombocythemia. c-Mpl contains two Trp-Ser-Xaa-Trp-Ser (Xaa represents any amino acids) sequences, which are characteristic sequences of type I cytokine receptors, corresponding to C-mannosylation consensus sequences: Trp-Xaa-Xaa-Trp/Cys. C-mannosylation is a post-translational modification of tryptophan residue in which one mannose is attached to the first tryptophan residue in the consensus sequence via C-C linkage. Although c-Mpl contains some C-mannosylation sequences, whether c-Mpl is C-mannosylated or not has been uninvestigated. We identified that c-Mpl is C-mannosylated not only at Trp(269) and Trp(474), which are putative C-mannosylation site, but also at Trp(272), Trp(416), and Trp(477). Using C-mannosylation defective mutant of c-Mpl, the C-mannosylated tryptophan residues at four sites (Trp(269), Trp(272), Trp(474), and Trp(477)) are essential for c-Mpl-mediated JAK-STAT signaling. Our findings suggested that C-mannosylation of c-Mpl is a possible therapeutic target for platelet disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Essential software architecture

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Gorton, Ian

2011-01-01

Job titles like ""Technical Architect"" and ""Chief Architect"" nowadays abound in software industry, yet many people suspect that ""architecture"" is one of the most overused and least understood terms in professional software development. Gorton's book tries to resolve this dilemma. It concisely describes the essential elements of knowledge and key skills required to be a software architect. The explanations encompass the essentials of architecture thinking, practices, and supporting technologies. They range from a general understanding of structure and quality attributes through technical i

Post-mortem imaging compared with autopsy in trauma victims--A systematic review.

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Jalalzadeh, Hamid; Giannakopoulos, Georgios F; Berger, Ferco H; Fronczek, Judith; van de Goot, Frank R W; Reijnders, Udo J; Zuidema, Wietse P

2015-12-01

Post-mortem imaging or virtual autopsy is a rapidly advancing field of post-mortem investigations of trauma victims. In this review we evaluate the feasibility of complementation or replacement of conventional autopsy by post-mortem imaging in trauma victims. A systematic review was performed in compliance with the PRISMA guidelines. MEDLINE, Embase and Cochrane databases were systematically searched for studies published between January 2008 and January 2014, in which post-mortem imaging was compared to conventional autopsy in trauma victims. Studies were included when two or more trauma victims were investigated. Twenty-six studies were included, with a total number of 563 trauma victims. Post-mortem computer tomography (PMCT) was performed in 22 studies, post-mortem magnetic resonance imaging (PMMRI) in five studies and conventional radiography in two studies. PMCT and PMMRI both demonstrate moderate to high-grade injuries and cause of death accurately. PMCT is more sensitive than conventional autopsy or PMMRI in detecting skeletal injuries. For detecting minor organ and soft tissue injuries, autopsy remains superior to imaging. Aortic injuries are missed frequently by PMCT and PMMRI and form their main limitation. PMCT should be considered as an essential supplement to conventional autopsy in trauma victims since it detects many additional injuries. Despite some major limitations, PMCT could be used as an alternative for conventional autopsy in situations where conventional autopsy is rejected or unavailable. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Increase of essential amino acids in the bovine uterine lumen during preimplantation development.

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Groebner, Anna E; Rubio-Aliaga, Isabel; Schulke, Katy; Reichenbach, Horst D; Daniel, Hannelore; Wolf, Eckhard; Meyer, Heinrich H D; Ulbrich, Susanne E

2011-05-01

Amino acids (AAs) are crucial for the developing conceptus prior to implantation. To provide insights into the requirements of the bovine embryo, we determined the AA composition of the uterine fluid. At days 12, 15, and 18 post-estrus, the uteri of synchronized pregnant and non-pregnant Simmental heifers were flushed for the analysis of 41 AAs and their derivatives by liquid chromatography-tandem mass spectrometry. The ipsilateral endometrium was sampled for quantitative PCR. In addition to a pregnancy-dependent increase of the essential AAs (P<0.01), we detected elevated concentrations for most non-essential proteinogenic AAs. Histidine (His) and the expression of the His/peptide transporter solute carrier 15A3 (SLC15A3) were significantly increased at day 18 of pregnancy in vivo. In addition, SLC15A3 was predominantly stimulated by trophoblast-derived interferon-τ in stroma cells of an in vitro co-culture model of endometrial cells. Our results show an increased concentration of AAs most likely to optimally provide the elongating pre-attachment conceptus with nutrients.

CMI Conditionality and Post-CMI Architecture

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Gongpil Choi

2003-06-01

Full Text Available The CMI (Chiang Mai Initiative is designed to provide regional liquidity facility after Asian financial crisis of 1997. The current setting of the CMI is centered on four areas: swap network, regional surveillance, monitoring capital flows, and training personnel. However, since the size of bilateral swap is around 1-3 billion dollars and only 10 percent of the drawings available to a nation can be provided for a limited period without an IMF agreement, the CMI cannot be enough to counteract sudden capital flights or volatile movements of regional exchange rates. Based on the evaluation of IMF program, CMI conditionality needs to satisfy a certain set of requirements that address the local issues. Therefore, in modeling the post-CMI architecture, it is essential to consider the institutional issues to implement numerous agendas for regional cooperation. The role of the institution should be focused on overcoming structural deficiencies in the regional capital markets. It is important that the issues of surveillance and conditionality need to be discussed in the context of implementing region-wide inflation targeting, which can help to stabilize the real exchange rate. The success of the post-CMI would depend on how effectively the arrangement addresses the local issues that could not be handled by the IMF program.

Essential travel medicine

CERN Document Server

Zuckerman, Jane N; Leggat, Peter

2015-01-01

This 1st edition of Essential Travel Medicine provides an excellent concise introduction to the specialty of Travel Medicine. This core text will enable health care practitioners particularly those new to the clinical practice of Travel Medicine, to gain a fundamental understanding of the diverse and complex issues which can potentially affect the health of the many millions of people who undertake international travel. Jane N Zuckerman is joined by Gary W Brunette from CDC and Peter A Leggat from Australia as Editors. Leading international specialists in their fields have contributed authoritative chapters reflecting current knowledge to facilitate best clinical practice in the different aspects of travel medicine. The aim of Essential Travel Medicine is to provide a comprehensive guide to Travel Medicine as well as a fundamental knowledge base to support international undergraduate and postgraduate specialty training programmes in the discipline of Travel Medicine. The 1st edition of Essential Travel ...

Essential Oils and Antifungal Activity

Science.gov (United States)

Coppola, Raffaele; De Feo, Vincenzo

2017-01-01

Since ancient times, folk medicine and agro-food science have benefitted from the use of plant derivatives, such as essential oils, to combat different diseases, as well as to preserve food. In Nature, essential oils play a fundamental role in protecting the plant from biotic and abiotic attacks to which it may be subjected. Many researchers have analyzed in detail the modes of action of essential oils and most of their components. The purpose of this brief review is to describe the properties of essential oils, principally as antifungal agents, and their role in blocking cell communication mechanisms, fungal biofilm formation, and mycotoxin production. PMID:29099084

Physical chemistry II essentials

CERN Document Server

REA, The Editors of

1992-01-01

REA's Essentials provide quick and easy access to critical information in a variety of different fields, ranging from the most basic to the most advanced. As its name implies, these concise, comprehensive study guides summarize the essentials of the field covered. Essentials are helpful when preparing for exams, doing homework and will remain a lasting reference source for students, teachers, and professionals. Physical Chemistry II includes reaction mechanisms, theoretical approaches to chemical kinetics, gravitational work, electrical and magnetic work, surface work, kinetic theory, collisional and transport properties of gases, statistical mechanics, matter and waves, quantum mechanics, and rotations and vibrations of atoms and molecules.

