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Sample records for adult acute promyelocytic

  1. Current standard treatment of adult acute promyelocytic leukaemia.

    PubMed

    Lo-Coco, Francesco; Cicconi, Laura; Breccia, Massimo

    2016-03-01

    The outcome of patients with acute promyelocytic leukaemia (APL) has dramatically improved over the last two decades, due to the introduction of combined all-trans retinoic acid (ATRA) and chemotherapy regimens and, more recently, to the advent of arsenic trioxide (ATO). ATRA and anthracycline-based chemotherapy remains a widely used strategy, providing cure rates above 80%, but it is associated with risk of severe infections and occurrence of secondary leukaemias. ATO is the most effective single agent in APL and, used alone or in combination with ATRA or ATRA and reduced-intensity chemotherapy, results in greater efficacy with considerably less haematological toxicity. The toxic profile of ATO includes frequent, but manageable, QTc prolongation and increase of liver enzymes. Two large randomized studies have shown that ATRA + ATO is superior to ATRA + chemotherapy for newly diagnosed low-risk APL resulting in 2-4 year event-free survival rates above 90% and very few relapses. According to real world data, the spectacular progress in APL outcomes reported in clinical trials has not been paralleled by a significant improvement in early death rates, this remains the most challenging issue for the final cure of the disease.

  2. Current standard treatment of adult acute promyelocytic leukaemia.

    PubMed

    Lo-Coco, Francesco; Cicconi, Laura; Breccia, Massimo

    2016-03-01

    The outcome of patients with acute promyelocytic leukaemia (APL) has dramatically improved over the last two decades, due to the introduction of combined all-trans retinoic acid (ATRA) and chemotherapy regimens and, more recently, to the advent of arsenic trioxide (ATO). ATRA and anthracycline-based chemotherapy remains a widely used strategy, providing cure rates above 80%, but it is associated with risk of severe infections and occurrence of secondary leukaemias. ATO is the most effective single agent in APL and, used alone or in combination with ATRA or ATRA and reduced-intensity chemotherapy, results in greater efficacy with considerably less haematological toxicity. The toxic profile of ATO includes frequent, but manageable, QTc prolongation and increase of liver enzymes. Two large randomized studies have shown that ATRA + ATO is superior to ATRA + chemotherapy for newly diagnosed low-risk APL resulting in 2-4 year event-free survival rates above 90% and very few relapses. According to real world data, the spectacular progress in APL outcomes reported in clinical trials has not been paralleled by a significant improvement in early death rates, this remains the most challenging issue for the final cure of the disease. PMID:26687281

  3. Acute Promyelocytic Leukemia

    PubMed Central

    Kingsley, Edwin C.; Durie, Brian G. M.; Garewal, Harinder S.

    1987-01-01

    Acute promyelocytic leukemia (APL) is a subtype of acute myelogenous leukemia frequently associated with disseminated intravascular coagulation (DIC). Data on 11 patients with APL treated at our institution were analyzed and compared with those of 147 published cases. Most had a bleeding diathesis at presentation and evidence of DIC eventually developed in all. Seven patients (64%) showed the t(15;17)(q22;q21) karyotype or a similar translocation. Using a chemotherapy induction regimen containing an anthracycline, complete remission, requiring a total of 14 courses of treatment, was achieved in six patients (55%). The median duration of response and median survival for complete responders were 10 and 15 months, respectively. Three patients (27%) died of bleeding complications during induction therapy. The tritiated-thymidine labeling index of leukemia cells predicted which patients would achieve a complete remission. Review of six studies of 147 patients with APL from the past 12 years supports the use of a chemotherapy induction regimen containing anthracycline or amsacrine and heparin for the treatment of DIC. PMID:3472414

  4. Tretinoin, Cytarabine, and Daunorubicin Hydrochloride With or Without Arsenic Trioxide Followed by Tretinoin With or Without Mercaptopurine and Methotrexate in Treating Patients With Acute Promyelocytic Leukemia

    ClinicalTrials.gov

    2013-06-04

    Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Promyelocytic Leukemia (M3); Childhood Acute Promyelocytic Leukemia (M3); Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

  5. Gemtuzumab Ozogamicin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Acute Promyelocytic Leukemia

    ClinicalTrials.gov

    2016-07-26

    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 Acute Promyelocytic Leukemia (M3); Childhood Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia

  6. Genetics Home Reference: acute promyelocytic leukemia

    MedlinePlus

    ... acute myeloid leukemia, a cancer of the blood-forming tissue ( bone marrow ). In normal bone marrow, hematopoietic ... 7186-203. Review. Citation on PubMed de Thé H, Chen Z. Acute promyelocytic leukaemia: novel insights into ...

  7. Tretinoin and Arsenic Trioxide in Treating Patients With Untreated Acute Promyelocytic Leukemia

    ClinicalTrials.gov

    2016-07-08

    Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Childhood Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Myeloid Neoplasm

  8. Acute Appendicitis Secondary to Acute Promyelocytic Leukemia

    PubMed Central

    Rodriguez, Eduardo A.; Lopez, Marvin A.; Valluri, Kartik; Wang, Danlu; Fischer, Andrew; Perdomo, Tatiana

    2015-01-01

    Patient: Female, 43 Final Diagnosis: Myeloid sarcoma appendicitis Symptoms: Abdominal pain • chills • fever Medication: — Clinical Procedure: Laparoscopic appendectomy, bone marrow biopsy Specialty: Gastroenterology and Hepatology Objective: Rare disease Background: The gastrointestinal tract is a rare site for extramedullary involvement in acute promyelocytic leukemia (APL). Case Report: A 43-year-old female with no past medical history presented complaining of mild abdominal pain, fever, and chills for the past day. On examination, she was tachycardic and febrile, with mild tenderness of her right lower quadrant and without signs of peritoneal irritation. Laboratory examination revealed pancytopenia and DIC, with a fibrinogen level of 290 mg/dL. CT of the abdomen showed a thickened and hyperemic appendix without perforation or abscess, compatible with acute appendicitis. The patient was given IV broad-spectrum antibiotics and was transfused with packed red blood cells and platelets. She underwent uncomplicated laparoscopic appendectomy and bone marrow biopsy, which revealed neo-plastic cells of 90% of the total bone marrow cellularity. Flow cytometry indicated presence of 92.4% of immature myeloid cells with t (15: 17) and q (22: 12) mutations, and FISH analysis for PML-RARA demonstrated a long-form fusion transcript, positive for APL. Appendix pathology described leukemic infiltration with co-expression of myeloperoxidase and CD68, consistent with myeloid sarcoma of the appendix. The patient completed a course of daunorubicin, cytarabine, and all trans-retinoic acid. Repeat bone marrow biopsy demonstrated complete remission. She will follow up with her primary care physician and hematologist/oncologist. Conclusions: Myeloid sarcoma of the appendix in the setting of APL is very rare and it might play a role in the development of acute appendicitis. Urgent management, including bone marrow biopsy for definitive diagnosis and urgent surgical intervention

  9. Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia

    PubMed Central

    Azevedo, M.C.; Velloso, E.D.R.P.; Buccheri, V.; Chamone, D.A.F.; Dorlhiac-Llacer, P.E.

    2014-01-01

    In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival. PMID:25517921

  10. Global Characteristics of Childhood Acute Promyelocytic Leukemia

    PubMed Central

    Zhang, L; Samad, A; Pombo-de-Oliveira, MS; Scelo, G; Smith, MT; Feusner, J; Wiemels, JL; Metayer, C

    2014-01-01

    Acute promyelocytic leukemia (APL) comprises approximately 5–10% of childhood acute myeloid leukemia (AML) cases in the US. While variation in this percentage among other populations was noted previously, global patterns of childhood APL have not been thoroughly characterized. In this comprehensive review of childhood APL, we examined its geographic pattern and the potential contribution of environmental factors to observed variation. In 142 studies (spanning >60 countries) identified, variation was apparent—de novo APL represented from 2% (Switzerland) to >50% (Nicaragua) of childhood AML in different geographic regions. Because a limited number of previous studies addressed specific environmental exposures that potentially underlie childhood APL development, we gathered 28 childhood cases of therapy-related APL, which exemplified associations between prior exposures to chemotherapeutic drugs/radiation and APL diagnosis. Future population-based studies examining childhood APL patterns and the potential association with specific environmental exposures and other risk factors are needed. PMID:25445717

  11. Minimal residual disease in acute promyelocytic leukemia.

    PubMed

    Weil, S C

    2000-03-01

    In the last decade our understanding of acute promyelocytic leukemia (APL) has advanced tremendously. The recognition of all-trans retinoic acid (ATRA) as a powerful therapeutic agent paralleled the cloning of the t(15;17) breakpoint. RtPCR for the PML-RARA hybrid mRNA has become the hallmark of molecular diagnosis and molecular monitoring in APL. Current techniques are useful in predicting complete remission and a possible cure in many patients who repeatedly test negative by PCR. Standardizing techniques and improving the sensitivity of the assay are important. Doing this in a way so that clinically relevant minimal residual disease can be distinguished from "indolent disease" remains among the future challenges in APL. PMID:10702899

  12. Acute promyelocytic leukemia: a curable disease.

    PubMed

    Lo Coco, F; Nervi, C; Avvisati, G; Mandelli, F

    1998-12-01

    The Second International Symposium on Acute Promyelocytic Leukemia (APL) was held in Rome in 12-14 November 1997. Clinical and basic investigators had the opportunity to discuss in this meeting the important advances in the biology and treatment of this disease achieved in the last 4 years, since the First Roman Symposium was held in 1993. The first part of the meeting was dedicated to relevant aspects of laboratory research, and included the following topics: molecular mechanisms of leukemogenesis and of response/resistance to retinoids, biologic and therapeutic effects of new agents such as arsenicals and novel synthetic retinoids; characterization of APL heterogeneity at the morphological, cytogenetic and immunophenotypic level. The updated results of large cooperative clinical trials using variable combinations of all-trans retinoic acid (ATRA) and chemotherapy were presented by the respective group chairmen, and formed the 'core' part of the meeting. These studies, which in most cases integrated the molecular assessment of response to treatment, provided a stimulating framework for an intense debate on the most appropriate frontline treatment options to be adopted in the future. The last day was dedicated to special entities such as APL in the elderly and in the child, as well as the role of bone marrow transplantation. The prognostic value of molecular monitoring studies was also discussed in the final session of the meeting. In this article, we review the major advances and controversial issues in APL biology and treatment discussed in this symposium and emerging from very recent publications. We would like to credit the successful outcome of this meeting to the active and generous input of all invited speakers and to participants from all over the world who provided constructive and fruitful discussions.

  13. Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure.

    PubMed

    Ablain, Julien; Rice, Kim; Soilihi, Hassane; de Reynies, Aurélien; Minucci, Saverio; de Thé, Hugues

    2014-02-01

    Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-α (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml-transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA-driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies.

  14. Thrombo-hemorrhagic deaths in acute promyelocytic leukemia.

    PubMed

    Breccia, Massimo; Lo Coco, Francesco

    2014-05-01

    Acute promyelocytic leukemia (APL) has become the most curable form of acute myeloid leukemia after the advent of all-trans retinoic acid (ATRA). However, early deaths (ED) mostly due to the disease-associated coagulopathy remain the major cause of treatment failure. In particular, hemorrhagic events account for 40-65% of ED and several prognostic factors have been identified for such hemorrhagic deaths, including poor performance status, high white blood cell (WBC) count and coagulopathy. Occurrence of thrombosis during treatment with ATRA may be associated with differentiation syndrome (DS) or represent an isolated event. Some prognostic factors have been reported to be associated with thrombosis, including increased WBC or aberrant immunophenotype of leukemic promyelocytes. Aim of this review is to report the incidence, severity, possible pathogenesis and clinical manifestations of thrombo-haemorrhagic deaths in APL.

  15. Thrombo-hemorrhagic deaths in acute promyelocytic leukemia.

    PubMed

    Breccia, Massimo; Lo Coco, Francesco

    2014-05-01

    Acute promyelocytic leukemia (APL) has become the most curable form of acute myeloid leukemia after the advent of all-trans retinoic acid (ATRA). However, early deaths (ED) mostly due to the disease-associated coagulopathy remain the major cause of treatment failure. In particular, hemorrhagic events account for 40-65% of ED and several prognostic factors have been identified for such hemorrhagic deaths, including poor performance status, high white blood cell (WBC) count and coagulopathy. Occurrence of thrombosis during treatment with ATRA may be associated with differentiation syndrome (DS) or represent an isolated event. Some prognostic factors have been reported to be associated with thrombosis, including increased WBC or aberrant immunophenotype of leukemic promyelocytes. Aim of this review is to report the incidence, severity, possible pathogenesis and clinical manifestations of thrombo-haemorrhagic deaths in APL. PMID:24862130

  16. Massive Pulmonary Embolism at the Onset of Acute Promyelocytic Leukemia

    PubMed Central

    Sorà, Federica; Chiusolo, Patrizia; Laurenti, Luca; Autore, Francesco; Giammarco, Sabrina; Sica, Simona

    2016-01-01

    Life-threatening bleeding is a major and early complication of acute promyelocytic leukemia (APL), but in the last years there is a growing evidence of thromboses in APL. We report the first case of a young woman with dyspnea as the first symptom of APL due to massive pulmonary embolism (PE) successfully treated with thrombolysis for PE and heparin. APL has been processed with a combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) obtaining complete remission. PMID:27413520

  17. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia.

    PubMed

    Madan, V; Shyamsunder, P; Han, L; Mayakonda, A; Nagata, Y; Sundaresan, J; Kanojia, D; Yoshida, K; Ganesan, S; Hattori, N; Fulton, N; Tan, K-T; Alpermann, T; Kuo, M-C; Rostami, S; Matthews, J; Sanada, M; Liu, L-Z; Shiraishi, Y; Miyano, S; Chendamarai, E; Hou, H-A; Malnassy, G; Ma, T; Garg, M; Ding, L-W; Sun, Q-Y; Chien, W; Ikezoe, T; Lill, M; Biondi, A; Larson, R A; Powell, B L; Lübbert, M; Chng, W J; Tien, H-F; Heuser, M; Ganser, A; Koren-Michowitz, M; Kornblau, S M; Kantarjian, H M; Nowak, D; Hofmann, W-K; Yang, H; Stock, W; Ghavamzadeh, A; Alimoghaddam, K; Haferlach, T; Ogawa, S; Shih, L-Y; Mathews, V; Koeffler, H P

    2016-08-01

    Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential. PMID:27063598

  18. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia

    PubMed Central

    Madan, V; Shyamsunder, P; Han, L; Mayakonda, A; Nagata, Y; Sundaresan, J; Kanojia, D; Yoshida, K; Ganesan, S; Hattori, N; Fulton, N; Tan, K-T; Alpermann, T; Kuo, M-C; Rostami, S; Matthews, J; Sanada, M; Liu, L-Z; Shiraishi, Y; Miyano, S; Chendamarai, E; Hou, H-A; Malnassy, G; Ma, T; Garg, M; Ding, L-W; Sun, Q-Y; Chien, W; Ikezoe, T; Lill, M; Biondi, A; Larson, R A; Powell, B L; Lübbert, M; Chng, W J; Tien, H-F; Heuser, M; Ganser, A; Koren-Michowitz, M; Kornblau, S M; Kantarjian, H M; Nowak, D; Hofmann, W-K; Yang, H; Stock, W; Ghavamzadeh, A; Alimoghaddam, K; Haferlach, T; Ogawa, S; Shih, L-Y; Mathews, V; Koeffler, H P

    2016-01-01

    Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential. PMID:27063598

  19. Delirium in acute promyelocytic leukemia patients: two case reports

    PubMed Central

    2013-01-01

    Background Delirium is a frequently misdiagnosed and inadequately treated neuropsychiatric complication most commonly observed in terminally ill cancer patients. To our knowledge this is the first report describing delirium in two patients aged less than 60 years and enrolled in an intensive chemotherapeutic protocol for acute promyelocytic leukemia. Case presentation Two female Caucasian acute promyelocytic leukemia patients aged 46 and 56 years developed delirium during their induction treatment with all-trans retinoic acid and idarubicin. In both cases symptoms were initially attributed to all-trans retinoic acid that was therefore immediately suspended. In these two patients several situations may have contribute to the delirium: in patient 1 a previous psychiatric disorder, concomitant treatments with steroids and benzodiazepines, a severe infection and central nervous system bleeding while in patient 2 steroid treatment and isolation. In patient 1 delirium was treated with short-term low-doses of haloperidol while in patient 2 non-pharmacologic interventions had a beneficial role. When the diagnosis of delirium was clear, induction treatment was resumed and both patients completed their therapeutic program without any relapse of the psychiatric symptoms. Both patients are alive and in complete remission as far as their leukemia is concerned. Conclusions We suggest that patients with acute promyelocytic leukemia eligible to intensive chemotherapy should be carefully evaluated by a multisciplinary team including psychiatrists in order to early recognize symptoms of delirium and avoid inadequate treatments. In case of delirium, both pharmacologic and non-pharmacologic interventions may be considered. PMID:24237998

  20. Targeting of leukemia-initiating cells in acute promyelocytic leukemia

    PubMed Central

    Lo-Coco, Francesco

    2015-01-01

    Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with peculiar molecular, phenotypic and clinical features and unique therapeutic response to specific treatments. The disease is characterized by a single, pathognomonic molecular event, consisting of the translocation t(15;17) which gives rise to the PML/retinoic acid receptor α (RARα) hybrid protein. The development of this leukemia is mainly related to the fusion oncoprotein PML/RARα, acting as an altered RAR mediating abnormal signalling and repression of myeloid differentiation, with consequent accumulation of undifferentiated promyelocytes. The prognosis of APL has dramatically been improved with the introduction in therapy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). The main effect of these two drugs is linked to the targeting of either RAR moiety of the PML/RARα molecule and induction of cell differentiation (ATRA) or of the PML moiety of the fusion protein and induction of leukemic cell apoptosis, including leukemic progenitors (mostly induced by ATO). These two drugs exhibited excellent synergism and determine a very high rate of durable remissions in low/intermediate-risk APLs, when administered in the absence of any chemotherapeutic drug. The strong synergism and the marked clinical efficacy of these two agents when administered together seem to be related to their capacity to induce PML/RARα degradation and complete eradication of leukemia stem cells. PMID:27358876

  1. Therapy Related Acute Myeloid Leukemia with t(8;16) Mimicking Acute Promyelocytic Leukemia.

    PubMed

    Chharchhodawala, Taher; Gajendra, Smeeta; Tiwari, Priya; Gogia, Ajay; Gupta, Ritu

    2016-06-01

    Acute myeloid leukemia (AML) with t(8;16)(p11;q13) is a distinct clinical and morphological entity with poor prognosis, which is characterized by a high frequency of extramedullary involvement, most commonly leukemia cutis; association with therapy related AML; frequent coagulopathy and morphologic features overlapping acute promyelocytic leukemia(APL). Herein, we present a case of 47 year-old post-menopausal woman developing secondary AML with t(8;16)(p11;q13) after 1 year of completion of therapy for breast carcinoma. Blasts were granulated with few showing clefted nucleus resembling promyelocytes and immnuophenotyping showed high side scatter with MPO positivity and CD 34 and HLA-DR negativity. In view of promyelocyte like morphology and immunophenotyping of blasts, possibility of APL was considered but, reverse transcription polymerase chain reaction (RT-PCR) for PML-RARα fusion transcript came out to be negative. Conventional cytogenetics showed t(8;16)(p11;q13). So, we should keep possibility of t(8;16) (p11;q13) in therapy related acute myeloid leukemia in patient showing clinical and morphological features of acute promyelocytic leukemia. PMID:27408347

  2. Acute promyelocytic leukemia during pregnancy: a systematic analysis of outcome.

    PubMed

    Verma, Vivek; Giri, Smith; Manandhar, Samyak; Pathak, Ranjan; Bhatt, Vijaya Raj

    2016-01-01

    The outcomes of acute promyelocytic leukemia (APL) in pregnancy are largely unknown. The MEDLINE database was systematically searched to obtain 43 articles with 71 patients with new-onset APL during pregnancy. Induction therapy included various regimens of all-trans retinoic acid (ATRA), cytarabine, and anthracycline and resulted in a complete remission rate of 93%. Obstetric and fetal complications included pre-term deliveries (46%), spontaneous/therapeutic abortion/intrauterine death (33.3%) and other neonatal complications (25.9%). Mothers diagnosed in the first trimester were more likely to experience obstetric (p < 0.01) and fetal (p < 0.01) complications. To our knowledge, this is the largest systematic review of APL in pregnancy. The vast majority of APL patients in pregnancy may achieve remission with initial induction therapy. APL or its therapy in pregnancy, however, is associated with a high risk of fetal and obstetrical complications. The results of our study may help in patient counseling and informed decision-making. PMID:26110880

  3. Current management of newly diagnosed acute promyelocytic leukemia.

    PubMed

    Cicconi, L; Lo-Coco, F

    2016-08-01

    The management of acute promyelocytic leukemia (APL) has considerably evolved during the past two decades. The advent of all-trans retinoic acid (ATRA) and its inclusion in combinatorial regimens with anthracycline chemotherapy has provided cure rates exceeding 80%; however, this widely adopted approach also conveys significant toxicity including severe myelosuppression and rare occurrence of secondary leukemias. More recently, the advent of arsenic trioxide (ATO) and its use in association with ATRA with or without chemotherapy has further improved patient outcome by allowing to minimize the intensity of chemotherapy, thus reducing serious toxicity while maintaining high anti-leukemic efficacy. The advantage of ATRA-ATO over ATRA chemotherapy has been recently demonstrated in two large randomized trials and this option has now become the new standard of care in low-risk (i.e. non-hyperleukocytic) patients. In light of its rarity, abrupt onset and high risk of early death and due to specific treatment requirements, APL remains a challenging condition that needs to be managed in highly experienced centers. We review here the results of large clinical studies conducted in newly diagnosed APL as well as the recommendations for appropriate diagnosis, prevention and management of the main complications associated with modern treatment of the disease. PMID:27084953

  4. Retinoid receptor signaling and autophagy in acute promyelocytic leukemia

    SciTech Connect

    Orfali, Nina; McKenna, Sharon L.; Cahill, Mary R.; Gudas, Lorraine J.; Mongan, Nigel P.

    2014-05-15

    Retinoids are a family of signaling molecules derived from vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies. - Highlights: • Normal and aberrant retinoid signaling in hematopoiesis and leukemia is reviewed. • We suggest a novel role for RARα in the development of X-RARα gene fusions in APL. • ATRA therapy in APL activates transcription and promotes onco-protein degradation. • Autophagy may be involved in both onco-protein degradation and differentiation. • Pharmacologic autophagy induction may potentiate ATRA's therapeutic effects.

  5. PML, a growth suppressor disrupted in acute promyelocytic leukemia.

    PubMed Central

    Mu, Z M; Chin, K V; Liu, J H; Lozano, G; Chang, K S

    1994-01-01

    The nonrandom chromosomal translocation t(15;17)(q22;q21) in acute promyelocytic leukemia (APL) juxtaposes the genes for retinoic acid receptor alpha (RAR alpha) and the putative zinc finger transcription factor PML. The breakpoint site encodes fusion protein PML-RAR alpha, which is able to form a heterodimer with PML. It was hypothesized that PML-RAR alpha is a dominant negative inhibitor of PML. Inactivation of PML function in APL may play a critical role in APL pathogenesis. Our results demonstrated that PML, but not PML-RAR alpha, is a growth suppressor. This is supported by the following findings: (i) PML suppressed anchorage-independent growth of APL-derived NB4 cells on soft agar and tumorigenicity in nude mice, (ii) PML suppressed the oncogenic transformation of rat embryo fibroblasts by cooperative oncogenes, and (iii) PML suppressed transformation of NIH 3T3 cells by the activated neu oncogene. Cotransfection of PML with PML-RAR alpha resulted in a significant reduction in PML's transformation suppressor function in vivo, indicating that the fusion protein can be a dominant negative inhibitor of PML function in APL cells. This observation was further supported by the finding that cotransfection of PML and PML-RAR alpha resulted in altered normal cellular localization of PML. Our results also demonstrated that PML, but not PML-RAR alpha, is a promoter-specific transcription suppressor. Therefore, we hypothesized that disruption of the PML gene, a growth or transformation suppressor, by the t(15;17) translocation in APL is one of the critical events in leukemogenesis. Images PMID:7935403

  6. Metabolism of arsenic trioxide in acute promyelocytic leukemia cells.

    PubMed

    Khaleghian, Ali; Ghaffari, Seyed H; Ahmadian, Shahin; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir

    2014-10-01

    Arsenic trioxide (As2O3) effectively induces complete clinical and molecular remissions in acute promyelocytic leukemia (APL) patients and triggers apoptosis in APL cells. The effect induced by As2O3 is also associated with extensive genomic-wide epigenetic changes with large-scale alterations in DNA methylation. We investigated the As2O3 metabolism in association with factors involved in the production of its methylated metabolites in APL-derived cell line, NB4. We used high performance liquid chromatography (HPLC) technique to detect As2O3 metabolites in NB4 cells. The effects of As2O3 on glutathione level, S-Adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels were investigated. Also, we studied the expression levels of arsenic methyltransferase (AS3MT) and DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) by real-time PCR. Our results show that after As2O3 entry into the cell, it was converted into methylated metabolites, mono-methylarsenic (MMA) and dimethylarsenic (DMA). The glutathione (GSH) production was increased in parallel with the methylated metabolites formations. As2O3 treatment inhibited DNMTs (DNMT1, DNMT3a, and DNMT3b) in dose- and time-dependent manners. The SAH levels in As2O3-treated cells were increased; however, the SAM level was not affected. The present study shows that APL cell is capable of metabolizing As2O3. The continuous formation of intracellular methylated metabolites, the inhibition of DNMTs expression levels and the increase of SAH level by As2O3 biotransformation would probably affect the DNMTs-methylated DNA methylation in a manner related to the extent of DNA hypomethylation. Production of intracellular methylated metabolites and epigenetic changes of DNA methylation during As2O3 metabolism may contribute to the therapeutic effect of As2O3 in APL. PMID:24819152

  7. Pathogenesis and treatment of thrombohemorrhagic diathesis in acute promyelocytic leukemia.

    PubMed

    Falanga, Anna; Russo, Laura; Tartari, Carmen J

    2011-01-01

    Acute promyelocytic leukemia (APL) is a distinct subtype of myeloid leukemia characterized by t(15;17) chromosomal translocation, which involves the retinoic acid receptor-alpha (RAR-alpha). APL typically presents with a life-threatening hemorrhagic diathesis. Before the introduction of all-trans retinoic acid (ATRA) for the cure of APL, fatal hemorrhages due, at least in part, to the APL-associated coagulopathy, were a major cause of induction remission failure. The laboratory abnormalities of blood coagulation found in these patients indicate the occurrence of a hypercoagulable state. Major determinants of the coagulopathy of APL are endogenous factors expressed by the leukemic cells, including procoagulant factors, fibrinolytic proteins, and non-specific proteolytic enzymes. In addition, these cells have an increased capacity to adhere to the vascular endothelium, and to secrete inflammatory cytokines [i.e. interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF-alpha)], which in turn stimulate the expression of prothrombotic activities by endothelial cells and leukocytes. ATRA can interfere with each of the principal hemostatic properties of the leukemic cell, thus reducing the APL cell procoagulant potential, in parallel to the induction of cellular differentiation. This effect occurs in vivo, in the bone marrow of APL patients receiving ATRA, and is associated with the improvement of the bleeding symptoms. Therapy with arsenic trioxide (ATO) also beneficially affects coagulation in APL. However, early deaths from bleeding still remain a major problem in APL and further research is required in this field. In this review, we will summarize our current knowledge of the pathogenesis of the APL-associated coagulopathy and will overview the therapeutic approaches for the management of this complication. PMID:22220265

  8. Pathogenesis and Treatment of Thrombohemorrhagic Diathesis in Acute Promyelocytic Leukemia

    PubMed Central

    Falanga, Anna; Russo, Laura; Tartari, Carmen J

    2011-01-01

    Acute promyelocytic leukemia (APL) is a distinct subtype of myeloid leukemia characterized by t(15;17) chromosomal translocation, which involves the retinoic acid receptor-alpha (RAR-alpha). APL typically presents with a life-threatening hemorrhagic diathesis. Before the introduction of all-trans retinoic acid (ATRA) for the cure of APL, fatal hemorrhages due, at least in part, to the APL-associated coagulopathy, were a major cause of induction remission failure. The laboratory abnormalities of blood coagulation found in these patients indicate the occurrence of a hypercoagulable state. Major determinants of the coagulopathy of APL are endogenous factors expressed by the leukemic cells, including procoagulant factors, fibrinolytic proteins, and non-specific proteolytic enzymes. In addition, these cells have an increased capacity to adhere to the vascular endothelium, and to secrete inflammatory cytokines [i.e. interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF-alpha)], which in turn stimulate the expression of prothrombotic activities by endothelial cells and leukocytes. ATRA can interfere with each of the principal hemostatic properties of the leukemic cell, thus reducing the APL cell procoagulant potential, in parallel to the induction of cellular differentiation. This effect occurs in vivo, in the bone marrow of APL patients receiving ATRA, and is associated with the improvement of the bleeding symptoms. Therapy with arsenic trioxide (ATO) also beneficially affects coagulation in APL. However, early deaths from bleeding still remain a major problem in APL and further research is required in this field. In this review, we will summarize our current knowledge of the pathogenesis of the APL-associated coagulopathy and will overview the therapeutic approaches for the management of this complication. PMID:22220265