[Prevention of the post-surgical insatisfactions and possible medico-legal complications].

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Flageul, G; Pessis, R

2017-10-01

The purpose of this work is to better understand the reasons for post-surgical instability and what makes up the bed of medico-legal complications. Beyond technical competence, it is essential to observe a very high degree of rigor in listening to the real motivations in order to give the most accurate possible surgical indications and in particular to know to detect and never to operate certain patients who, whatever we do, will always be dissatisfied. The quality of information is one of the essential elements of prevention: information is part of the care and there is no therapeutic success without a successful relationship between a caregiver and a carereceiver. Before the surgery, it is essential to pre-establish written proof of the proper delivery of the information by signing a receipt and an informed consent document. However, the information does not stop at the time of the operative gesture and it is necessary to be able to provide complete and timely information about any post-surgical complications. Furthermore, aesthetic medicine is well understood and rigorously implemented, contributes to the prevention of surgical and medico-legal complications, reducing the heaviness of certain surgical gestures. The question of e-reputation should in no way be neglected. From this point of view, prevention consists in controlling as much as possible the Internet environment. Indeed, where, in the past, in the presence of a dissatisfied patient awaited us, the fear of word-of-mouth or trial is added to the risk of harm E-reputation whose implications can be very damaging. At a time when the intensive use of the Internet allows anyone to get out of anonymity, we must also control these tools at the risk of sacrificing our expertise at the coronation of amateurs. Copyright © 2017. Published by Elsevier Masson SAS.

Moving toward a precise nutrition: preferential loading of seeds with essential nutrients over non-essential toxic elements.

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Mather A. Khan

2014-02-01

Full Text Available Plants and seeds are the main source of essential nutrients for humans and livestock. Many advances have recently been made in understanding the molecular mechanisms by which plants take up and accumulate micronutrients such as iron, zinc, copper and manganese. Some of these mechanisms however, also facilitate the accumulation of non-essential toxic elements such as cadmium (Cd and arsenic (As. In humans, Cd and As intake has been associated with multiple disorders including kidney failure, diabetes, cancer and mental health issues. Recent studies have shown that some transporters can discriminate between essential metals and non-essential elements. Furthermore, sequestration of non-essential elements in roots has been described in several plant species as a key process limiting the translocation of non-essential elements to aboveground edible tissues, including seeds. Increasing the concentration of bioavailable micronutrients (biofortification in grains while lowering the accumulation of non-essential elements will likely require the concerted action of several transporters. This review discusses the most recent advances on mineral nutrition that could be used to preferentially enrich seeds with micronutrients and also illustrates how precision breeding and transport engineering could be used to enhance the nutritional value of crops by re-routing essential and non-essential elements to separate sink tissues (roots and seeds.

WOMEN POST OFFICE WORKERS IN BRITAIN: THE LONG STRUGGLE FOR GENDER EQUALITY AND THE POSITIVE IMPACT OF WORLD WAR II

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Mark James Crowley

2012-01-01

Full Text Available In Britain during the Second World War, the Post Office constituted the single largest employer of women. Historically, the Post Office, like many other employers, had discriminated against women. During World War I, shortages of male labor had resulted in some opportunities for women at the Post Office, but the improvement had neither been comprehensive nor enduring. Unlike World War I, World War II, however, proved to a real turning point in the Post Office's personnel practices. By the end of the Second World War, while the Post Office still did not treat women workers completely equally (persisting, for instance, in gender-biased pay practices, management nevertheless had made strides in their treatment and perception of women workers. Post Office executives increasingly perceived women on the payroll not as temporary wartime employees, but as permanent employees, who would be just as essential peacetime as in war.

Evaluating the Quality of Patient Decision-Making Regarding Post-Acute Care.

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Burke, Robert E; Jones, Jacqueline; Lawrence, Emily; Ladebue, Amy; Ayele, Roman; Leonard, Chelsea; Lippmann, Brandi; Matlock, Daniel D; Allyn, Rebecca; Cumbler, Ethan

2018-05-01

Despite a national focus on post-acute care brought about by recent payment reforms, relatively little is known about how hospitalized older adults and their caregivers decide whether to go to a skilled nursing facility (SNF) after hospitalization. We sought to understand to what extent hospitalized older adults and their caregivers are empowered to make a high-quality decision about utilizing an SNF for post-acute care and what contextual or process elements led to satisfaction with the outcome of their decision once in SNF. Qualitative inquiry using the Ottawa Decision Support Framework (ODSF), a conceptual framework that describes key components of high-quality decision-making. Thirty-two previously community-dwelling older adults (≥ 65 years old) and 22 caregivers interviewed at three different hospitals and three skilled nursing facilities. We used key components of the ODSF to identify elements of context and process that affected decision-making and to what extent the outcome was characteristic of a high-quality decision: informed, values based, and not associated with regret or blame. The most important contextual themes were the presence of active medical conditions in the hospital that made decision-making difficult, prior experiences with hospital readmission or SNF, relative level of caregiver support, and pressure to make a decision quickly for which participants felt unprepared. Patients described playing a passive role in the decision-making process and largely relying on recommendations from the medical team. Patients commonly expressed resignation and a perceived lack of choice or autonomy, leading to dissatisfaction with the outcome. Understanding and intervening to improve the quality of decision-making regarding post-acute care supports is essential for improving outcomes of hospitalized older adults. Our results suggest that simply providing information is not sufficient; rather, incorporating key contextual factors and improving the

Relining effects on the push-out shear bond strength of glass fiber posts

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Adriana Rosado Valente ANDRIOLI

Full Text Available Abstract Introduction The correct use of glass fiber posts in endodontically treated teeth is essential for the clinical success of restorative treatment. Objective This study evaluated the push-out shear bond strength of relined (R or non-relined (NR glass fiber posts, cemented with self-adhesive resin cement [RelyXTM U100 (U100] and conventional resin cement [RelyXTM ARC (ARC]. Material and method Sixty human single-rooted teeth were endodontically treated and divided into ARC-NR; U100-NR; ARC-R; U100-R groups. The teeth were sectioned into cervical, middle and apical thirds, and subjected to the push-out test. Bond strength was analyzed by the Friedman test; cement and post types were compared by the Mann Whitney test. The pattern of failures was evaluated with digital camera through images at 200x magnification, and was classified as adhesive (at the cement/dentin or cement/post interface, cohesive (cement or post, and mixed failures. Result In ARC-NR, bond strength values were higher in the cervical third; in U100-NR and ARC-R they were similar between the thirds. In U100-R, in the cervical and middle thirds the bond strength values were similar, and there was lower value in the apical third. For non-relined glass fiber posts, the highest mean bond strength values were observed with self-adhesive resin cement. Whereas, relined posts cemented with conventional resin cement had stronger cement layer in comparison with non-relined fiber posts. Conclusion The post relining technique was efficient in ARC-R. ARC-NR and U100-R showed improved bond strength in the cervical region of canal walls. The main failures were adhesive at the cement-post interface.

Essentialism Promotes Children's Inter-ethnic Bias

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Gil eDiesendruck

2015-08-01

Full Text Available The present study investigated the developmental foundation of the relation between social essentialism and attitudes. Forty-eight Jewish Israeli secular 6-year-olds were exposed to either a story emphasizing essentialism about ethnicity, or stories controlling for the salience of ethnicity or essentialism per se. After listening to a story, children’s attitudes were assessed in a drawing and in an IAT task. Compared to the control conditions, children in the ethnic essentialism condition drew a Jewish and an Arab character as farther apart from each other, and the Jewish character with a more positive affect than the Arab character. Moreover, boys in the ethnic essentialism condition manifested a stronger bias in the IAT. These findings reveal an early link between essentialism and inter-group attitudes.