  9. Acute promyelocytic leukemia: where did we start, where are we now, and the future

    PubMed Central

    Coombs, C C; Tavakkoli, M; Tallman, M S

    2015-01-01

    Historically, acute promyelocytic leukemia (APL) was considered to be one of the most fatal forms of acute leukemia with poor outcomes before the introduction of the vitamin A derivative all-trans retinoic acid (ATRA). With considerable advances in therapy, including the introduction of ATRA initially as a single agent and then in combination with anthracyclines, and more recently by development of arsenic trioxide (ATO)-containing regimens, APL is now characterized by complete remission rates of 90% and cure rates of ∼80%, even higher among low-risk patients. Furthermore, with ATRA–ATO combinations, chemotherapy may safely be omitted in low-risk patients. The disease is now considered to be the most curable subtype of acute myeloid leukemia (AML) in adults. Nevertheless, APL remains associated with a significant incidence of early death related to the characteristic bleeding diathesis. Early death, rather than resistant disease so common in all other subtypes of AML, has emerged as the major cause of treatment failure. PMID:25885425

  10. Development of Acute Promyelocytic Leukemia in a Patient With Gouty Arthritis on Long Term Colchicine.

    PubMed

    Buyukkurt, Nurhilal; Korur, Asli; Boga, Can

    2016-06-01

    Colchicine is a frequently used drug in rheumatological diseases. Acute promyelocytic leukemia developed in a patient who used colchicine for gouty arthritis since 10 years is presented and the possible relation between the long term use of colchicine and hematological malignancies is discussed. PMID:27408362

  11. Acute myocardial/cerebral infarction as first/relapse manifestation in one acute promyelocytic leukemia patient

    PubMed Central

    Li, Ying; Suo, Shanshan; Mao, Liping; Wang, Lei; Yang, Chunmei; Xu, Weilai; Lou, Yinjun; Mai, Wenyuan

    2015-01-01

    In the clinical setting, bleeding is a common manifestation of acute promyelocytic leukemia (APL), whereas thrombosis is relatively rare, especially as an initial symptom. Here, we report an unusual case of APL with acute myocardial infarction as the first manifestation and cerebral infarction as the relapse manifestation in a healthy young woman. This unique case emphasizes that a thrombotic event could be the first manifestation of an underlying hematological disorder such as APL and could also be a sign of relapse. Rapid detection of the underlying disorder and the timely use of anticoagulation therapy and ATRA are crucial for preventing further deterioration of the disease and saving the patient’s life. PMID:26550398

  12. Clinico-pathological profile of acute promyelocytic leukaemia at Al-Amal Oncology-Haematology Centre, Qatar.

    PubMed

    Ibrahim, F A; Yassin, M A; El-Ayoubi, H R; Alhiji, I A; Albinali, A S; Almansour, S M; Qafoud, F M

    2010-09-01

    This cases series describes the profile of adult patients with acute promyelocytic leukaemia (APt) at a referral hospital in Qatar. Of 34 acute myeloid leukaemia (AML) cases diagnosed, 11(32%) were classified as APt. Disseminated intravascular coagulation was common at presentation (91%). Severe thrombocytopenia was seen in 73%, leukocytosis in 55% and severe anaemia in 45%. Only 2 patients were of the classic hypergranular type. In the remaining 9 patients, 3 morphological subtypes were recognized: microgranular variant (6 patients), hyperbasophilic (2 patients) and regular nuclear outline M3r (1 patient). Translocation t(15;17) was detected in 63% of cases. APL constitutes a high proportion of AML cases in Qatar, with considerable morphological heterogeneity and a oredominance of APL variants with unfavourable oresenting features. PMID:21218723

  13. Acute promyelocytic leukemia after renal transplant and filgrastim treatment for neutropenia

    PubMed Central

    Krause, John R.

    2016-01-01

    Prolonged immunosuppression in solid organ transplant recipients has been considered a risk for developing opportunistic infections and malignancies. Acute leukemia is a rare complication. We report a case of acute promyelocytic leukemia (APL) (FAB M3) after cadaveric renal transplant for focal segmental glomerulosclerosis in a 24-year-old woman. Her immunosuppressive therapy included tacrolimus, mycophenolate mofetil, and prednisone. Approximately 2 years after transplant, she became pancytopenic, prompting administration of filgrastim. A few doses caused a markedly increased blast count, resulting in a diagnosis of APL. She was successfully treated with all-trans-retinoic acid and arsenic trioxide. Myeloproliferative neoplasms after organ transplant or due to filgrastim are rare. PMID:27695174

  14. Acute promyelocytic leukemia after renal transplant and filgrastim treatment for neutropenia

    PubMed Central

    Krause, John R.

    2016-01-01

    Prolonged immunosuppression in solid organ transplant recipients has been considered a risk for developing opportunistic infections and malignancies. Acute leukemia is a rare complication. We report a case of acute promyelocytic leukemia (APL) (FAB M3) after cadaveric renal transplant for focal segmental glomerulosclerosis in a 24-year-old woman. Her immunosuppressive therapy included tacrolimus, mycophenolate mofetil, and prednisone. Approximately 2 years after transplant, she became pancytopenic, prompting administration of filgrastim. A few doses caused a markedly increased blast count, resulting in a diagnosis of APL. She was successfully treated with all-trans-retinoic acid and arsenic trioxide. Myeloproliferative neoplasms after organ transplant or due to filgrastim are rare.

  15. Severe Acute Axonal Neuropathy following Treatment with Arsenic Trioxide for Acute Promyelocytic Leukemia: a Case Report

    PubMed Central

    Kühn, Marcus; Sammartin, Kety; Nabergoj, Mitja; Vianello, Fabrizio

    2016-01-01

    Peripheral neuropathy is a common complication of arsenic toxicity. Symptoms are usually mild and reversible following discontinuation of treatment. A more severe chronic sensorimotor polyneuropathy characterized by distal axonal-loss neuropathy can be seen in chronic arsenic exposure. The clinical course of arsenic neurotoxicity in patients with coexistence of thiamine deficiency is only anecdotally known but this association may potentially lead to severe consequences. We describe a case of acute irreversible axonal neuropathy in a patient with hidden thiamine deficiency who was treated with a short course of arsenic trioxide for acute promyelocytic leukemia. Thiamine replacement therapy and arsenic trioxide discontinuation were not followed by neurological recovery and severe polyneuropathy persisted at 12-month follow-up. Thiamine plasma levels should be measured in patients who are candidate to arsenic trioxide therapy. Prophylactic administration of vitamin B1 may be advisable. The appearance of polyneuropathy signs early during the administration of arsenic trioxide should prompt electrodiagnostic testing to rule out a pattern of axonal neuropathy which would need immediate discontinuation of arsenic trioxide. PMID:27158436

  16. Genital ulcers after treatment with all-trans-retinoic acid in a child with acute promyelocytic leukemia.

    PubMed

    Unal, Selma; Gümrük, Fatma; Cetin, Mualla; Hiçsönmez, Gönül

    2005-01-01

    All-trans-retinoic acid (ATRA) has been shown to improve the outcome of patients with acute promyelocytic leukemia (APL). However, various adverse effects of ATRA treatment have been noted, such as scrotal and genital ulcers in adult patients. The authors report genital ulcers that developed in a child with APL after ATRA treatment. An 8-year-old girl with APL was treated with ATRA for 21 days and after discontinuation of ATRA treatment she developed genital ulcers. Systemic and local antibiotic pomades were applied and the lesions improved within 15 days. In conclusion, genital ulcers may develop in children with APL as a complication of ATRA treatment and physicians should be alert to this possibility.

  17. Aberrant phenotypic expression of CD15 and CD56 identifies poor prognostic acute promyelocytic leukemia patients.

    PubMed

    Breccia, Massimo; De Propris, Maria Stefania; Minotti, Clara; Stefanizzi, Caterina; Raponi, Sara; Colafigli, Gioia; Latagliata, Roberto; Guarini, Anna; Foà, Robin

    2014-02-01

    Limited information is available on the relationship between expression of some additional aberrant phenotypic features and outcome of acute promyelocytic leukemia (APL) patients. Here, we set out to assess the frequency of CD15 and CD56 expression, and their prognostic value in a large series of APL patients. One hundred and fourteen adult patients consecutively diagnosed with PML/RARα-positive APL and homogeneously treated with the AIDA induction schedule at a single institution were included in the study. Twelve (10.5%) and 9 (8%) of the 114 patients expressed CD15 and CD56, respectively. CD15 expression identified a subset of patients with a classic morphologic subtype (92%), a prevalent association with a bcr1 expression (67%) with an unexpectedly higher frequency of relapses (42% vs 20% for the CD15- patients, p=0.03) and a low overall survival (OS) (median OS at 5 years 58% vs 85% for the CD15- patients, p=0.01). CD56 expression was detected only in patients with a classic morphologic subtype, a prevalent bcr3 expression (67%), high incidence of differentiation syndrome (55%), higher frequency of relapse (34% vs 20% for the CD56- population, p=0.04) and a low OS (60% vs 85% for the CD56- population p=0.02). We hereby confirm the negative prognostic value of CD56 and we show that the same applies also to cases expressing CD15. These aberrant markers may be considered for the refinement of risk-adapted therapeutic strategies in APL patients.

  18. Epidemiology and Treatment of Acute Promyelocytic Leukemia in Latin America

    PubMed Central

    Rego, E.M.; Jácomo, R.H.

    2011-01-01

    Distinct epidemiological characteristics have been described in Acute Promielocytic Leukemia (APL). Populations from Latin America have a higher incidence of APL and in some geographic areas a distinct distribution of the PML-RARA isoforms is present. Here, we review the main differences in APL epidemilogy in Latin America as well as treatment outcomes. PMID:22110899

  19. The acute promyelocytic leukaemia success story: curing leukaemia through targeted therapies.

    PubMed

    Rice, K L; de Thé, H

    2014-07-01

    The recent finding that almost all patients with acute promyelocytic leukaemia (APL) may be cured using a combination of retinoic acid (RA) and arsenic trioxide (As(2)O(3)) (N Engl J Med, 369, 2013 and 111) highlights the progress made in our understanding of APL pathogenesis and therapeutic approaches over the past 25 years. The study of APL has revealed many important lessons related to transcriptional control, nuclear organization, epigenetics and the role of proteolysis in biological control. Even more important has been the clinical demonstration that molecularly targeted therapy can eradicate disease.

  20. The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.

    PubMed

    de Thé, Hugues; Le Bras, Morgane; Lallemand-Breitenbach, Valérie

    2012-07-01

    Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation.

  1. Retinoic acid plus arsenic trioxide, the ultimate panacea for acute promyelocytic leukemia?

    PubMed

    Lallemand-Breitenbach, Valérie; de Thé, Hugues

    2013-09-19

    Rarely in the field of cancer treatment did we experience as many surprises as with acute promyelocytic leukemia (APL). Yet, the latest clinical trial reported by Lo-Coco et al in the New England Journal of Medicine is a practice-changing study, as it reports a very favorable outcome of virtually all enrolled low-intermediate risk patients with APL without any DNA-damaging chemotherapy. Although predicted from previous small pilot studies, these elegant and stringently controlled results open a new era in leukemia therapy.

  2. High frequency of acute promyelocytic leukemia among Latinos with acute myeloid leukemia.

    PubMed

    Douer, D; Preston-Martin, S; Chang, E; Nichols, P W; Watkins, K J; Levine, A M

    1996-01-01

    A high frequency (24%) of acute promyelocytic leukemia (APL) was noted among acute myelocytic leukemia (AML) cases at the Los Angeles County-University of Southern California (LAC-USC) Medical Center, in comparison with the expected frequency of 5% to 15%. Because of the high proportion of Latinos in this center, we questioned if APL is more common in this ethnic group. The proportion of APL among the 80 AML patients of Latino origin was significantly higher (30; 37.5%) when compared with the 62 non-Latinos (4; 6.5%) (P = .00001). In an attempt to verify this finding on a larger group of patients, we analyzed 276 pathologically verified cases of AML in patients aged 30 to 69 years from the entire County of Los Angeles, registered on an ongoing population-based epidemiologic study of AML. APL was more frequent among the 47 Latinos (24.3%) than in the 229 non-Latinos (8.3%) (P = .0075). APL is seen in younger patients with AML, but Latino AML patients also had a higher frequency of APL after accounting for their younger age (age-adjusted odds ratio for APL among Latinos in LAC-USC Medical Center, 9.4 [95% confidence interval (CI) 2.9, 30] P = .0002; among Latinos in the population-based study, 3.0 [95% CI 1.3 to 6.9] P = .01). The different ethnic distribution of AML was found to be due to a higher proportion of APL cases per se, and not to a lower proportion of any other French-American-British subtype (P = .0004). These results, from two different populations of AML patients, indicate that Latinos with AML have a higher likelihood of the APL subtype of disease, which may suggest a genetic predisposition to APL and/or exposure to distinct environmental factor(s).

  3. Synergistic targeted therapy for acute promyelocytic leukaemia: a model of translational research in human cancer.

    PubMed

    Mi, J-Q; Chen, S-J; Zhou, G-B; Yan, X-J; Chen, Z

    2015-12-01

    Acute promyelocytic leukaemia (APL), the M3 subtype of acute myeloid leukaemia, was once a lethal disease, yet nowadays the majority of patients with APL can be successfully cured by molecularly targeted therapy. This dramatic improvement in the survival rate is an example of the advantage of modern medicine. APL is characterized by a balanced reciprocal chromosomal translocation fusing the promyelocytic leukaemia (PML) gene on chromosome 15 with the retinoic acid receptor α (RARα) gene on chromosome 17. It has been found that all-trans-retinoic acid (ATRA) or arsenic trioxide (ATO) alone exerts therapeutic effect on APL patients with the PML-RARα fusion gene, and the combination of both drugs can act synergistically to further enhance the cure rate of the patients. Here, we provide an insight into the pathogenesis of APL and the mechanisms underlying the respective roles of ATRA and ATO. In addition, treatments that lead to more effective differentiation and apoptosis of APL cells, including leukaemia-initiating cells, and more thorough eradication of the disease will be discussed. Moreover, as a model of translational research, the development of a cure for APL has followed a bidirectional approach of 'bench to bedside' and 'bedside to bench', which can serve as a valuable example for the diagnosis and treatment of other malignancies.

  4. LG-362B targets PML-RARα and blocks ATRA resistance of acute promyelocytic leukemia.

    PubMed

    Wang, X; Lin, Q; Lv, F; Liu, N; Xu, Y; Liu, M; Chen, Y; Yi, Z

    2016-07-01

    Acute promyelocytic leukemia (APL) is a M3 subtype of acute myeloid leukemia (AML). Promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) translocation generally occurs in APL patients and makes APL unique both for diagnosis and treatment. However, some conventional drugs like all-transretinoic acid (ATRA) and arsenic trioxide (ATO), as the preferred ones for APL therapy, induce irreversible resistance and responsible for clinical failure of complete remission. Herein, we screened a library of novel chemical compounds with structural diversity and discovered a novel synthetic small compound, named LG-362B, specifically inhibited the proliferation of APL and induced apoptosis. Notably, the differentiation arrest was also relieved by LG-362B in cultured APL cells and APL mouse models. Moreover, LG-362B overcame the ATRA resistance on cellular differentiation and transplantable APL mice. These positive effects were driven by caspases-mediated degradation of PML-RARα when treated with LG-362B, making it specific to APL and reasonable for ATRA resistance relief. We propose that LG-362B would be a potential candidate agent for the treatment of the relapsed APL with ATRA resistance in the future.

  5. Acute promyelocytic leukemia presenting as pulmonary thromboembolism: Not all APLs bleed

    PubMed Central

    Vaid, Ashok K; Batra, Sandeep; Karanth, Suman S; Gupta, Sachin

    2015-01-01

    We present a rare case of acute promyelocytic leukemia (APL) presenting as pulmonary thromboembolism being misdiagnosed as community-acquired pneumonia. Thrombotic phenomenon in APL are poorly understood and grossly underreported. In our case, following no response to standard antibiotic treatment, the patient was further investigated and detected to have an acute pulmonary thromboembolism following right lower limb deep vein thrombosis (DVT). Though, complete blood picture revealed only mild hyperleukocytosis, bone marrow biopsy and aspiration revealed 60% blasts and a positive t (15,17)(q22,12) and PML retinoic acid receptor alpha (RARA) fusion protein on molecular cytogenetics. He was diagnosed as APL and received treatment with all-transretinoic acid (ATRA) and arsenic trioxide (ATO) and therapeutic anticoagulation PMID:26629469

  6. Erythema multiforme due to arsenic trioxide in a case of acute promyelocytic leukemia: A diagnostic challenge

    PubMed Central

    Badarkhe, Girish V.; Sil, Amrita; Bhattacharya, Sabari; Nath, Uttam Kumar; Das, Nilay Kanti

    2016-01-01

    Erythema multiforme (EM) is an acute, self-limited, Type IV hypersensitivity reactions associated with infections and drugs. In this case of acute promyelocytic leukemia, EM diagnosed during the induction phase was mistakenly attributed to vancomycin used to treat febrile neutropenia during that period. However, the occurrence of the lesions of EM again during the consolidation phase with arsenic trioxide (ATO) lead to a re-evaluation of the patient and both the Naranjo and World Health Organization-Uppsala Monitoring Centre scale showed the causality association as “probable.” The rash responded to topical corticosteroids and antihistamines. This rare event of EM being caused by ATO may be attributed to the genetic variation of methyl conjugation in the individual which had triggered the response, and the altered metabolic byproducts acted as a hapten in the subsequent keratinocyte necrosis. PMID:27114640

  7. Transient ischemic attack as an unusual initial manifestation of acute promyelocytic leukemia.

    PubMed

    Liu, Lifeng; Yuan, Xiaoling

    2016-07-01

    Patients with acute promyelocytic leukemia (APL) are prone to both bleeding and thrombosis. Both of these have a significant impact on the morbidity and mortality of patients with this disease. Here we report a case of a 41-year-old male, who presented with transient ischemic attack (TIA) and early neurological deterioration (END) as initial manifestations prior to an ultimate diagnosis of APL. This patient had no cerebrovascular risk factors or familial cerebrovascular disease. The patient experienced an acute ischemic stroke, verified by magnetic resonance imaging (MRI), in less than 24 h after his second hospital admission. Some APL patients suffer from cerebral ischemia as an initial manifestation or during induction therapy, and patients presenting this condition may continue to deteriorate until their death during hospitalization. Thus, APL should be considered as a possible underlying disease in patients with TIA without cerebrovascular risk factors. Delayed diagnosis and treatment of APL can be fatal.

  8. Erythema multiforme due to arsenic trioxide in a case of acute promyelocytic leukemia: A diagnostic challenge.

    PubMed

    Badarkhe, Girish V; Sil, Amrita; Bhattacharya, Sabari; Nath, Uttam Kumar; Das, Nilay Kanti

    2016-01-01

    Erythema multiforme (EM) is an acute, self-limited, Type IV hypersensitivity reactions associated with infections and drugs. In this case of acute promyelocytic leukemia, EM diagnosed during the induction phase was mistakenly attributed to vancomycin used to treat febrile neutropenia during that period. However, the occurrence of the lesions of EM again during the consolidation phase with arsenic trioxide (ATO) lead to a re-evaluation of the patient and both the Naranjo and World Health Organization-Uppsala Monitoring Centre scale showed the causality association as "probable." The rash responded to topical corticosteroids and antihistamines. This rare event of EM being caused by ATO may be attributed to the genetic variation of methyl conjugation in the individual which had triggered the response, and the altered metabolic byproducts acted as a hapten in the subsequent keratinocyte necrosis. PMID:27114640

  9. Additional chromosome abnormalities in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy

    PubMed Central

    Cervera, José; Montesinos, Pau; Hernández-Rivas, Jesús M.; Calasanz, María J.; Aventín, Anna; Ferro, María T.; Luño, Elisa; Sánchez, Javier; Vellenga, Edo; Rayón, Chelo; Milone, Gustavo; de la Serna, Javier; Rivas, Concha; González, José D.; Tormo, Mar; Amutio, Elena; González, Marcos; Brunet, Salut; Lowenberg, Bob; Sanz, Miguel A.

    2010-01-01

    Background Acute promyelocytic leukemia is a subtype of acute myeloid leukemia characterized by the t(15;17). The incidence and prognostic significance of additional chromosomal abnormalities in acute promyelocytic leukemia is still a controversial matter. Design and Methods Based on cytogenetic data available for 495 patients with acute promyelocytic leukemia enrolled in two consecutive PETHEMA trials (LPA96 and LPA99), we analyzed the incidence, characteristics, and outcome of patients with acute promyelocytic leukemia with and without additional chromosomal abnormalities who had been treated with all-trans retinoic acid plus anthracycline monochemotherapy for induction and consolidation. Results Additional chromosomal abnormalities were observed in 140 patients (28%). Trisomy 8 was the most frequent abnormality (36%), followed by abn(7q) (5%). Patients with additional chromosomal abnormalities more frequently had coagulopathy (P=0.03), lower platelet counts (P=0.02), and higher relapse-risk scores (P=0.02) than their counterparts without additional abnormalities. No significant association with FLT3/ITD or other clinicopathological characteristics was demonstrated. Patients with and without additional chromosomal abnormalities had similar complete remission rates (90% and 91%, respectively). Univariate analysis showed that additional chromosomal abnormalities were associated with a lower relapse-free survival in the LPA99 trial (P=0.04), but not in the LPA96 trial. However, neither additional chromosomal abnormalities overall nor any specific abnormality was identified as an independent risk factor for relapse in multivariate analysis. Conclusions The lack of independent prognostic value of additional chromosomal abnormalities in acute promyelocytic leukemia does not support the use of alternative therapeutic strategies when such abnormalities are found. PMID:19903674

  10. Co-operative leukemogenesis in acute myeloid leukemia and acute promyelocytic leukemia reveals C/EBPα as a common target of TRIB1 and PML/RARA

    PubMed Central

    Keeshan, Karen; Vieugué, Pauline; Chaudhury, Shahzya; Rishi, Loveena; Gaillard, Coline; Liang, Lu; Garcia, Elaine; Nakamura, Takuro; Omidvar, Nader; Kogan, Scott C.

    2016-01-01

    The PML/RARA fusion protein occurs as a result of the t(15;17) translocation in the acute promyelocytic leukemia subtype of human acute myeloid leukemia. Gain of chromosome 8 is the most common chromosomal gain in human acute myeloid leukemia, including acute promyelocytic leukemia. We previously demonstrated that gain of chromosome 8-containing MYC is of central importance in trisomy 8, but the role of the nearby TRIB1 gene has not been experimentally addressed in this context. We have now tested the hypothesis that both MYC and TRIB1 have functional roles underlying leukemogenesis of trisomy 8 by using retroviral vectors to express MYC and TRIB1 in wild-type bone marrow and in marrow that expressed a PML/RARA transgene. Interestingly, although MYC and TRIB1 readily co-operated in leukemogenesis for wild-type bone marrow, TRIB1 provided no selective advantage to cells expressing PML/RARA. We hypothesized that this lack of co-operation between PML/RARA and TRIB1 reflected a common pathway for their effect: both proteins targeting the myeloid transcription factor C/EBPα. In support of this idea, TRIB1 expression abrogated the all-trans retinoic acid response of acute promyelocytic leukemia cells in vitro and in vivo. Our data delineate the common and redundant inhibitory effects of TRIB1 and PML/RARA on C/EBPα providing a potential explanation for the lack of selection of TRIB1 in human acute promyelocytic leukemia, and highlighting the key role of C/EBPs in acute promyelocytic leukemia pathogenesis and therapeutic response. In addition, the co-operativity we observed between MYC and TRIB1 in the absence of PML/RARA show that, outside of acute promyelocytic leukemia, gain of both genes may drive selection for trisomy 8. PMID:27390356

  11. Extracellular DNA traps released by acute promyelocytic leukemia cells through autophagy.

    PubMed

    Ma, R; Li, T; Cao, M; Si, Y; Wu, X; Zhao, L; Yao, Z; Zhang, Y; Fang, S; Deng, R; Novakovic, V A; Bi, Y; Kou, J; Yu, B; Yang, S; Wang, J; Zhou, J; Shi, J

    2016-01-01

    Acute promyelocytic leukemia (APL) cells exhibit disrupted regulation of cell death and differentiation, and therefore the fate of these leukemic cells is unclear. Here, we provide the first evidence that a small percentage of APL cells undergo a novel cell death pathway by releasing extracellular DNA traps (ETs) in untreated patients. Both APL and NB4 cells stimulated with APL serum had nuclear budding of vesicles filled with chromatin that leaked to the extracellular space when nuclear and cell membranes ruptured. Using immunofluorescence, we found that NB4 cells undergoing ETosis extruded lattice-like structures with a DNA-histone backbone. During all-trans retinoic acid (ATRA)-induced cell differentiation, a subset of NB4 cells underwent ETosis at days 1 and 3 of treatment. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were significantly elevated at 3 days, and combined treatment with TNF-α and IL-6 stimulated NB4 cells to release ETs. Furthermore, inhibition of autophagy by pharmacological inhibitors or by small interfering RNA against Atg7 attenuated LC3 autophagy formation and significantly decreased ET generation. Our results identify a previously unrecognized mechanism for death in promyelocytes and suggest that ATRA may accelerate ET release through increased cytokines and autophagosome formation. Targeting this cellular death pathway in addition to conventional chemotherapy may provide new therapeutic modalities for APL. PMID:27362801

  12. Retinoic acid signaling in cancer: The parable of acute promyelocytic leukemia.

    PubMed

    Ablain, Julien; de Thé, Hugues

    2014-11-15

    Inevitably fatal some 40 years, acute promyelocytic leukemia (APL) can now be cured in more than 95% of cases. This clinical success story is tightly linked to tremendous progress in our understanding of retinoic acid (RA) signaling. The discovery of retinoic acid receptor alpha (RARA) was followed by the cloning of the chromosomal translocations driving APL, all of which involve RARA. Since then, new findings on the biology of nuclear receptors have progressively enlightened the basis for the clinical efficacy of RA in APL. Reciprocally, the disease offered a range of angles to approach the cellular and molecular mechanisms of RA action. This virtuous circle contributed to make APL one of the best-understood cancers from both clinical and biological standpoints. Yet, some important questions remain unanswered including how lessons learnt from RA-triggered APL cure can help design new therapies for other malignancies. PMID:25130873

  13. Retinoic acid signaling in cancer: The parable of acute promyelocytic leukemia.

    PubMed

    Ablain, Julien; de Thé, Hugues

    2014-11-15

    Inevitably fatal some 40 years, acute promyelocytic leukemia (APL) can now be cured in more than 95% of cases. This clinical success story is tightly linked to tremendous progress in our understanding of retinoic acid (RA) signaling. The discovery of retinoic acid receptor alpha (RARA) was followed by the cloning of the chromosomal translocations driving APL, all of which involve RARA. Since then, new findings on the biology of nuclear receptors have progressively enlightened the basis for the clinical efficacy of RA in APL. Reciprocally, the disease offered a range of angles to approach the cellular and molecular mechanisms of RA action. This virtuous circle contributed to make APL one of the best-understood cancers from both clinical and biological standpoints. Yet, some important questions remain unanswered including how lessons learnt from RA-triggered APL cure can help design new therapies for other malignancies.

  14. Combined staurosporine and retinoic acid induces differentiation in retinoic acid resistant acute promyelocytic leukemia cell lines

    PubMed Central

    Ge, Dong-zheng; Sheng, Yan; Cai, Xun

    2014-01-01

    All-trans retinoic acid (ATRA) resistance has been a critical problem in acute promyelocytic leukemia (APL) relapsed patients. In ATRA resistant APL cell lines NB4-R1 and NB4-R2, the combination of staurosporine and ATRA synergized to trigger differentiation accompanied by significantly enhanced protein level of CCAAT/enhancer binding protein ε (C/EBPε) and C/EBPβ as well as the phosphorylation of mitogen-activated protein (MEK) and extracellular signal-regulated kinase (ERK). Furthermore, attenuation of the MEK activation blocked not only the differentiation but also the increased protein level of C/EBPε and C/EBPβ. Taken together, we concluded that the combination of ATRA and staurosporine could overcome differentiation block via MEK/ERK signaling pathway in ATRA-resistant APL cell lines. PMID:24769642

  15. The histone demethylase PHF8 governs retinoic acid response in acute promyelocytic leukemia.

    PubMed

    Arteaga, Maria Francisca; Mikesch, Jan-Henrik; Qiu, Jihui; Christensen, Jesper; Helin, Kristian; Kogan, Scott C; Dong, Shuo; So, Chi Wai Eric

    2013-03-18

    While all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) has been the paradigm of targeted therapy for oncogenic transcription factors, the underlying mechanisms remain largely unknown, and a significant number of patients still relapse and become ATRA resistant. We identified the histone demethylase PHF8 as a coactivator that is specifically recruited by RARα fusions to activate expression of their downstream targets upon ATRA treatment. Forced expression of PHF8 resensitizes ATRA-resistant APL cells, whereas its downregulation confers resistance. ATRA sensitivity depends on the enzymatic activity and phosphorylation status of PHF8, which can be pharmacologically manipulated to resurrect ATRA sensitivity to resistant cells. These findings provide important molecular insights into ATRA response and a promising avenue for overcoming ATRA resistance.