Intracranial involvement in extramedullary hematopoiesis: case report and review of the literature

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Haidar, Salwa; Ortiz-Neira, Clara; Shroff, Manohar; Gilday, David; Blaser, Susan [Hospital for Sick Children, Department of Diagnostic Imaging, Toronto, ON (Canada)

2005-06-01

Intracranial involvement in extramedullary hematopoiesis (EMH) is rare, but it should be suspected in patients with myelofibrosis presenting with chronic severe headache. We present a 9-year-old girl with known myelofibrosis whose headaches were unresponsive to routine treatment. CT and MRI studies of the brain showed diffuse pachymeningeal thickening. CT examinations of the chest and abdomen had demonstrated bilateral thoracic paraspinal masses caused by EMH, suggesting the possibility that the intracranial involvement might also be related to EMH. The diagnosis was confirmed by sulfur colloid isotope scan. (orig.)

Intracranial involvement in extramedullary hematopoiesis: case report and review of the literature

International Nuclear Information System (INIS)

Haidar, Salwa; Ortiz-Neira, Clara; Shroff, Manohar; Gilday, David; Blaser, Susan

2005-01-01

Intracranial involvement in extramedullary hematopoiesis (EMH) is rare, but it should be suspected in patients with myelofibrosis presenting with chronic severe headache. We present a 9-year-old girl with known myelofibrosis whose headaches were unresponsive to routine treatment. CT and MRI studies of the brain showed diffuse pachymeningeal thickening. CT examinations of the chest and abdomen had demonstrated bilateral thoracic paraspinal masses caused by EMH, suggesting the possibility that the intracranial involvement might also be related to EMH. The diagnosis was confirmed by sulfur colloid isotope scan. (orig.)

Mcl-1 Ubiquitination: Unique Regulation of an Essential Survival Protein

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Barbara Mojsa

2014-05-01

Full Text Available Mcl-1 is an anti-apoptotic protein of the Bcl-2 family that is essential for the survival of multiple cell lineages and that is highly amplified in human cancer. Under physiological conditions, Mcl-1 expression is tightly regulated at multiple levels, involving transcriptional, post-transcriptional and post-translational processes. Ubiquitination of Mcl-1, that targets it for proteasomal degradation, allows for rapid elimination of the protein and triggering of cell death, in response to various cellular events. In the last decade, a number of studies have elucidated different pathways controlling Mcl-1 ubiquitination and degradation. Four different E3 ubiquitin-ligases (e.g., Mule, SCFβ-TrCP, SCFFbw7 and Trim17 and one deubiquitinase (e.g., USP9X, that respectively mediate and oppose Mcl-1 ubiquitination, have been formerly identified. The interaction between Mule and Mcl-1 can be modulated by other Bcl-2 family proteins, while recognition of Mcl-1 by the other E3 ubiquitin-ligases and deubiquitinase is influenced by phosphorylation of specific residues in Mcl-1. The protein kinases and E3 ubiquitin-ligases that are involved in the regulation of Mcl-1 stability vary depending on the cellular context, highlighting the complexity and pivotal role of Mcl-1 regulation. In this review, we attempt to recapitulate progress in understanding Mcl-1 regulation by the ubiquitin-proteasome system.

Ser/Thr Phosphorylation Regulates the Fatty Acyl-AMP Ligase Activity of FadD32, an Essential Enzyme in Mycolic Acid Biosynthesis*

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Le, Nguyen-Hung; Molle, Virginie; Eynard, Nathalie; Miras, Mathieu; Stella, Alexandre; Bardou, Fabienne; Galandrin, Ségolène; Guillet, Valérie; André-Leroux, Gwenaëlle; Bellinzoni, Marco; Alzari, Pedro; Mourey, Lionel; Burlet-Schiltz, Odile; Daffé, Mamadou; Marrakchi, Hedia

2016-01-01

Mycolic acids are essential components of the mycobacterial cell envelope, and their biosynthetic pathway is a well known source of antituberculous drug targets. Among the promising new targets in the pathway, FadD32 is an essential enzyme required for the activation of the long meromycolic chain of mycolic acids and is essential for mycobacterial growth. Following the in-depth biochemical, biophysical, and structural characterization of FadD32, we investigated its putative regulation via post-translational modifications. Comparison of the fatty acyl-AMP ligase activity between phosphorylated and dephosphorylated FadD32 isoforms showed that the native protein is phosphorylated by serine/threonine protein kinases and that this phosphorylation induced a significant loss of activity. Mass spectrometry analysis of the native protein confirmed the post-translational modifications and identified Thr-552 as the phosphosite. Phosphoablative and phosphomimetic FadD32 mutant proteins confirmed both the position and the importance of the modification and its correlation with the negative regulation of FadD32 activity. Investigation of the mycolic acid condensation reaction catalyzed by Pks13, involving FadD32 as a partner, showed that FadD32 phosphorylation also impacts the condensation activity. Altogether, our results bring to light FadD32 phosphorylation by serine/threonine protein kinases and its correlation with the enzyme-negative regulation, thus shedding a new horizon on the mycolic acid biosynthesis modulation and possible inhibition strategies for this promising drug target. PMID:27590338

Evaluation of active ingredients and larvicidal activity of clove and cinnamon essential oils against Anopheles gambiae (sensu lato).

Science.gov (United States)

Thomas, Adelina; Mazigo, Humphrey D; Manjurano, Alphaxard; Morona, Domenica; Kweka, Eliningaya J

2017-09-06

Mosquitoes are well-known vectors of many diseases including malaria and lymphatic filariasis. Uses of synthetic insecticides are associated with high toxicity, resistance, environmental pollution and limited alternative, effective synthetic insecticides. This study was undertaken to evaluate the larvicidal efficacy of clove and cinnamon essential oils against laboratory Anopheles gambiae (sensu stricto) and wild An. arabiensis larvae. The standard WHO guideline for larvicides evaluation was used, and the GC-MS machine was used for active compounds percentage composition analysis and structures identification. Probit regression analysis was used for LC 50 and LC 95 calculations while a t-test was used to test for significant differences between laboratory-reared and wild larvae populations in each concentration of plant extract. Mortality effect of clove and cinnamon essential oils against wild and laboratory-reared larvae had variations indicated by their LC 50 and LC 95 values. The mortality at different concentrations of cinnamon and clove post-exposure for wild and laboratory-reared larvae were dosage-dependent and were higher for cinnamon than for clove essential oils. The mortality effect following exposure to a blend of the two essential oils was higher for blends containing a greater proportion of cinnamon oil. In the chemical analysis of the active ingredients of cinnamon essential oil, the main chemical content was Eugenol, and the rarest was β-Linalool while for clove essential oil, the main chemical content was Eugenol and the rarest was Bicyclo. The essential oils showed a larvicidal effect which was concentration-dependent for both laboratory and wild collected larvae. The active ingredient compositions triggered different responses in mortality. Further research in small-scale should be conducted with concentrated extracted compounds.

Do people essentialize emotions? Individual differences in emotion essentialism and emotional experience.