  16. Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia

    PubMed Central

    Bochtler, Tilmann; Fröhling, Stefan; Weichert, Wilko; Endris, Volker; Thiede, Christian; Hutter, Barbara; Hundemer, Michael; Ho, Anthony D.; Krämer, Alwin

    2016-01-01

    Here, we report the case of an acute promyelocytic leukemia (APL) patient who—although negative for FLT3 mutations at diagnosis—developed isolated FLT3 tyrosine kinase II domain (FLT3-TKD)-positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-yr-old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA (ATRA plus idarubicin) protocol. Thirteen months after the start of ATRA maintenance, the patient suffered clinically overt meningeal relapse along with minute molecular traces of PML/RARA (promyelocytic leukemia/retinoic acid receptor alpha) in the bone marrow. Following treatment with arsenic trioxide and ATRA in combination with intrathecal cytarabine and methotrexate, the patient achieved a complete molecular remission in both cerebrospinal fluid (CSF) and bone marrow, which currently lasts for 2 yr after completion of therapy. Whole-exome sequencing and subsequent ultradeep targeted resequencing revealed a heterozygous FLT3-TKD mutation in CSF leukemic cells (p.D835Y, c.2503G>T, 1000/1961 reads [51%]), which was undetectable in the concurrent bone marrow sample. Interestingly, the FLT3-TKD mutated meningeal clone originated from a small bone marrow subclone present in a variant allele frequency of 0.4% (6/1553 reads) at initial diagnosis. This case highlights the concept of clonal evolution with a subclone harboring an additional mutation being selected as the “fittest” and leading to meningeal relapse. It also further supports earlier suggestions that FLT3 mutations may play a role for migration and clonal expansion in the CSF sanctuary site. PMID:27626069

  17. Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia

    PubMed Central

    Bochtler, Tilmann; Fröhling, Stefan; Weichert, Wilko; Endris, Volker; Thiede, Christian; Hutter, Barbara; Hundemer, Michael; Ho, Anthony D.; Krämer, Alwin

    2016-01-01

    Here, we report the case of an acute promyelocytic leukemia (APL) patient who—although negative for FLT3 mutations at diagnosis—developed isolated FLT3 tyrosine kinase II domain (FLT3-TKD)-positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-yr-old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA (ATRA plus idarubicin) protocol. Thirteen months after the start of ATRA maintenance, the patient suffered clinically overt meningeal relapse along with minute molecular traces of PML/RARA (promyelocytic leukemia/retinoic acid receptor alpha) in the bone marrow. Following treatment with arsenic trioxide and ATRA in combination with intrathecal cytarabine and methotrexate, the patient achieved a complete molecular remission in both cerebrospinal fluid (CSF) and bone marrow, which currently lasts for 2 yr after completion of therapy. Whole-exome sequencing and subsequent ultradeep targeted resequencing revealed a heterozygous FLT3-TKD mutation in CSF leukemic cells (p.D835Y, c.2503G>T, 1000/1961 reads [51%]), which was undetectable in the concurrent bone marrow sample. Interestingly, the FLT3-TKD mutated meningeal clone originated from a small bone marrow subclone present in a variant allele frequency of 0.4% (6/1553 reads) at initial diagnosis. This case highlights the concept of clonal evolution with a subclone harboring an additional mutation being selected as the “fittest” and leading to meningeal relapse. It also further supports earlier suggestions that FLT3 mutations may play a role for migration and clonal expansion in the CSF sanctuary site.

  18. Evolution of a FLT3-TKD mutated subclone at meningeal relapse in acute promyelocytic leukemia.

    PubMed

    Bochtler, Tilmann; Fröhling, Stefan; Weichert, Wilko; Endris, Volker; Thiede, Christian; Hutter, Barbara; Hundemer, Michael; Ho, Anthony D; Krämer, Alwin

    2016-09-01

    Here, we report the case of an acute promyelocytic leukemia (APL) patient who-although negative for FLT3 mutations at diagnosis-developed isolated FLT3 tyrosine kinase II domain (FLT3-TKD)-positive meningeal relapse, which, in retrospect, could be traced back to a minute bone marrow subclone present at first diagnosis. Initially, the 48-yr-old female diagnosed with high-risk APL had achieved complete molecular remission after standard treatment with all-trans retinoic acid (ATRA) and chemotherapy according to the AIDA (ATRA plus idarubicin) protocol. Thirteen months after the start of ATRA maintenance, the patient suffered clinically overt meningeal relapse along with minute molecular traces of PML/RARA (promyelocytic leukemia/retinoic acid receptor alpha) in the bone marrow. Following treatment with arsenic trioxide and ATRA in combination with intrathecal cytarabine and methotrexate, the patient achieved a complete molecular remission in both cerebrospinal fluid (CSF) and bone marrow, which currently lasts for 2 yr after completion of therapy. Whole-exome sequencing and subsequent ultradeep targeted resequencing revealed a heterozygous FLT3-TKD mutation in CSF leukemic cells (p.D835Y, c.2503G>T, 1000/1961 reads [51%]), which was undetectable in the concurrent bone marrow sample. Interestingly, the FLT3-TKD mutated meningeal clone originated from a small bone marrow subclone present in a variant allele frequency of 0.4% (6/1553 reads) at initial diagnosis. This case highlights the concept of clonal evolution with a subclone harboring an additional mutation being selected as the "fittest" and leading to meningeal relapse. It also further supports earlier suggestions that FLT3 mutations may play a role for migration and clonal expansion in the CSF sanctuary site. PMID:27626069

  19. NPM and BRG1 Mediate Transcriptional Resistance to Retinoic Acid in Acute Promyelocytic Leukemia.

    PubMed

    Nichol, Jessica N; Galbraith, Matthew D; Kleinman, Claudia L; Espinosa, Joaquín M; Miller, Wilson H

    2016-03-29

    Perturbation in the transcriptional control of genes driving differentiation is an established paradigm whereby oncogenic fusion proteins promote leukemia. From a retinoic acid (RA)-sensitive acute promyelocytic leukemia (APL) cell line, we derived an RA-resistant clone characterized by a block in transcription initiation, despite maintaining wild-type PML/RARA expression. We uncovered an aberrant interaction among PML/RARA, nucleophosmin (NPM), and topoisomerase II beta (TOP2B). Surprisingly, RA stimulation in these cells results in enhanced chromatin association of the nucleosome remodeler BRG1. Inhibition of NPM or TOP2B abrogated BRG1 recruitment. Furthermore, NPM inhibition and targeting BRG1 restored differentiation when combined with RA. Here, we demonstrate a role for NPM and BRG1 in obstructing RA differentiation and implicate chromatin remodeling in mediating therapeutic resistance in malignancies. NPM mutations are the most common genetic change in patients with acute leukemia (AML); therefore, our model may be applicable to other more common leukemias driven by NPM.

  20. FLT3 and NPM-1 mutations in a cohort of acute promyelocytic leukemia patients from India

    PubMed Central

    Swaminathan, Suchitra; Garg, Swati; Madkaikar, Manisha; Gupta, Maya; Jijina, Farah; Ghosh, Kanjaksha

    2014-01-01

    Background: Acute promyelocytic leukemia (APL) with t (15;17) is a distinct category of acute myeloid leukemia (AML) and is reported to show better response to anthracyclin based chemotherapy. A favorable overall prognosis over other subtypes of AML has been reported for APL patients but still about 15% patients relapse. Methods: This study evaluated the presence of Famus like tyrosine kinase-3 (FLT3) and nucleophosmin-1 (NPM1) gene mutations in a cohort of 40 APL patients. Bone marrow/peripheral blood samples from patients at the time of diagnosis and follow-up were processed for immunophenotyping, cytogenetic markers and isolation of DNA and RNA. Samples were screened for the presence of mutations in FLT3 and NPM1 genes using polymerase chain reaction followed by sequencing. Results: Frequency of FLT3/internal tandem duplication and FLT3/tyrosine kinase domain was found to be 25% and 7% respectively. We observed a high frequency of NPM1 mutation (45%) in the present population of APL patients. PMID:25400345

  1. Autologous is Superior to Allogeneic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukemia in Second Complete Remission

    PubMed Central

    Chakrabarty, Jennifer L. Holter; Rubinger, Morel; Le-Rademacher, Jennifer; Wang, Hai-Lin; Grigg, Andrew; Selby, George B.; Szer, Jeffrey; Rowe, Jacob M.; Weisdorf, Daniel J.; Tallman, Martin S.

    2014-01-01

    PURPOSE To identify favored choice of transplantation in patients with acute promyelocytic leukemia in second complete remission. PATIENTS We studied 294 acute promyelocytic leukemia (APL) patients receiving allogeneic (n=232) or autologous (62) hematopoietic cell transplantation (HCT) in second complete remission (CR2) reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR) from 1995 to 2006 including pre-HCT PML/RAR∝ status in 155 (49% of allogeneic and 66% of autologous). METHODS Patient characteristics and transplant characteristics including treatment related mortality, overall survival, and disease free survival were collected and analyzed for both univariate and multivariate outcomes. RESULTS With median follow-up of 115 (allogeneic) and 72 months (autologous), 5-year disease-free survival (DFS) favored autologous 63% (49-75%) compared to allogeneic 50% (44-57%) (p=0.10) and overall survival (OS) 75% (63-85%) vs. 54% (48-61%) (p=.002) Multivariate analysis showed significantly worse DFS after allogeneic HCT (HR=1.88, 95% CI=1.16-3.06, p=0.011) and age >40 years (HR=2.30, 95% CI 1.44-3.67, p=0.0005). OS was significantly worse after allogeneic HCT (HR=2.66, 95%CI 1.52-4.65, p=0.0006; age >40 (HR=3.29, 95% CI 1.95-5.54, p<0.001) and CR1<12 months (HR=1.56 95% CI 1.07-2.26, p=0.021). Positive pre-HCT PML-RAR∝ status in 17/114 allogeneic and 6/41 autologous transplants did not influence relapse, treatment failure or survival in either group. The survival advantage for autografting was attributable to increased 3 years TRM: allogeneic 30%; autologous 2%, and GVHD. CONCLUSION We conclude that autologous HCT yields superior overall survival for APL in CR2. Long term DFS in autologous recipients, even with MRD+ grafts remains an important subject for further study. PMID:24691221

  2. Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia

    PubMed Central

    dos Santos, Guilherme Augusto; Kats, Lev

    2013-01-01

    Acute promyelocytic leukemia (APL) is a hematological malignancy driven by a chimeric oncoprotein containing the C terminus of the retinoic acid receptor-a (RARa) fused to an N-terminal partner, most commonly promyelocytic leukemia protein (PML). Mechanistically, PML-RARa acts as a transcriptional repressor of RARa and non-RARa target genes and antagonizes the formation and function of PML nuclear bodies that regulate numerous signaling pathways. The empirical discoveries that PML-RARa–associated APL is sensitive to both all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), and the subsequent understanding of the mechanisms of action of these drugs, have led to efforts to understand the contribution of molecular events to APL cell differentiation, leukemia-initiating cell (LIC) clearance, and disease eradication in vitro and in vivo. Critically, the mechanistic insights gleaned from these studies have resulted not only in a better understanding of APL itself, but also carry valuable lessons for other malignancies. PMID:24344243

  3. Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis.

    PubMed

    Daver, Naval; Kantarjian, Hagop; Marcucci, Guido; Pierce, Sherry; Brandt, Mark; Dinardo, Courtney; Pemmaraju, Naveen; Garcia-Manero, Guillermo; O'Brien, Susan; Ferrajoli, Alessandra; Verstovsek, Srdan; Popat, Uday; Hosing, Chitra; Anderlini, Paolo; Borthakur, Gautam; Kadia, Tapan; Cortes, Jorge; Ravandi, Farhad

    2015-03-01

    The clinical characteristics, treatment options and outcomes in patients with acute promyelocytic leukaemia (APL) and hyperleucocytosis remain poorly defined. This study reviewed 242 consecutive patients with APL; 29 patients (12%) had a white blood cell count (WBC) ≥ 50 × 10(9) /l at presentation (median WBC 85·5 × 10(9) /l). Patients with hyperleucocytosis had inferior complete remission (CR) rates (69% vs. 88%; P = 0·004) and higher 4-week mortality (24% vs. 9%; P = 0·018) compared to patients without hyperleucocytosis. We noted a trend towards inferior 3-year disease-free survival (DFS) (69% vs. 80%; P = 0·057) and inferior 3-year overall survival (OS) (74% vs. 92%; P = 0·2) for patients with hyperleucocytosis. Leukapheresis was performed in 11 (38%) of the 29 patients with hyperleucocytosis. CR rate and 3-year OS were not significantly improved in patients who received leukapheresis. CR rate and 3-year OS for the 15 patients with hyperleucocytosis treated with all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) plus cytotoxic therapy (idarubicin or gemtuzumab ozogamicin) combinations were 100% and 100% vs. 57% and 35% for the 14 patients treated with non-ATRA/ATO combinations (P = 0·004 and P = 0·002). Leukapheresis does not improve the outcomes in patients with APL presenting with hyperleucocytosis. ATRA/ATO-based combinations are superior to other regimens in these patients. PMID:25312977

  4. [New Retinoid SX-116 Induces Apoptosis of Acute Promyelocytic Leukemia Cell Line NB4

    PubMed

    Yao, Yi-Yun; Sun, Guan-Lin; Guo, Zong-Ru; Wu, Wei-Li; Wang, Yun; Su, Hui

    2001-03-01

    In this research, the effect of novel retinoid SX-116 on acute promyelocytic leukemia cell line NB4 was studied in vitro. Cell proliferation, cell morphological characters, flow cytometry, DNA electrophoresis and RT-PCR were observational parameters. The results showed that treated with SX-116 at 10(-6) mol/L, the growth and survival of NB4 cells were markedly inhibited, morphological changes of apoptosis, including membrane blebbing, chromosome condensation and fragmentation of nuclei were observed in NB4 cells after 24 hours exposure of SX-116. Further studies showed "DNA ladder" in genomic DNA electrophoresis, as well as a typical apoptotic peak below G(1) phase presented in flow cytometry. The expression of apoptosis - related gene bcl-2 and p53 were examined. The level of bcl-2 mRNA was downregulated by 6-hour treatment of SX-116, while the gene restored to the normal level by following 12-, 24- and 48-hour exposure. However, p53 mRNA was unchanged during the treatment. The results demonstrated that SX-116 could induce apoptosis of NB4 cells while the mechanism remains to be studied.

  5. Single-Nucleotide Polymorphism Array-Based Karyotyping of Acute Promyelocytic Leukemia

    PubMed Central

    Gómez-Seguí, Inés; Sánchez-Izquierdo, Dolors; Barragán, Eva; Such, Esperanza; Luna, Irene; López-Pavía, María; Ibáñez, Mariam; Villamón, Eva; Alonso, Carmen; Martín, Iván; Llop, Marta; Dolz, Sandra; Fuster, Óscar; Montesinos, Pau; Cañigral, Carolina; Boluda, Blanca; Salazar, Claudia

    2014-01-01

    Acute promyelocytic leukemia (APL) is characterized by the t(15;17)(q22;q21), but additional chromosomal abnormalities (ACA) and other rearrangements can contribute in the development of the whole leukemic phenotype. We hypothesized that some ACA not detected by conventional techniques may be informative of the onset of APL. We performed the high-resolution SNP array (SNP-A) 6.0 (Affymetrix) in 48 patients diagnosed with APL on matched diagnosis and remission sample. Forty-six abnormalities were found as an acquired event in 23 patients (48%): 22 duplications, 23 deletions and 1 Copy-Neutral Loss of Heterozygocity (CN-LOH), being a duplication of 8(q24) (23%) and a deletion of 7(q33-qter) (6%) the most frequent copy-number abnormalities (CNA). Four patients (8%) showed CNAs adjacent to the breakpoints of the translocation. We compared our results with other APL series and found that, except for dup(8q24) and del(7q33-qter), ACA were infrequent (≤3%) but most of them recurrent (70%). Interestingly, having CNA or FLT3 mutation were mutually exclusive events. Neither the number of CNA, nor any specific CNA was associated significantly with prognosis. This study has delineated recurrent abnormalities in addition to t(15;17) that may act as secondary events and could explain leukemogenesis in up to 40% of APL cases with no ACA by conventional cytogenetics. PMID:24959826

  6. Genital ulcers during treatment with ALL-trans retinoic acid for acute promyelocytic leukemia.

    PubMed

    Fukuno, Kenji; Tsurumi, Hisashi; Goto, Hideko; Oyama, Masami; Tanabashi, Shinobu; Moriwaki, Hisataka

    2003-11-01

    Scrotal ulcer is a unique adverse effect of all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). The pathogenesis of scrotal ulceration remains unknown. We describe genital ulcers that developed in four patients with APL who were undergoing ATRA therapy (45 mg/m2 per day p.o.). Two of the patients were female, in whom this condition is quite rare. Genital ulcers with concomitant fever appeared between 17 and 32 days of therapy in all four patients. Genital ulcers healed in three of the patients while another patient developed Fournier's gangrene and underwent left testectomy. Ulcer healing was brought by either local or intravenous corticosteroids. Intravenous dexamethasone actually enabled continued ATRA administration in one patient, while ATRA was discontinued in other two patients. If corticosteroids cannot control progression of genital ulcers nor concomitant fever, ATRA administration should be discontinued so as not to induce Fournier's gangrene nor retionic acid syndrome. Our experience indicates the importance of recognizing genital ulcers associated with ATRA in order that appropriate countermeasures can be taken.

  7. Lithium chloride antileukemic activity in acute promyelocytic leukemia is GSK-3 and MEK/ERK dependent.

    PubMed

    Zassadowski, F; Pokorna, K; Ferre, N; Guidez, F; Llopis, L; Chourbagi, O; Chopin, M; Poupon, J; Fenaux, P; Ann Padua, R; Pla, M; Chomienne, C; Cassinat, B

    2015-12-01

    We recently identified that the MEK/ERK1/2 pathway synergized with retinoic acid (RA) to restore both transcriptional activity and RA-induced differentiation in RA-resistant acute promyelocytic leukemia (APL) cells. To target the MEK/ERK pathway, we identified glycogen synthase kinase-3β (GSK-3β) inhibitors including lithium chloride (LiCl) as activators of this pathway in APL cells. Using NB4 (RA-sensitive) and UF-1 (RA-resistant) APL cell lines, we observed that LiCl as well as synthetic GSK-3β inhibitors decreased proliferation, induced apoptosis and restored, in RA-resistant cells, the expression of RA target genes and the RA-induced differentiation. Inhibition of the MEK/ERK1/2 pathway abolished these effects. These results were corroborated in primary APL patient cells and translated in vivo using an APL preclinical mouse model in which LiCl given alone was as efficient as RA in increasing survival of leukemic mice compared with untreated mice. When LiCl was combined with RA, we observed a significant survival advantage compared with mice treated by RA alone. In this work, we demonstrate that LiCl, a well-tolerated agent in humans, has antileukemic activity in APL and that it has the potential to restore RA-induced transcriptional activation and differentiation in RA-resistant APL cells in an MEK/ERK-dependent manner. PMID:26108692

  8. [RXR, a key member of the oncogenic complex in acute promyelocytic leukemia].

    PubMed

    Halftermeyer, Juliane; Le Bras, Morgane; De Thé, Hugues

    2011-11-01

    Acute promyelocytic leukaemia (APL) is induced by fusion proteins always implying the retinoic acid receptor RARa. Although PML-RARa and other fusion oncoproteins are able to bind DNA as homodimers, in vivo they are always found in association with the nuclear receptor RXRa (Retinoid X Receptor). Thus, RXRa is an essential cofactor of the fusion protein for the transformation. Actually, RXRa contributes to several aspects of in vivo -transformation: RARa fusion:RXRa hetero-oligomeric complexes bind DNA with a much greater affinity than RARa fusion homodimers. Besides, PML-RARa:RXRa recognizes an enlarged repertoire of DNA binding sites. Thus the association between fusion proteins and RXRa regulates more genes than the homodimer alone. Titration of RXRa by the fusion protein may also play a role in the transformation process, as well as post-translational modifications of RXRa in the complex. Finally, RXRa is required for rexinoid-induced APL differentiation. Thus, RXRa is a key member of the oncogenic complex.

  9. Analysis of factors affecting hemorrhagic diathesis and overall survival in patients with acute promyelocytic leukemia

    PubMed Central

    Lee, Ho Jin; Kim, Dong Hyun; Lee, Seul; Koh, Myeong Seok; Kim, So Yeon; Lee, Ji Hyun; Lee, Suee; Oh, Sung Yong; Han, Jin Yeong; Kim, Hyo-Jin; Kim, Sung-Hyun

    2015-01-01

    Background/Aims: This study investigated whether patients with acute promyelocytic leukemia (APL) truly fulfill the diagnostic criteria of overt disseminated intravascular coagulation (DIC), as proposed by the International Society on Thrombosis and Haemostasis (ISTH) and the Korean Society on Thrombosis and Hemostasis (KSTH), and analyzed which component of the criteria most contributes to bleeding diathesis. Methods: A single-center retrospective analysis was conducted on newly diagnosed APL patients between January 1995 and May 2012. Results: A total of 46 newly diagnosed APL patients were analyzed. Of these, 27 patients (58.7%) showed initial bleeding. The median number of points per patient fulfilling the diagnostic criteria of overt DIC by the ISTH and the KSTH was 5 (range, 1 to 7) and 3 (range, 1 to 4), respectively. At diagnosis of APL, 22 patients (47.8%) fulfilled the overt DIC diagnostic criteria by either the ISTH or KSTH. In multivariate analysis of the ISTH or KSTH diagnostic criteria for overt DIC, the initial fibrinogen level was the only statistically significant factor associated with initial bleeding (p = 0.035), but it was not associated with overall survival (OS). Conclusions: Initial fibrinogen level is associated with initial presentation of bleeding of APL patients, but does not affect OS. PMID:26552464

  10. Acute promyelocytic leukemia co-existing with JAK2 V617F positive myeloproliferative neoplasm: a case report

    PubMed Central

    Mamorska-Dyga, Aleksandra; Wu, Jingjing; Khattar, Pallavi; Ronny, Faisal M. H.; Islam, Humayun; Seiter, Karen

    2016-01-01

    The V617F mutation of Janus-associated kinase 2 (JAK2) is commonly seen in myeloproliferative neoplasms (MPN). Transformation of JAK2 positive MPNs to acute leukemia has been reported. We here report a case of acute promyelocytic leukemia which was later confirmed to have a co-existing JAK2 V617F positive MPN. In addition, the patient was found to have FLT3-TKD mutation, which, together with PML/RARa, could play a role in the MPN transformation to APL. PMID:27358900

  11. Fucoidan Suppresses the Growth of Human Acute Promyelocytic Leukemia Cells In Vitro and In Vivo.

    PubMed

    Atashrazm, Farzaneh; Lowenthal, Ray M; Woods, Gregory M; Holloway, Adele F; Karpiniec, Samuel S; Dickinson, Joanne L

    2016-03-01

    Fucoidan, a natural component of seaweeds, is reported to have immunomodulatory and anti-tumor effects. The mechanisms underpinning these activities remain poorly understood. In this study, the cytotoxicity and anti-tumor activities of fucoidan were investigated in acute myeloid leukemia (AML) cells. The human AML cell lines NB4, KG1a, HL60, and K562 were treated with fucoidan and cell cycle, cell proliferation, and expression of apoptotic pathways molecules were analyzed. Fucoidan suppressed the proliferation and induced apoptosis through the intrinsic and extrinsic pathways in the acute promyelocytic leukemia (APL) cell lines NB4 and HL60, but not in KG1a and K562 cells. In NB4 cells, apoptosis was caspase-dependent as it was significantly attenuated by pre-treatment with a pan-caspase inhibitor. P21/WAF1/CIP1 was significantly up-regulated leading to cell cycle arrest. Fucoidan decreased the activation of ERK1/2 and down-regulated the activation of AKT through hypo-phosphorylation of Thr(308) residue but not Ser(473). In vivo, a xenograft model using the NB4 cells was employed. Mice were fed with fucoidan and tumor growth was measured following inoculation with NB4 cells. Subsequently, splenic natural killer (NK) cell cytotoxic activity was also examined. Oral doses of fucoidan significantly delayed tumor growth in the xenograft model and increased cytolytic activity of NK cells. Taken together, these data suggest that the selective inhibitory effect of fucoidan on APL cells and its protective effect against APL development in mice warrant further investigation of fucoidan as a useful agent in treatment of certain types of leukemia.

  12. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

    SciTech Connect

    Huai, Lei; Wang, Cuicui; Zhang, Cuiping; Li, Qihui; Chen, Yirui; Jia, Yujiao; Li, Yan; Xing, Haiyan; Tian, Zheng; Rao, Qing; Wang, Min; Wang, Jianxiang

    2012-06-08

    Highlights: Black-Right-Pointing-Pointer Metformin induces differentiation in NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces activation of the MEK/ERK signaling pathway in APL cells. Black-Right-Pointing-Pointer Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces the relocalization and degradation of the PML-RAR{alpha} fusion protein. Black-Right-Pointing-Pointer The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR{alpha} and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.

  13. Treatment of an acute promyelocytic leukemia relapse using arsenic trioxide and all-trans-retinoic in a 6-year-old child.

    PubMed

    Rock, Nathalie; Mattiello, V; Judas, C; Huezo-Diaz, P; Bourquin, J P; Gumy-Pause, F; Ansari, M

    2014-03-01

    In adult therapy, arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) are recognized as active treatment of relapsed acute promyelocytic leukemia (APL). The efficacy of this combination in pediatric APL has not yet been well established. We report the case of a 6-year-old girl with relapsed APL, with a PML-RARα mutation, treated with a combination of ATO and ATRA. Over a period of 5 months, she received in total, 75 doses of intravenous ATO and 40 doses of oral ATRA. Currently, 22 months after relapse, she is still in complete remission. Here, we describe treatment of a relapsed APL in a child with limited treatment of ATO and ATRA and review the literature. PMID:24498972

  14. Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: an useful salvage therapy.

    PubMed

    Huan, S Y; Yang, C H; Chen, Y C

    2000-07-01

    Arsenic trioxide (As2O3) was recently identified as a very potent agent against acute promyelocytic leukemia (APL). Intravenous infusion of 10 mg As2O3 daily for one to two months can induce significant complete remission (CR) of APL, and there is no cross drug-resistance between As2O3 and other antileukemic agents, including all-trans retinoic acid (ATRA). The CR rate of relapsed and/or refractory APL patients who received As2O3 treatment ranged from 52.3% to 93.3%. The median duration to CR ranged from 38 to 51 days, with accumulative As2O3 dosage of 340-430 mg. Although most adverse reactions of As2O3 treatment were tolerable, certain infrequent but severe toxicities related to As2O3 were observed, including renal failure, hepatic damage, cardiac arrhythmia and chronic neuromuscular degeneration, which should be monitored carefully. As2O3 can induce partial differentiation and subsequent apoptosis of APL cells through degradation of wild type PML and PML/RAR alpha chimeric proteins and possible anti-mitochondrial effects. Like the treatment of ATRA in APL, early relapses from As2O3 treatment within a few months were not infrequently seen, indicating that rapid emerging resistance to As2O3 can occur. Nevertheless, the PML/RAR alpha fusion protein was reported to disappear in some APL patients who received As2O3, and who might earn long-survival. However, the follow-up is still too short to draw the conclusion. Intriguingly, it has been shown that As2O3 can also induce apoptosis of other non-APL tumor cells with clinical achievable concentrations. However, the detailed molecular mechanisms are not yet fully understood. Further studies regarding to the pharmacological characters, clinical efficacies, toxicities, apoptogenic mechanisms, and spectrum of anti-tumor activity of As2O3 are warranted.

  15. Significance of AZD1152 as a potential treatment against Aurora B overexpression in acute promyelocytic leukemia.

    PubMed

    Ghanizadeh-Vesali, Samad; Zekri, Ali; Zaker, Farhad; Zaghal, Azam; Yousefi, Meysam; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H

    2016-06-01

    Aurora B kinase as a chromosomal passenger protein plays multiple roles in regulating mitosis and cytokinesis. The function of Aurora B in leukemic cells has made it an important treatment target. In this study, we explored the expressions of Aurora (A, B, and C) kinases in newly diagnosed acute promyelocytic leukemia (APL) patients. In addition, we investigated the effects of AZD1152 as a specific inhibitor of Aurora B on cell survival, DNA synthesis, nuclear morphology, apoptosis induction, cell cycle distribution, and gene expression in an APL-derived NB4 cell line. Our results showed that Aurora B was overexpressed in 88 % of APL patients. AZD1152 treatment of NB4 cells led to viability reduction and G2/M arrest followed by an increase in cell size and polyploidy induction. These giant cells showed morphological evidence of mitotic catastrophe. AZD1152 treatment induced activation of G2/M checkpoint which in turn led to transient G2/M arrest in a p21-independent manner. Lack of functional p53 in NB4 cells might provide an opportunity to escape from G2/M block and to endure repeated rounds of replication and polyploidy. Treated cells were probably eliminated via p73-mediated overexpression of BAX, PUMA, and APAF1 and downregulation of survivin and MCL-1. In summary, AZD1152 treatment led to endomitosis and polyploidy in TP53-mutated NB4 cells. These giant polyploid cells might undergo mitotic catastrophe and p73-mediated apoptosis. It seems that induction of polyploidy via AZD1152 could be a novel form of anti-cancer therapy for APL that may be clinically accessible in the near future. PMID:27091351

  16. Simple, rapid and accurate molecular diagnosis of acute promyelocytic leukemia by loop mediated amplification technology.