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Lindquist, Kristen A; Gendron, Maria; Oosterwijk, Suzanne; Barrett, Lisa Feldman

2013-08-01

Many scientific models of emotion assume that emotion categories are natural kinds that carve nature at its joints. These beliefs remain strong, despite the fact that the empirical record on the issue has remained equivocal for over a century. In this research, the authors examined one reason for this situation: People essentialize emotion categories by assuming that members of the same category (e.g., fear) have a shared metaphysical essence (i.e., a common causal mechanism). In Study 1, the authors found that lay people essentialize emotions by assuming that instances of the same emotion category have a shared essence that defines them, even when their surface features differ. Study 2 extended these findings, demonstrating that lay people tend to essentialize categories the more a category is of the body (vs. the mind). In Study 3, we examined the links between emotion essentialism and the complexity of actual emotional experiences. In particular, we predicted and found that individuals who hold essentialist beliefs about emotions describe themselves as experiencing highly differentiated emotional experiences but do not show evidence of stronger emotional differentiation in their momentary ratings of experience in everyday life. Implications for the science of emotion are discussed. PsycINFO Database Record (c) 2013 APA, all rights reserved.

English as a Lingua Franca: Applied Linguistics, Marxism, and Post-Marxist theory

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John Robert Schmitz

2017-03-01

Full Text Available ABSTRACT This paper is motived by a reading of “English as a Lingua Franca: An Immanent Critique” (O’REGAN, 2014, who claims that ELF researchers place their work at the forefront of debates with regard to what function and form English should play in the lives of its numerous speakers worldwide. O’Regan questions the use of an epistemology based on a positivist and objectivist paradigm, connected to a postmodernist and poststructuralist ‘sensibility’. To attempt a fair analysis of O’Regan’s critique of ELF, I consider it essential to examine Marxist theory in the light of the analyses of Sim’s (2000 Post-Marxism and of the work published by Laclau and Mouffe (1985. My reading leads me to claim that traditional Marxist thinking is compromised by its association with authoritarian and totalitarian stances, as opposed to Post-Marxist views of pluralism, libertarianism, and openness to the cultural climate of postmodernism. Based on the disillusions of post-Marxist thinkers, I conclude that the views of classical Marxism are not applicable to ‘English as a Lingua Franca’

The post-transcriptional regulatory system CSR controls the balance of metabolic pools in upper glycolysis of Escherichia coli.

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Morin, Manon; Ropers, Delphine; Letisse, Fabien; Laguerre, Sandrine; Portais, Jean-Charles; Cocaign-Bousquet, Muriel; Enjalbert, Brice

2016-05-01

Metabolic control in Escherichia coli is a complex process involving multilevel regulatory systems but the involvement of post-transcriptional regulation is uncertain. The post-transcriptional factor CsrA is stated as being the only regulator essential for the use of glycolytic substrates. A dozen enzymes in the central carbon metabolism (CCM) have been reported as potentially controlled by CsrA, but its impact on the CCM functioning has not been demonstrated. Here, a multiscale analysis was performed in a wild-type strain and its isogenic mutant attenuated for CsrA (including growth parameters, gene expression levels, metabolite pools, abundance of enzymes and fluxes). Data integration and regulation analysis showed a coordinated control of the expression of glycolytic enzymes. This also revealed the imbalance of metabolite pools in the csrA mutant upper glycolysis, before the phosphofructokinase PfkA step. This imbalance is associated with a glucose-phosphate stress. Restoring PfkA activity in the csrA mutant strain suppressed this stress and increased the mutant growth rate on glucose. Thus, the carbon storage regulator system is essential for the effective functioning of the upper glycolysis mainly through its control of PfkA. This work demonstrates the pivotal role of post-transcriptional regulation to shape the carbon metabolism. © 2016 John Wiley & Sons Ltd.

Defining post-sternotomy mediastinitis for clinical evidence-based studies.

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van Wingerden, Jan J; de Mol, Bas A J M; van der Horst, Chantal M A M

2016-05-01

Considerable advances have already been made in the treatment of deep thoracic wound infections following a median sternotomy for cardiac surgery. Further improvement in diagnosis, treatment, and outcome will require a targeted approach by multidisciplinary teams. Clear communication and synergy between the various clinical and supportive disciplines would assist in removing the last barriers to standardized evidence-based studies and the development of improved evidence-based guidelines. An extensive literature search without language restrictions was carried out on PubMed (Medline), EMBASE, and Web of Science, covering the period 1988 to week 16, 2014, and a manual search of the reference lists was performed regarding all possible definitions and classifications of post-sternotomy mediastinitis. Two hundred and eighteen papers describing post-sternotomy infections in a multitude of terms were identified, and the strengths and weaknesses of the most popular definitions and terms relating specifically to post-sternotomy infections were examined. This study revealed that clinicians use a multitude of terms to describe post-sternotomy infections without defining the condition under treatment. Occasionally, older epidemiological (surveillance) definitions were used. It also shows that supportive disciplines have their own definitions, or interpretations of existing definitions, to describe these infections. The outcome of this study is that clinicians have adopted no single definition, which is essential for further improvement for evidence-based studies. We suggest that it is possible to adopt a single term for thoracic infection after a sternotomy (and only sternotomy), and propose a clinical definition for this purpose. © The Author(s) 2016.

Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

Science.gov (United States)

2017-03-27

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); B-cell Adult Acute Lymphoblastic Leukemia; B-cell Childhood Acute Lymphoblastic Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; T-cell Childhood Acute Lymphoblastic Leukemia

The C allele of JAK2 rs4495487 is an additional candidate locus that contributes to myeloproliferative neoplasm predisposition in the Japanese population

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Ohyashiki Junko H

2012-01-01

Full Text Available Abstract Background Polycythemia vera (PV, essential thrombocythemia (ET, and primary myelofibrosis (PMF are myeloproliferative neoplasms (MPNs characterized in most cases by a unique somatic mutation, JAK2 V617F. Recent studies revealed that JAK2 V617F occurs more frequently in a specific JAK2 haplotype, named JAK2 46/1 or GGCC haplotype, which is tagged by rs10974944 (C/G and/or rs12343867 (T/C. This study examined the impact of single nucleotide polymorphisms (SNPs of the JAK2 locus on MPNs in a Japanese population. Methods We sequenced 24 JAK2 SNPs in Japanese patients with PV. We then genotyped 138 MPN patients (33 PV, 96 ET, and 9 PMF with known JAK2 mutational status and 107 controls for a novel SNP, in addition to two SNPs known to be part of the 46/1 haplotype (rs10974944 and rs12343867. Associations with risk of MPN were estimated by odds ratios and their 95% confidence intervals using logistic regression. Results A novel locus, rs4495487 (T/C, with a mutated T allele was significantly associated with PV. Similar to rs10974944 and rs12343867, rs4495487 in the JAK2 locus is significantly associated with JAK2-positive MPN. Based on the results of SNP analysis of the three JAK2 locus, we defined the "GCC genotype" as having at least one minor allele in each SNP (G allele in rs10974944, C allele in rs4495487, and C allele in rs12343867. The GCC genotype was associated with increased risk of both JAK2 V617F-positive and JAK2 V617F-negative MPN. In ET patients, leukocyte count and hemoglobin were significantly associated with JAK2 V617F, rather than the GCC genotype. In contrast, none of the JAK2 V617F-negative ET patients without the GCC genotype had thrombosis, and splenomegaly was frequently seen in this subset of ET patients. PV patients without the GCC genotype were significantly associated with high platelet count. Conclusions Our results indicate that the C allele of JAK2 rs4495487, in addition to the 46/1 haplotype, contributes

Essential oils and anxiolytic aromatherapy.

Science.gov (United States)

Setzer, William N

2009-09-01

A number of essential oils are currently in use as aromatherapy agents to relieve anxiety, stress, and depression. Popular anxiolytic oils include lavender (Lavandula angustifolia), rose (Rosa damascena), orange (Citrus sinensis), bergamot (Citrus aurantium), lemon (Citrus limon), sandalwood (Santalum album), clary sage (Salvia sclarea), Roman chamomile (Anthemis nobilis), and rose-scented geranium (Pelargonium spp.). This review discusses the chemical constituents and CNS effects of these aromatherapeutic essential oils, as well as recent studies on additional essential oils with anxiolytic activities.

Pre-genomic, genomic and post-genomic study of microbial communities involved in bioenergy.

Science.gov (United States)

Rittmann, Bruce E; Krajmalnik-Brown, Rosa; Halden, Rolf U

2008-08-01

Microorganisms can produce renewable energy in large quantities and without damaging the environment or disrupting food supply. The microbial communities must be robust and self-stabilizing, and their essential syntrophies must be managed. Pre-genomic, genomic and post-genomic tools can provide crucial information about the structure and function of these microbial communities. Applying these tools will help accelerate the rate at which microbial bioenergy processes move from intriguing science to real-world practice.

Post-Fire Peat Land Understory Plant in Rimba Panjang, Sumatera, Indonesia

Science.gov (United States)

Firdaus, L. N.; Nursal; Wulandari, Sri; Syafi'i, Wan; Fauziah, Yuslim

2017-12-01

The existence of understory plants during early post-fire succession is essential in term of natural post-fire ecological restoration. More than fifty percent of fire incidents in Riau, Sumatera, Indonesia occurred in shallow peat lands which have the huge impact on vegetation damage. This study aims to explore the understory plants species and diversity in post-fire peat land at Rimba Panjang, Kampar Regency, Sumatera, Indonesia. By using survey method, the observations were conducted on 150 plots which were distributed randomly over four locations based on the year after fire: 2009, 2014, 2015 and 2016. We found respectively 12, 14, 19 and 17 species at that sites with respective Shannon Wiener diversity index were 1.72, 2.00, 2.14 and 2.40. All the sites were dominated by Stenochlaena palustris (Burm.). Coverage percentage of understory vegetation were respectively 28.87%, 25.50%, 51.60% and 54.13%. Overall, we found 31 species of 17 familia. The result showed that the species composition, diversity index and coverage percentage of understory plant are likely to decrease in line with the length of time after the fire. Post peatland fires in Rimba Panjang are still having the characteristics of the peat swamp habitat which was dominated by Stenochlaena palustris (Burm.). Ecological restoration of that habitat is still possible, but it is necessary to consider technological and socio-economical aspects of local communities.

Assessment of the efficiency of essential oils in the preservation of postharvest papaya in an antimicrobial packaging system

OpenAIRE

Espitia,Paula Judith Perez; Soares,Nilda de Fátima Ferreira; Botti,Laura Costa Moreira; Melo,Nathália Ramos de; Pereira,Olinto Liparini; Silva,Washington Azevêdo da

2012-01-01

Rot and damage caused by post-harvest phytopathogenic fungi affect fruit quality. Essential oils (EO) are considered as an alternative to fungicides. Postharvest diseases of fruits may also be controlled by the bagging approach and the use of antimicrobial packaging. Based on the beneficial properties of EO and the concepts of bagging and antimicrobial packaging, this study aimed to develop sachets containing EO to be used as part of an antimicrobial packaging system. The activities of oregan...

Post-ovulatory contraception.

Science.gov (United States)

Glasier, A; Baird, D T

1990-06-01

It is possible to prevent pregnancy after unprotected intercourse by suppressing ovulation, inhibiting fertilization or interfering with tubal transport and/or implantation of the early embryo. IUCDs probably prevent implantation by stimulating the release of prostaglandins from the endometrium but are not acceptable to many women. Post-coital contraceptive steroids, e.g. high-dose oestrogens, are associated with a relatively high incidence of side-effects and must be taken within 72 hours of coitus. As these agents are effective by creating a uterine environment unfavourable for implantation, it may be possible to use antigestagens or antioestrogens in this way. It is already known that an antigestagen in combination with a prostaglandin is a highly effective method of inducing abortion in very early pregnancy. The corpus luteum is essential for the maintenance of pregnancy and its destruction by a luteolytic agent should dislodge the implanting embryo. If an effective method of preventing implantation could be developed which was relatively free from side-effects, it should be possible to use it as a regular form of contraception to be taken only when the risk of pregnancy had occurred.

Essential AOP

DEFF Research Database (Denmark)

De Fraine, Bruno; Ernst, Erik; Südholt, Mario

2010-01-01

Aspect-oriented programming (AOP) has produced interesting language designs, but also ad hoc semantics that needs clarification. We contribute to this clarification with a calculus that models essential AOP, both simpler and more general than existing formalizations. In AOP, advice may intercept...

Post-traumatic Stress Disorder Post Partum

Science.gov (United States)

Schwab, W.; Marth, C.; Bergant, A. M.

2012-01-01

Traumatic birth experiences may lead to serious psychological impairment. Recent studies show that a considerable number of women can develop post-traumatic stress disorder (PTSD), in some cases in a subsyndromal form. Until now, the possibility that postpartum psychological symptoms might be a continuum of a pre-existing disorder in pregnancy has rarely been considered. This study therefore aimed to evaluate the proportion of women who develop post-traumatic stress disorder as a result of childbirth. Materials and Methods: 56 multiparous women were recruited for the study. The diagnosis of PTSD was made according to the criteria for psychological disorders in the DSM-IV (Diagnostics and Statistical Manual of Mental Disorders). The data were collected in structured interviews in the 30th to 38th week of gestation and in the 6th week post partum. Results: Of the 56 women participating, 52 (93 %) completed the survey. Uncontrolled results showed that 21.15 % of the multiparous women met the full diagnostic PTSD criteria in the 6th week post partum. After the exclusion of all cases already characterised by all criteria or a subsyndromal form of PTSD caused by previous traumatisation, the PTSD rate was below 8 % at 6 weeks postpartum (= incidence rate of PTSD post partum). Conclusions: The present study is the first prospective longitudinal study to demonstrate the occurrence of full criteria PTSD in multiparous women as a result of childbirth after having excluded pre-existing PTSD. The results of our study show a high prevalence rate of PTSD during pregnancy. A number of women report all aspects of post-traumatic stress disorder as a result of childbirth. PMID:25253905

Feeding behaviour of sheep fed lucerne v. grass hays with controlled post-ingestive consequences

OpenAIRE

Favreau, Angelique; Ginane, Cécile; Baumont, Rene

2010-01-01

Understanding what determines feeding behaviour in herbivores is essential to optimise the use of forages in breeding systems. Herbivores can evaluate foods by associative learning of their pre-ingestive characteristics (taste, odour, etc.) and their postingestive consequences. Post-ingestive consequences are acknowledged as influencing intake and food choices, but the role of pre-ingestive characteristics is still being debated. Our experiment was designed to test their separate effects on d...

Ydre 2.0 A Time-Spatial Approach towards Post-Monetarism and Integrated Sustainable Development

OpenAIRE

Assmo, Per; Wihlborg, Elin

2010-01-01

The post-industrial information society leads to new patterns of societal change. Despite the changes, the conventional monetary market oriented economic view of development is still dominant. However, essential values are often concealed or even excluded in conventional monetary analyses. Rural areas have a possibility to be in the forefront of new alternative routes to achieve sustainable integrated ecological, social and economic development processes that reaches beyond the conventional m...