    PubMed

    Spinelli, Orietta; Rambaldi, Alessandro; Rigo, Francesca; Zanghì, Pamela; D'Agostini, Elena; Amicarelli, Giulia; Colotta, Francesco; Divona, Mariadomenica; Ciardi, Claudia; Coco, Francesco Lo; Minnucci, Giulia

    2015-01-01

    The diagnostic work-up of acute promyelocytic leukemia (APL) includes the cytogenetic demonstration of the t(15;17) translocation and/or the PML-RARA chimeric transcript by RQ-PCR or RT-PCR. This latter assays provide suitable results in 3-6 hours. We describe here two new, rapid and specific assays that detect PML-RARA transcripts, based on the RT-QLAMP (Reverse Transcription-Quenching Loop-mediated Isothermal Amplification) technology in which RNA retrotranscription and cDNA amplification are carried out in a single tube with one enzyme at one temperature, in fluorescence and real time format. A single tube triplex assay detects bcr1 and bcr3 PML-RARA transcripts along with GUS housekeeping gene. A single tube duplex assay detects bcr2 and GUSB. In 73 APL cases, these assays detected in 16 minutes bcr1, bcr2 and bcr3 transcripts. All 81 non-APL samples were negative by RT-QLAMP for chimeric transcripts whereas GUSB was detectable. In 11 APL patients in which RT-PCR yielded equivocal breakpoint type results, RT-QLAMP assays unequivocally and accurately defined the breakpoint type (as confirmed by sequencing). Furthermore, RT-QLAMP could amplify two bcr2 transcripts with particularly extended PML exon 6 deletions not amplified by RQ-PCR. RT-QLAMP reproducible sensitivity is 10(-3) for bcr1 and bcr3 and 10(-)2 for bcr2 thus making this assay particularly attractive at diagnosis and leaving RQ-PCR for the molecular monitoring of minimal residual disease during the follow up. In conclusion, PML-RARA RT-QLAMP compared to RT-PCR or RQ-PCR is a valid improvement to perform rapid, simple and accurate molecular diagnosis of APL. PMID:25815362

  17. Acute promyelocytic leukemia in patients aged >70 years: the cure beyond the age.

    PubMed

    Finsinger, Paola; Breccia, Massimo; Minotti, Clara; Carmosino, Ida; Girmenia, Corrado; Chisini, Marta; Volpicelli, Paola; Vozella, Federico; Romano, Angela; Montagna, Chiara; Colafigli, Gioia; Cimino, Giuseppe; Avvisati, Giuseppe; Petti, Maria Concetta; Lo-Coco, Francesco; Foà, Roberto; Latagliata, Roberto

    2015-02-01

    All-trans retinoic acid (ATRA) has made acute promyelocytic leukemia (APL) a very curable disease also in patients aged >60 years; however, there are only few case reports in very elderly APL patients. To address this issue, we reviewed treatment results in 13 patients aged >70 years with newly diagnosed APL followed at our institution from January 1991 to December 2008. According to Sanz score, seven patients were at low risk, five at intermediate risk, and one at high risk. Induction therapy consisted of ATRA + idarubicin in nine patients (3/9 with reduced idarubicin dosage) and ATRA alone in four patients; in this latter group, however, 2/4 needed to add chemotherapy (CHT) due to hyperleukocytosis during ATRA treatment. All patients achieved both morphological and molecular complete remission (CR) after a median time of 51 [interquartile range (IR) 43-55] and 114 (IR 74-155) days, respectively. Infective complications were observed in 10/13 patients, APL differentiation syndrome in 3/13 patients. Twelve patients received consolidation therapy, followed by maintenance treatment in nine patients. Five patients relapsed after 7, 8, 11, 35, and 56 months. At present, seven patients are still alive, five died due to disease progression (four) or senectus while in CR (one), and one was lost to follow-up while in CR. The 5-year event-free survival was 56.1 % (95 % CI, 26.0-86.2); the 5-year overall survival (OS) was 64.5 % (95 % CI, 35.6-93.4). ATRA-based treatment of APL is safe and effective also in very elderly patients, with long-lasting disease-free OS. PMID:25186786

  18. Simple, rapid and accurate molecular diagnosis of acute promyelocytic leukemia by loop mediated amplification technology

    PubMed Central

    Spinelli, Orietta; Rambaldi, Alessandro; Rigo, Francesca; Zanghì, Pamela; D'Agostini, Elena; Amicarelli, Giulia; Colotta, Francesco; Divona, Mariadomenica; Ciardi, Claudia; Coco, Francesco Lo; Minnucci, Giulia

    2015-01-01

    The diagnostic work-up of acute promyelocytic leukemia (APL) includes the cytogenetic demonstration of the t(15;17) translocation and/or the PML-RARA chimeric transcript by RQ-PCR or RT-PCR. This latter assays provide suitable results in 3-6 hours. We describe here two new, rapid and specific assays that detect PML-RARA transcripts, based on the RT-QLAMP (Reverse Transcription-Quenching Loop-mediated Isothermal Amplification) technology in which RNA retrotranscription and cDNA amplification are carried out in a single tube with one enzyme at one temperature, in fluorescence and real time format. A single tube triplex assay detects bcr1 and bcr3 PML-RARA transcripts along with GUS housekeeping gene. A single tube duplex assay detects bcr2 and GUSB. In 73 APL cases, these assays detected in 16 minutes bcr1, bcr2 and bcr3 transcripts. All 81 non-APL samples were negative by RT-QLAMP for chimeric transcripts whereas GUSB was detectable. In 11 APL patients in which RT-PCR yielded equivocal breakpoint type results, RT-QLAMP assays unequivocally and accurately defined the breakpoint type (as confirmed by sequencing). Furthermore, RT-QLAMP could amplify two bcr2 transcripts with particularly extended PML exon 6 deletions not amplified by RQ-PCR. RT-QLAMP reproducible sensitivity is 10−3 for bcr1 and bcr3 and 10−2 for bcr2 thus making this assay particularly attractive at diagnosis and leaving RQ-PCR for the molecular monitoring of minimal residual disease during the follow up. In conclusion, PML-RARA RT-QLAMP compared to RT-PCR or RQ-PCR is a valid improvement to perform rapid, simple and accurate molecular diagnosis of APL. PMID:25815362

  19. Clinical impact of FLT3 mutation load in acute promyelocytic leukemia with t(15;17)/PML-RARA

    PubMed Central

    Schnittger, Susanne; Bacher, Ulrike; Haferlach, Claudia; Kern, Wolfgang; Alpermann, Tamara; Haferlach, Torsten

    2011-01-01

    Background Combined treatment with all-trans-retinoic acid and chemotherapy is extremely efficient in patients with acute promyelocytic leukemia with t(15;17)/PML-RARA, but up to 15% of patients relapse. Design and Methods To further clarify the prognostic impact of parameters such as FLT3 mutations, we comprehensively characterized the relation between genetic features and outcome in 147 patients (aged 19.7–86.3 years) with acute promyelocytic leukemia. Results Internal tandem duplications of the FLT3 gene (FLT3-ITD) were detected in 47/147 (32.0%) and tyrosine kinase domain mutations (FLT3-TKD) in 19/147 (12.9%) patients. FLT3-ITD or FLT3-TKD mutation status did not have a significant prognostic impact, whereas FLT3-ITD mutation load, as defined by a mutation/wild-type ratio of less than 0.5 was associated with trends to a better 2-year overall survival rate (86.7% versus 72.7%; P=0.075) and 2-year event-free survival rate (84.5% versus 62.1%, P=0.023) compared to the survival rates of patients with a ratio of 0.5 or more. Besides the t(15;17), an additional chromosomal abnormality was detected in 57 of 147 cases and did not show a significant impact on survival. White blood cell counts of 10×109/L or less versus more than 10×109/L were associated with a better 2-year overall survival rate (88.3% versus 69.4%, respectively; P=0.015), as was male sex (P=0.040). In multivariate analysis, only higher age had a significant adverse impact. Conclusions Prospective trials should further investigate the clinical impact of the FLT3-ITD/wild-type mutation load aiming to evaluate whether this parameter might be included in risk stratification in patients with acute promyelocytic leukemia. PMID:21859732

  20. High pseudotumor cerebri incidence in tretinoin and arsenic treated acute promyelocytic leukemia and the role of topiramate after acetazolamide failure

    PubMed Central

    Smith, Morgan B.; Griffiths, Elizabeth A.; Thompson, James E.; Wang, Eunice S.; Wetzler, Meir; Freyer, Craig W.

    2014-01-01

    Dual differentiation therapy with arsenic trioxide and tretinoin (all-trans-retinoic acid; ATRA) for the management of low and intermediate risk acute promyelocytic leukemia has recently been recommended by the National Comprehensive Cancer Network. Some less common toxicities of the combination may have yet to be fully realized. Of ten patients we have treated thus far, five (50%) have developed pseudotumor cerebri. In one patient, temporary discontinuation of ATRA and initiation of acetazolamide controlled symptoms. In four patients, topiramate was substituted for acetazolamide to relieve symptoms and allow ATRA dose re-escalation. We conclude that providers should monitor for pseudotumor cerebri and consider topiramate if acetazolamide fails. PMID:25180154

  1. The differentiation syndrome in patients with acute promyelocytic leukemia: experience of the pethema group and review of the literature.

    PubMed

    Montesinos, Pau; Sanz, Miguel A

    2011-01-01

    Differentiation syndrome (DS), formerly known as retinoic acid syndrome, is the main life-threatening complication of therapy with differentiating agents (all-trans retinoic acid [ATRA] or arsenic trioxide [ATO]) in patients with acute promyelocytic leukemia (APL). The differentiation of leukemic blasts and promyelocytes induced by ATRA and/or ATO may lead to cellular migration, endothelial activation, and release of interleukins and vascular factors responsible of tissue damage. Roughly one quarter of patients with APL undergoing induction therapy will develop the DS, characterized by unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, and/or a vascular capillary leak syndrome leading to acute renal failure. Although the development of the DS, particularly of the severe form, is still associated with a significant increase in morbidity and mortality during induction, the early administration of high-dose dexamethasone at the onset of the first symptoms seems likely to have dramatically reduced the mortality rate of this complication. In this article, we will review the clinical features, incidence, prognostic factors, management, and outcome of the DS reported in the scientific literature. We will make focus in the experience of the three consecutive Programa Español de Tratamientos en Hematología trials (PETHEMA LPA96, LPA99, and LPA2005), in which more than one thousand patients were treated with ATRA plus idarubicin for induction.

  2. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL.

    PubMed

    Rego, Eduardo M; Kim, Haesook T; Ruiz-Argüelles, Guillermo J; Undurraga, Maria Soledad; Uriarte, Maria del Rosario; Jacomo, Rafael H; Gutiérrez-Aguirre, Homero; Melo, Raul A M; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Fagundes, Evandro M; Chauffaille, Maria de Lourdes; Chiattone, Carlos S; Martinez, Lem; Meillón, Luis A; Gómez-Almaguer, David; Kwaan, Hau C; Garcés-Eisele, Javier; Gallagher, Robert; Niemeyer, Charlotte M; Schrier, Stanley L; Tallman, Martin; Grimwade, David; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C; Lo-Coco, Francesco; Löwenberg, Bob; Sanz, Miguel A

    2013-03-14

    Thanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries. PMID:23319575

  3. High ΔNp73/TAp73 ratio is associated with poor prognosis in acute promyelocytic leukemia

    PubMed Central

    Lucena-Araujo, Antonio R.; Kim, Haesook T.; Thomé, Carolina; Jacomo, Rafael H.; Melo, Raul A.; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Glória, Ana Beatriz F.; Chauffaille, Maria de Lourdes; Athayde, Melina; Chiattone, Carlos S.; Mito, Ingrid; Bendlin, Rodrigo; Souza, Carmino; Bortolheiro, Cristina; Coelho-Silva, Juan L.; Schrier, Stanley L.; Tallman, Martin S.; Grimwade, David; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C.; Lo-Coco, Francesco; Löwenberg, Bob; Sanz, Miguel A.

    2015-01-01

    The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells. PMID:26429976

  4. ZBTB16-RARα variant of acute promyelocytic leukemia with tuberculosis: a case report and review of literature

    PubMed Central

    Palta, Anshu; Cruz, Sanjay D.

    2012-01-01

    A 23-year-old male presented with pulmonary tuberculosis and swelling of both lower limbs. He was put on antitubercular treatment. Hemogram showed mild anemia and Pseudo Pelger-huet cells. The bone marrow (BM) examination showed 52% promyelocytes with regular round to oval nuclei, few granules and were positive for CD13 and CD33, and negative for HLA-DR. Cytogenetic analysis of the BM aspirate revealed an apparently balanced t(11;17)(q23;q21). Final diagnosis rendered was acute promyelocytic leukemia (APL) with t(11;17)(q23;q21); ZBTB16/RARA. APL is a distinct subtype of acute myeloid leukemia. The variant APL with t(11;17)(q23;q21) cases that are associated with the ZBTB16/RARA fusion gene have been reported as being resistant to all-trans-retinoic acid (ATRA). Therefore, differential diagnosis of variant APL with t(11;17)(q23;q12) from classical APL with t(15;17)(q22;q12); PML-RARA is very important. Here we have discussed the importance of distinct morphology of variant APL and also significance of rare presentation with tuberculosis. PMID:23071480

  5. Gemtuzumab Ozogamicin in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-09-23

    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 Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

  6. Induction of high-affinity GM-CSF receptors during all-trans retinoic acid treatment of acute promyelocytic leukemia.

    PubMed

    de Gentile, A; Toubert, M E; Dubois, C; Krawice, I; Schlageter, M H; Balitrand, N; Castaigne, S; Degos, L; Rain, J D; Najean, Y

    1994-10-01

    Differentiation of normal myeloid cells is accompanied by the increase of high-affinity GM-CSF receptors necessary for progenitor proliferation/differentiation and mature neutrophil function. All-trans retinoic acid (ATRA) induces terminal differentiation of acute promyelocytic leukemia cells (AML3 subtype). We report in this study that AML3 cells, like other AML subtypes, harbor high-affinity GM-CSF R (n = 138.3 +/- 69.3 sites/cell, Kd = 76.9 +/- 68.8 pM). In all cases, incubation with ATRA induces either an increase in the number of affinity of GM-CSF R (n = 212.7 +/- 116.2 sites/cell, Kd = 43.2 +/- 22.5 pM). The data presented show that modulation of GM-CSF receptors cells is correlated to the degree of ATRA-induced granulocytic differentiation but not to increased cell growth.

  7. Comparative proteomic analysis of all-trans-retinoic acid treatment reveals systematic posttranscriptional control mechanisms in acute promyelocytic leukemia.