Autodesk 3ds Max 2012 Essentials

CERN Document Server

Derakhshani, Randi L

2011-01-01

Get a jump-start on Autodesk 3ds Max 2012 essentials-with the Essentials! The new Essentials books from Sybex are beautiful, task-based, full-color Autodesk Official Training Guides that help you get up to speed on Autodesk topics quickly and easily. Autodesk 3ds Max 2012 Essentials thoroughly covers the fundamentals of this popular 3D animation effects, and visualization software, teaching you what you need to become quickly productive. By following the book's clear explanations, practical tutorials, and step-by-step exercises, you'll cover all the bases. Topics include modeling, animation,

Control of eight predominant Eimeria spp. involved in economic coccidiosis of broiler chicken by a chemically characterized essential oil.

Science.gov (United States)

Barbour, E K; Bragg, R R; Karrouf, G; Iyer, A; Azhar, E; Harakeh, S; Kumosani, T

2015-03-01

To control eight most predominant Eimeria spp. involved in the economic disease of coccidiosis in broiler chicken, by a chemically characterized essential oil of eucalyptus and peppermint. The experimental design consisted of 160 day-old-broiler chicks, divided into four equal groups (G1 , G2 , G3 and G4 ), with 40 birds per group. Each group was divided into four equal subgroups. Birds in G1 were deprived of essential oil treatment and of Eimeria challenge. Birds in G2 were unchallenged, and administered the essential oil in drinking water at 0.69 ml kg(-1) body weight. Birds in G3 were untreated with essential oil, and each of its four subgroups was challenged at a different age (14, 21, 28 and 35 days). Birds in G4 were treated with essential oil, and challenged in the same manner as for G3 . Equal number of birds from all subgroups (n = 10) were sacrificed at the sixth day after the time allocated for each challenge. The 6 day incubation period post challenge resulted in respective mean per cent weight increase in G2 and G1 birds equivalent to 57.8 and 53.1% (P essential oil improved the per cent weight increase in challenged birds (54.6%) compared to the challenged-untreated birds (18.6%) (P essential oils of eucalyptus and peppermint to control the most prevalent Eimeria spp. involved in coccidiosis of broiler chicken, helping in improvement of their production, alleviation of lesions and reduction in intestinal oocyst counts. This study provides information about the possibility of using this blend of essential oil as a coccidiostat for the protection of broiler chickens against the prevalent eight Eimeria spp. of coccidiosis. © 2014 The Society for Applied Microbiology.

A forward genetic screen reveals essential and non-essential RNAi factors in Paramecium tetraurelia

Science.gov (United States)

Marker, Simone; Carradec, Quentin; Tanty, Véronique; Arnaiz, Olivier; Meyer, Eric

2014-01-01

In most eukaryotes, small RNA-mediated gene silencing pathways form complex interacting networks. In the ciliate Paramecium tetraurelia, at least two RNA interference (RNAi) mechanisms coexist, involving distinct but overlapping sets of protein factors and producing different types of short interfering RNAs (siRNAs). One is specifically triggered by high-copy transgenes, and the other by feeding cells with double-stranded RNA (dsRNA)-producing bacteria. In this study, we designed a forward genetic screen for mutants deficient in dsRNA-induced silencing, and a powerful method to identify the relevant mutations by whole-genome sequencing. We present a set of 47 mutant alleles for five genes, revealing two previously unknown RNAi factors: a novel Paramecium-specific protein (Pds1) and a Cid1-like nucleotidyl transferase. Analyses of allelic diversity distinguish non-essential and essential genes and suggest that the screen is saturated for non-essential, single-copy genes. We show that non-essential genes are specifically involved in dsRNA-induced RNAi while essential ones are also involved in transgene-induced RNAi. One of the latter, the RNA-dependent RNA polymerase RDR2, is further shown to be required for all known types of siRNAs, as well as for sexual reproduction. These results open the way for the dissection of the genetic complexity, interconnection, mechanisms and natural functions of RNAi pathways in P. tetraurelia. PMID:24860163

Proteomics of post-irradiation recovery in D. radiodurans

International Nuclear Information System (INIS)

Basu, Bhakti; Apte, Shree Kumar

2012-01-01

An extremophile Deinococcus radiodurans is bestowed with an extraordinary DNA repair ability that renders it virtually resistant to all known forms of DNA damage caused by ionizing radiations (10 kGy of gamma rays), UV (1 kJ/m 2 ) or weeks of desiccation etc. The genome of D. radiodurans encodes a unique combination of DNA repair pathways such as prokaryotic type RecFOR mediated homologous recombination (HR) and nucleotide/base excision repair along with eukaryotic type strand annealing (SA) and non-homologous end joining (NHEJ), but is devoid of universal prokaryotic DNA repair pathways such as RecBCD mediated HR, photo-reactivation and SOS response. Collective evidence obtained so far from multiple approaches, have indicated (i) that all genes essential for DNA repair are not necessarily induced following radiation stress (ii) early RecA independent DNA assembly occurs, and (iii) absolute necessity of RecA dependent HR for final genome restitution. The 6 kGy gamma irradiation inducible proteome dynamics were mapped during the post-irradiation growth arrest phase by 2D protein electrophoresis coupled with mass spectrometry. Radiation inducible expression of at least 33 proteins was evident in the first 1h of post irradiation recovery

Political Evolution at NATO Level in Post Cold War Era

Directory of Open Access Journals (Sweden)

Tomescu Cătălin Tomiţă

2015-06-01

Full Text Available The beginning of the post Cold era sounds like that: „The world has changed dramatically. The Alliance has made an essential contribution. The peoples of North America and the whole of Europe can now join in a community of shared values based on freedom, democracy, human rights and the rule of law. As an agent of change, a source of stability and the indispensable guarantor of its members' security, our Alliance will continue to play a key role in building a new, lasting order of peace in Europe: a Europe of cooperation and prosperity”[1].

ANALYSIS OF RAIN BY WILLIAM SOMERSET MAUGHAM IN TERMS OF POST-COLONIAL TERMS

Directory of Open Access Journals (Sweden)

Şaban KÖKTÜRK

2015-04-01

Full Text Available This study dealt with the analysis of a short story, Rain by William Somerset Maugham in terms of post-colonial terms or elements. Before the analysis, the writer of the book was introduced and then the plot was explained so as to make readers familiar with the short story. In the analysis section, post-colonial elements or related terms such as missionary, colonial authority, the state of being subaltern, Manichean allegory, mimicry, ambivalence, surveillance, imperial hegemony, hybridity, essentialism, monolithic culture, alienation, dislocation, misuse of power, gender difference were analyzed from some of the excerpts whether to see how strong these concepts affect the course of the fiction. The study targeted at showing students of language & literature departments the application of the related terms or elements in such stories.

The application of post yield fracture methodology to the evaluation of large structures

International Nuclear Information System (INIS)

Landes, J.D.

1979-01-01

The objective of this work is to determine how to use small specimens test results to measure fracture toughness values for application to the evaluation of large structural components. Linear elastic fracture mechanics concepts based on the crack tip stress intensity factor, K, have been extended into the post yield regime by the use of elastic-plastic characterizing parameters such as J integral and COD. One of the primary applications of this technology is the determination of fracture toughness values from small specimens tests taken primarily in the post yield regime which can be used to evaluate structures operating in an essentially linear elastic regime. The fracture toughness values may be either conservative or unconservative depending on the fracture mode; extreme care must be taken in interpretting these results. (orig.)

Post-Earthquake Reconstruction — in Context of Housing

Science.gov (United States)

Sarkar, Raju

Comprehensive rescue and relief operations are always launched with no loss of time with active participation of the Army, Governmental agencies, Donor agencies, NGOs, and other Voluntary organizations after each Natural Disaster. There are several natural disasters occurring throughout the world round the year and one of them is Earthquake. More than any other natural catastrophe, an earthquake represents the undoing of our most basic pre-conceptions of the earth as the source of stability or the first distressing factor due to earthquake is the collapse of our dwelling units. Earthquake has affected buildings since people began constructing them. So after each earthquake a reconstruction of housing program is very much essential since housing is referred to as shelter satisfying one of the so-called basic needs next to food and clothing. It is a well-known fact that resettlement (after an earthquake) is often accompanied by the creation of ghettos and ensuing problems in the provision of infrastructure and employment. In fact a housing project after Bhuj earthquake in Gujarat, India, illustrates all the negative aspects of resettlement in the context of reconstruction. The main theme of this paper is to consider few issues associated with post-earthquake reconstruction in context of housing, all of which are significant to communities that have had to rebuild after catastrophe or that will face such a need in the future. Few of them are as follows: (1) Why rebuilding opportunities are time consuming? (2) What are the causes of failure in post-earthquake resettlement? (3) How can holistic planning after an earthquake be planned? (4) What are the criteria to be checked for sustainable building materials? (5) What are the criteria for success in post-earthquake resettlement? (6) How mitigation in post-earthquake housing can be made using appropriate repair, restoration, and strengthening concepts?

Microleakage of Different Post Systems and a Custom Adapted Fiber Post

Directory of Open Access Journals (Sweden)

Farideh Geramipanah

2013-01-01

Full Text Available Objective: The effects of closely adapting a prefabricated fiber to the post space remain unknown. The purpose of this study was to quantify the microleakages of a custom adapted fiber-reinforced post, a prefabricated quartz fiber post and a cast post using nondestructive methods.Materials and Methods: Sixty-five extracted human premolars were endodontically treated and randomly divided into three groups (n=15, which were restored using a cast post-and-core, a custom adapted fiber post (Refropost with a microhybrid microfiller resin composite (Gradia, or a prefabricated quartz fiber post (DT light post and two groups of control ( n=10. All groups were cemented using a dual polymerizing resin cement (Panavia F2.0. A composite core (Z100 was used for the fiber posts. The microleakage was calculated for the experimental and control groups before and after thermal cycling and cycling loading using a radiotracer solution (thallium 201 chloride and a gamma counter device. Data were subjected to statistical analysis of ANOVA and Tukey HSD at significant level of P< 0.05.Results: Significantly lower microleakage values were found for the cast post-and-core (mean value =16.04 ×104 and custom adapted fiber post groups (mean value=14.36×104. Thermal cycling and cyclic loading had no significant effect on the microleakage value of any tested group.Conclusion: Post systems with improved adaptation showed similar microleakage to casting post

Levels of Essential and Non-Essential Elements in Commercially ...

African Journals Online (AJOL)

Enebi Jasper

INTRODUCTION. Plants have been ... plant metabolism and biosynthesis and act as cofactors for ... plant body. 3 . Some metals are essential nutrients (zinc, iron, copper, and chromium), ... non-destructive analysis, increased total speed, ... oleifera play both a curative and preventive ... maintenance of cardiac rhythm. 16.

La Poste

CERN Multimedia

2004-01-01

http://www.cern.ch/cern50/ The French Post Office has issued ten commemorative envelopes bearing original images depicting CERN and its history. This special fiftieth anniversary collector's edition will be available on the French Post Office (« La Poste ») stand at the Open Day on 16 October, in the CMS experiment hall at Cessy. Information for collectors: a pictorial postmark and date stamp have been specially designed and produced for the occasion with the assistance of CERN's graphics team. Sending a philatelic souvenir is a great way to commemorate the Open Day, so La Poste will be setting up a large post-box for that very purpose next to its stand. A perfect way to send images of CERN all around the world...

Comparison of transcriptomic signature of post-Chernobyl and post radiotherapy thyroid tumors

International Nuclear Information System (INIS)

Ory, Catherine; Ugolin, Nicolas; Chevillard, Sylvie; Hofman, Paul; Schlumberger, Martin; Likhtarev, Illya A.

2013-01-01

We previously identified two highly discriminating and predictive radiation-induced transcriptomic signatures by comparing series of sporadic and post radiotherapy thyroid tumors (322-gene signature), and by reanalyzing a previously published data set of sporadic and post-Chernobyl thyroid tumors (106-gene signature). The aim of the present work was (i) to compare the two signatures in terms of gene expression de-regulations and molecular features/pathways, and (ii) to test the capacity of the post radiotherapy signature in classifying the post-Chernobyl series of tumors and reciprocally of the post-Chernobyl signature in classifying the post radiotherapy-induced tumors. We now explored if post radiotherapy and post-Chernobyl papillary thyroid carcinomas (PTC) display common molecular features by comparing molecular pathways deregulated in the two tumor series, and tested the potential of gene subsets of the post radiotherapy signature to classify the post-Chernobyl series (14 sporadic and 12 post-Chernobyl PTC), and reciprocally of gene subsets of the post-Chernobyl signature to classify the post radiotherapy series (15 sporadic and 12 post radiotherapy PTC), by using conventional principal component analysis. We found that the five genes common to the two signatures classified the learning/training tumors (used to search these signatures) of both the post radiotherapy (seven PTC) and the post-Chernobyl (six PTC) thyroid tumor series as compared with the sporadic tumors (seven sporadic PTC in each series). Importantly, these five genes were also effective for classifying independent series of post radiotherapy (five PTC) and post-Chernobyl (six PTC) tumors compared to independent series of sporadic tumors (eight PTC and six PTC respectively; testing tumors). Moreover, part of each post radiotherapy (32 genes) and post-Chernobyl signature (16 genes) cross-classified the respective series of thyroid tumors. Finally, several molecular pathways deregulated in post

TREAT experiment M2 post-test examination

International Nuclear Information System (INIS)

Holland, J.W.; Teske, G.M.; Florek, J.C.

1986-01-01

Transient Reactor Test (TREAT) Facility experiment M2 was performed to evaluate the transient behavior of metal-alloy fuel under accident conditions to investigate the inherent safety features of the fuel in integral fast reactor (IFR) system designs. Objectives were to obtain early information on the key fuel behavior characteristics at transient overpower (TOP) conditions in metal-fueled fast reactors; namely, margin to cladding breach and extent of axial self-extrusion of fuel within intact cladding. The onset of cladding breaching depends on fuel/cladding eutectic formation, as well as cladding pressurization and melting. Driving forces for fuel extrusion are fission gas, liquid sodium, and volatile fission products trapped within the fuel matrix. The post-test examination provided data essential for correctly modeling fuel behavior in accident codes

Post-purchase reassessment and improvement of neuroendoscope holder: importance of physician-manufacturer communication.

Science.gov (United States)

Ogawa, Yoshikazu; Nakata, Yusuke; Tominaga, Teiji

2014-01-01

Modern medical management requires constant quality improvement of the various instruments used for surgical procedures. Higher quality, less complicated handling, and reduced maintenance are all desirable qualities. However, any improvements in instrumentation require that surgeons must clearly understand the application of the device by adherence to the manufacturer's instructions. The weakness of this one-way information flow depends on the low interest among medical personnel for post-purchase reassessment. Service industries have research departments to investigate the post-purchase behavior of customers, and service recovery is considered essential to retain customers after service failure. All service providers can suffer service failures, and even the best providers may make errors in delivering service. Such an approach has been increasingly adopted in the risk management at medical institutions. We report our clinical trials of the post-purchase reassessment and product improvement of surgical instrumentation. Medical personnel reassessed the use of a newly developed endoscope holder based on the manufacturer's manual and made recommendations for possible improvements, which were examined by the manufacturer. Simple but important improvement was achieved for reducing the instability and uncertainty of instrument fixation. This bi-directional post-purchase communication between medical personnel and manufacturers can improve risk management in medical institutions.

Essential Oils for Alternative Teak Rust Control

Directory of Open Access Journals (Sweden)

Pedro Raymundo Argüelles Osorio

2018-03-01

Full Text Available ABSTRACT The objectives of this study were to evaluate the effect of lemon grass, citronella grass, Mexican-tea and noni essential oils on urediniospore germination of Olivea neotectonae , the agent responsible for rust in Teak (Tectona grandis L.f.; to evaluate the phytotoxic effect of these essential oils on teak seedlings; and to evaluate the use of essential oils to control rust in teak plants when preventively and curatively applied. We found that the noni and lemon grass essential oils inhibited 100% of urediniospore germination. On the other hand, the essential oils from noni and lemon grass caused phytotoxicity when applied to seedlings at concentrations of 2000 and 1500 μL L-1, respectively. The major constituents found in lemon grass essential oil were Geranial and Neral, while Octanoic Acid was found in noni oil. Lower values in the area below the rust progress curve were observed with the preventive application of lemon grass and noni essential oils.

Against essential normativity of the mental

DEFF Research Database (Denmark)

Steglich-Petersen, Asbjørn

2008-01-01

A number of authors have recently developed and defended various versions of ‘normative essentialism’ about the mental, i.e. the claim that propositional attitudes are constitutively or essentially governed by normative principles. I present two arguments to the effect that this claim cannot be r...... essentially normative, propositional attitude ascriptions could not support normative rationality judgments, which would remove the central appeal of normative essentialism....

Neurotherapy of Traumatic Brain Injury/Post-Traumatic Stress Symptoms in Vietnam Veterans.

Science.gov (United States)

Nelson, David V; Esty, Mary Lee

2015-10-01

Previous report suggested the beneficial effects of an adaptation of the Flexyx Neurotherapy System (FNS) for the amelioration of mixed traumatic brain injury/post-traumatic stress symptoms in veterans of the Afghanistan and Iraq wars. As a novel variant of electroencephalograph biofeedback, FNS falls within the bioenergy domain of complementary and alternative medicine. Rather than learning voluntary control over the production/inhibition of brain wave patterns, FNS involves offsetting stimulation of brain wave activity by means of an external energy source, specifically, the conduction of electromagnetic energy stimulation via the connecting electroencephalograph cables. Essentially, these procedures subliminally induce strategic distortion of ongoing brain wave activity to presumably facilitate resetting of more adaptive patterns of activity. Reported herein are two cases of Vietnam veterans with mixed traumatic brain injury/post-traumatic stress symptoms, each treated with FNS for 25 sessions. Comparisons of pre- and post-treatment questionnaire assessments revealed notable decreases for all symptoms, suggesting improvements across the broad domains of cognition, pain, sleep, fatigue, and mood/emotion, including post-traumatic stress symptoms, as well as for overall activity levels. Findings suggest FNS treatment may be of potential benefit for the partial amelioration of symptoms, even in some individuals for whom symptoms have been present for decades. Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.

Swift essentials

CERN Document Server

Blewitt, Alex

2014-01-01

Whether you are a seasoned Objective-C developer or new to the Xcode platform, Swift Essentials will provide you with all you need to know to get started with the language. Prior experience with iOS development is not necessary, but will be helpful to get the most out of the book.

Leucine-Enriched Essential Amino Acids Augment Mixed Protein Synthesis, But Not Collagen Protein Synthesis, in Rat Skeletal Muscle after Downhill Running

OpenAIRE

Kato, Hiroyuki; Suzuki, Hiromi; Inoue, Yoshiko; Suzuki, Katsuya; Kobayashi, Hisamine

2016-01-01

Mixed and collagen protein synthesis is elevated for as many as 3 days following exercise. Immediately after exercise, enhanced amino acid availability increases synthesis of mixed muscle protein, but not muscle collagen protein. However, the potential for synergic effects of amino acid ingestion with exercise on both mixed and collagen protein synthesis remains unclear. We investigated muscle collagen protein synthesis in rats following post-exercise ingestion of leucine-enriched essential a...

Studies of bone marrow scintigrams with sup(99m)technetium sulfur colloid on various hematological disorders

International Nuclear Information System (INIS)

Mizuno, Takashi

1984-01-01

One hundred and eighty-five bone marrow scintigraphy on the whole body was performed on eight healthy adults and 151 patients with various hematologic diseases including 64 leukemia, 41 anemia, 23 other malignancy, etc. The positions of the investigated bone marrow were divided into the central marrow (five positions on the trunk bones) and the peripheral marrow (11 positions on the upper and 11 positions on the lower extremities) on the scintigram. The bone marrow scintigram was estimated by following three criteria. The first, ''Yuu-ryoiki'' (positive area), was the existence of sup(99m)Tc sulfur colloid accumulation on bone marrow (two grades; presence or absence). The second, ''Bunpu-kei'' (distribution form), was the extent of the sup(99m)Tc accumulation area of the investigated bone marrow and was divided into five grades. The last, ''Kido'' (intensity of radioactivity), was the density of the sup(99m)Tc accumulation on the area and was divided into five grades. Using this estimation, in the diseases with bone marrow hyperplasia such as Primary Thrombocythemia and Hemolytic Anemia, ''Yuu-ryoiki'' was enlarged, ''Bunpu-kei'' was extended, and ''Kido'' was increased comparing with those in healty adult. In contrast, in the diseases with bone marrow hypoplasia such as Myelofibrosis and Aplastic Anemia, ''Yuu-ryoiki'' was reduced, ''Bunpu-kei'' was contracted, and ''Kido'' was decreased. However, the enlargement of ''Yuu-ryoiki'' did not always mean bone marrow hyperplasia. The author could evaluate not only the range and distribution of hemopoiesis as a whole in malignant or benign diseases but also the residual effective hemopoiesis to know the suitable time of the initiation of the therapy or to predict the prognosis of these cases. In this study it was shown that the bone marrow scintigraphy with sup(99m)Tc sulfur colloid was an useful method to estimate the hemopoietic activity of the bone marrow. (J.P.N.)

Characterization equipment essential drawing plan

International Nuclear Information System (INIS)

WILSON, G.W.

1999-01-01

The purpose of this document is to list the Characterization equipment drawings that are classified as Essential Drawings. Essential Drawings: Are those drawings identified by the facility staff as necessary to directly support the safe operation of the facility or equipment (HNF 1997a). The Characterization equipment drawings identified in this report are deemed essential drawings as defined in HNF-PRO-242, Engineering Drawing Requirements (HNF 1997a). These drawings will be prepared, revised, and maintained per HNF-PRO-440, Engineering Document Change Control (HNF 1997b). All other Characterization equipment drawings not identified in this document will be considered Support drawings until the Characterization Equipment Drawing Evaluation Report is completed

Epigenetic changes in myelofibrosis

DEFF Research Database (Denmark)

Nielsen, Helene Myrtue; Andersen, Christen Lykkegaard; Westman, Maj

2017-01-01

, in 'inflammatory disease' in MF mononuclear cells, and in 'immunological diseases' in MF granulocytes. Only few differentially methylated CpG sites were common among the three cell populations. Mutations in the epigenetic regulators ASXL1 (47%) and TET2 (20%) were not associated with a specific DNA methylation...

The Role of Land Records in Support of Post-Conflict Land Administration within overall State Building – the Case of Rwanda

NARCIS (Netherlands)

Todorovski, D.; Manirakiza, Jean Guillaume; Zevenbergen, J.A.; Boerboom, L.G.J.

2018-01-01

An essential component of every land administration system are the land records. These records contain information about ownership, value and use of land. Conflict and post-conflict contexts, both in literature and in practice, have shown that land administration systems are mostly affected by the