    PubMed

    Harris, Michael N; Ozpolat, Bulent; Abdi, Fadi; Gu, Sheng; Legler, Allison; Mawuenyega, Kwasi G; Tirado-Gomez, Maribel; Lopez-Berestein, Gabriel; Chen, Xian

    2004-09-01

    All-trans-retinoic acid (ATRA) induces growth inhibition, differentiation, and apoptosis in cancer cells, including acute promyelocytic leukemia (APL). In APL, expression of promyelocytic leukemia protein retinoic acid receptor-alpha (PML-RARalpha) fusion protein, owing to the t(15; 17) reciprocal translocation, leads to a block in the promyelocytic stage of differentiation. Here, we studied molecular mechanisms involved in ATRA-induced growth inhibition and myeloid cell differentiation in APL. By employing comprehensive high-throughput proteomic methods of 2-dimensional (2-D) gel electrophoresis and amino acid-coded mass tagging coupled with electrospray ionization (ESI) mass spectrometry, we systematically identified a total of 59 differentially expressed proteins that were consistently modulated in response to ATRA treatment. The data revealed significant down-regulation of eukaryotic initiation and elongation factors, initiation factor 2 (IF2), eukaryotic initiation factor 4AI (eIF4AI), eIF4G, eIF5, eIF6, eukaryotic elongation factor 1A-1 (eEF1A-1), EF-1-delta, eEF1gamma, 14-3-3epsilon, and 14-3-3zeta/delta (P <.05). The translational inhibitor DAP5/p97/NAT1 (death-associated protein 5) and PML isoform-1 were found to be up-regulated (P <.05). Additionally, the down-regulation of heterogeneous nuclear ribonucleoproteins (hnRNPs) C1/C2, UP2, K, and F; small nuclear RNPs (snRNPs) D3 and E; nucleoprotein tumor potentiating region (TPR); and protein phosphatase 2A (PP2A) were found (P <.05); these were found to function in pre-mRNA processing, splicing, and export events. Importantly, these proteomic findings were validated by Western blot analysis. Our data in comparison with previous cDNA microarray studies and our reverse transcription-polymerase chain reaction (RT-PCR) experiments demonstrate that broad networks of posttranscriptional suppressive pathways are activated during ATRA-induced growth inhibition processes in APL. PMID:15142884

  8. Romidepsin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-12-03

    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 Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

  9. Diarrhoea in adults (acute)

    PubMed Central

    2008-01-01

    Introduction An estimated 4000 million cases of diarrhoea occurred worldwide in 1996, resulting in 2.5 million deaths. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute diarrhoea in adults living in resource-rich countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults from resource-rich countries traveling to resource-poor countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults living in resource-poor countries? What are the effects of treatments for acute severe diarrhoea in adults living in resource-poor countries? We searched: Medline, Embase, The Cochrane Library and other important databases up to January 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, antimotility agents, antisecretory agents, bismuth subsalicylate, diet, intravenous rehydration, nasogastric tube rehydration, and oral rehydration solutions (amino acid oral rehydration solution, bicarbonate oral rehydration solution, reduced osmolarity oral rehydration solution, rice-based oral rehydration solution, standard oral rehydration solution). PMID:19450323

  10. Diarrhoea in adults (acute)

    PubMed Central

    2011-01-01

    Introduction An estimated 4.6 billion cases of diarrhoea occurred worldwide in 2004, resulting in 2.2 million deaths. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute diarrhoea in adults living in resource-rich countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults from resource-rich countries travelling to resource-poor countries? What are the effects of treatments for acute mild-to-moderate diarrhoea in adults living in resource-poor countries? What are the effects of treatments for acute severe diarrhoea in adults living in resource-poor countries? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 72 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, antimotility agents, antisecretory agents, bismuth subsalicylate, diet, intravenous rehydration, nasogastric tube rehydration, oral rehydration solutions (amino acid oral rehydration solution, bicarbonate oral rehydration solution, reduced osmolarity oral rehydration solution, rice-based oral rehydration solution, standard oral rehydration solution), vitamin A supplementation, and zinc supplementation. PMID:21718555

  11. Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia, and its treatment using recombinant human soluble thrombomodulin.

    PubMed

    Ikezoe, Takayuki

    2014-07-01

    Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia characterized by the proliferation of blasts with distinct morphology, a specific balanced reciprocal translocation t(15;17), and life-threatening hemorrhage caused mainly by enhanced fibrinolytic-type disseminated intravascular coagulation (DIC). The introduction of all-trans retinoic acid (ATRA) into anthracycline-based induction chemotherapy regimens has dramatically improved overall survival of individuals with APL, although hemorrhage-related death during the early phase of therapy remains a serious problem. Moreover, population-based studies have shown that the incidence of early death during induction chemotherapy is nearly 30 %, and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required. Recombinant human soluble thrombomodulin (rTM) comprises the active extracellular domain of TM, and has been used for treatment of DIC since 2008 in Japan. Use of rTM in combination with remission induction chemotherapy, including ATRA, produces potent resolution of DIC without exacerbation of bleeding tendency in individuals with APL. This review article discusses the pathogenesis and features of DIC caused by APL, as well as the possible anticoagulant and anti-leukemic action of rTM in APL patients.

  12. [PML-RARα and p21 are key factors for maintaining acute promyelocytic leukemia stem cells survival].

    PubMed

    Ding, Fei; Li, Jun-Min

    2011-10-01

    Tumor stem/progenitor cells are the cells with the characteristics of self-renewal, differentiating to all the other cell populations within tumor, which are also regarded as the source of tumor relapse, drug-resistance and metastasis. As a subtype of acute myeloid leukemia, acute promyelocytic leukemia (APL) represents the target of therapy due to the good response of the oncogenic protein PML-RARα to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). This review summarizes the latest research results of APL as follows: (1) there probably are two APL stem/progenitor cell populations within APL, and self-renewal and survival of APL stem/progenitor cells highly depend on PML-RARα expression, cell cycle inhibitor p21, self-renewal associated molecules and chemokines; and (2) ATRA and ATO eradicate APL stem/progenitor cells mainly by PML-RARα degradation, FOXO3A activation and the inhibition of self-renewal-associated signaling pathway of sonic hedgehog. These findings are helpful to improve other tumor therapy.

  13. Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-05-05

    Acute Myeloid Leukemia; 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); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

  14. From molecular interaction to acute promyelocytic leukemia: Calculating leukemogenesis and remission from endogenous molecular-cellular network

    PubMed Central

    Yuan, Ruoshi; Zhu, Xiaomei; Radich, Jerald P.; Ao, Ping

    2016-01-01

    Acute promyelocytic leukemia (APL) remains the best example of a malignancy that can be cured clinically by differentiation therapy. We demonstrate that APL may emerge from a dynamical endogenous molecular-cellular network obtained from normal, non-cancerous molecular interactions such as signal transduction and translational regulation under physiological conditions. This unifying framework, which reproduces APL, normal progenitor, and differentiated granulocytic phenotypes as different robust states from the network dynamics, has the advantage to study transition between these states, i.e. critical drivers for leukemogenesis and targets for differentiation. The simulation results quantitatively reproduce microarray profiles of NB4 and HL60 cell lines in response to treatment and normal neutrophil differentiation, and lead to new findings such as biomarkers for APL and additional molecular targets for arsenic trioxide therapy. The modeling shows APL and normal states mutually suppress each other, both in “wiring” and in dynamical cooperation. Leukemogenesis and recovery under treatment may be a consequence of spontaneous or induced transitions between robust states, through “passes” or “dragging” by drug effects. Our approach rationalizes leukemic complexity and constructs a platform towards extending differentiation therapy by performing “dry” molecular biology experiments. PMID:27098097

  15. JNK and NFκB dependence of apoptosis induced by vinblastine in human acute promyelocytic leukaemia cells.

    PubMed

    Calviño, Eva; Tejedor, M Cristina; Sancho, Pilar; Herráez, Angel; Diez, José C

    2015-06-01

    The relationship between the mitogen-activated protein kinase response, nuclear factor-κB (NFκB) expression and the apoptosis in human acute promyelocytic leukaemia NB4 cells treated with vinblastine was investigated in this work. Cell viability, subdiploid DNA and cell cycle were analysed by propidium iodide permeability and flow cytometry analyses. Apoptosis was determined by annexin V-Fluorescein isothiocyanate assays. Western-blot analysis was used for determination of expression levels of apoptotic factors (p53, Bax and Bcl2), intracellular kinases [serine/threonine-specific protein kinase, extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK)], NFκB factor and caspases. Electrophoretic mobility shift assay was usefully applied to study DNA-NFκB interaction. In NB4 cells, vinblastine produces alteration of p53 and DNA fragmentation. Vinblastine treatment had an antiproliferative effect via the induction of apoptosis producing Bax/Bcl-2 imbalance. Vinblastine treatment suppressed NFκB expression and depressed NFκB-DNA binding activity while maintaining JNK activation that subsequently resulted in apoptotic response through caspase-dependent pathway. Our study provides a possible anti-cancer mechanism of vinblastine action on NB4 cells by deregulation of the intracellular signalling cascade affecting to JNK activation and NFκB expression. Moreover, JNK activation and NFκB depression can be very significant factors in apoptosis induction by vinblastine. PMID:25914345

  16. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer

    PubMed Central

    Wei, Shuo; Kozono, Shingo; Kats, Lev; Nechama, Morris; Li, Wenzong; Guarnerio, Jlenia; Luo, Manli; You, Mi-Hyeon; Yao, Yandan; Kondo, Asami; Hu, Hai; Bozkurt, Gunes; Moerke, Nathan J.; Cao, Shugeng; Reschke, Markus; Chen, Chun-Hau; Rego, Eduardo M.; LoCoco, Francesco; Cantley, Lewis; Lee, Tae Ho; Wu, Hao; Zhang, Yan; Pandolfi, Pier Paolo; Zhou, Xiao Zhen; Lu, Kun Ping

    2015-01-01

    A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency. Using mechanism-based screening, here we find that all-trans retinoic acid (ATRA)--a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but its drug target remains elusive--inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RARα and treats APL in cell and animal models and human patients. ATRA-induced Pin1 ablation also inhibits triple negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors. PMID:25849135

  17. The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.

    PubMed

    Ibáñez, Mariam; Carbonell-Caballero, José; García-Alonso, Luz; Such, Esperanza; Jiménez-Almazán, Jorge; Vidal, Enrique; Barragán, Eva; López-Pavía, María; LLop, Marta; Martín, Iván; Gómez-Seguí, Inés; Montesinos, Pau; Sanz, Miguel A; Dopazo, Joaquín; Cervera, José

    2016-01-01

    Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations. PMID:26886259

  18. The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations

    PubMed Central

    García-Alonso, Luz; Such, Esperanza; Jiménez-Almazán, Jorge; Vidal, Enrique; Barragán, Eva; López-Pavía, María; LLop, Marta; Martín, Iván; Gómez-Seguí, Inés; Montesinos, Pau; Sanz, Miguel A.; Dopazo, Joaquín; Cervera, José

    2016-01-01

    Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations. PMID:26886259

  19. Acute promyelocytic leukemia with cryptic t(15;17) on isochromosome 17: a case report and review of literature

    PubMed Central

    Tang, Yuting; Wang, Ying; Hu, Liang; Meng, Fankai; Xu, Danmei; Wan, Kai; Huang, Lifang; Li, Chunrui; Zhou, Jianfeng

    2015-01-01

    Acute Promyelocytic Leukemia (APL) is one of the most curable leukemia which shows great sensitivity to all-trans retinoic acid (ATRA) although a small number of the patients present poor prognosis and short survival. Isochromosome 17 in APL which usually bears an additional copy of RARA/PML fusion gene is considered to be a negative factor on its prognosis. Cryptic t(15;17) on i(17q) leads to an extra copy of PML/RARA rather than RARA/PML which may confer a worse prognosis. We describe here a rare APL case with complex chromosomal abnormality including isochromosome 17 bearing cryptic t(15;17) showing poor outcome. The patient lacks a classic t(15;17) and fluorescence in situ hybridization (FISH) presents 2 PML/RARA fusion signals on both long arms of the isochromosome. The patient also acquired a secondary mutation at relapse when the initial karyotype was already a complex karyotype involving chromosome 13, 17 and 22 at the same time. The poor response of this patient to traditional chemotherapy like ATRA and novel therapy like arsenic trioxide (ATO) suggests that early auto-hematological stem cell transplantation may be the choice of APL with isochromosome 17 especially with cryptic t(15;17) on i(17q). We are the first to show a clear history and evidence of FISH of these kind of cases. A small summary of cases with cryptic t(15;17) on isochromosome 17 is also made. PMID:26823883

  20. All-transretinoic acid (ATRA) treatment-related pancarditis and severe pulmonary edema in a child with acute promyelocytic leukemia.

    PubMed

    Işık, Pamir; Çetin, Ilker; Tavil, Betul; Azik, Fatih; Kara, Abdurrahman; Yarali, Nese; Tunc, Bahattin

    2010-11-01

    Use of all-transretinoic acid (ATRA) with other chemotherapeutic agents in the treatment of acute promyelocytic leukemia (APL) has been shown to cause the differentiation of abnormally granulated specific blast cells into mature granulocytes by acting on the t(15; 17) fusion gene product. The complete remission rate is increased and survival time is prolonged in APL patients who receive chemotherapy plus ATRA, whereas ATRA syndrome and other ATRA-related adverse effects including pseudo tumor cerebri, headache, severe bone pain, mucosal and skin dryness, hypercholesterolemia, and cheilitis may be observed especially during induction phase of the treatment. In this paper, we report a 9-year-old girl with APL who developed pancarditis while receiving the APL-93 treatment protocol. In our patient, endocarditis and myocarditis were initially determined after ATRA treatment during the induction part of the protocol. All findings disappeared after ATRA was discontinued. When ATRA was readministered in the maintenance part of the treatment protocol, she developed pancarditis and severe pulmonary edema. As her symptoms decreased dramatically with the discontinuation of ATRA and the initiation of steroid treatment, the clinical picture strongly suggested the ATRA treatment as the causative factor. To the best of our knowledge, this clinical picture of pancarditis secondary to ATRA treatment has not been reported earlier in the English literature. PMID:20881874

  1. Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet.

    PubMed

    Lengfelder, E; Lo-Coco, F; Ades, L; Montesinos, P; Grimwade, D; Kishore, B; Ramadan, S M; Pagoni, M; Breccia, M; Huerta, A J G; Nloga, A M; González-Sanmiguel, J D; Schmidt, A; Lambert, J-F; Lehmann, S; Di Bona, E; Cassinat, B; Hofmann, W-K; Görlich, D; Sauerland, M-C; Fenaux, P; Sanz, M

    2015-05-01

    In 2008, a European registry of relapsed acute promyelocytic leukemia was established by the European LeukemiaNet. Outcome data were available for 155 patients treated with arsenic trioxide in first relapse. In hematological relapse (n=104), 91% of the patients entered complete hematological remission (CR), 7% had induction death and 2% resistance, 27% developed differentiation syndrome and 39% leukocytosis, whereas no death or side effects occurred in patients treated in molecular relapse (n=40). The rate of molecular (m)CR was 74% in hematological and 62% in molecular relapse (P=0.3). All patients with extramedullary relapse (n=11) entered clinical and mCR. After 3.2 years median follow-up, the 3-year overall survival (OS) and cumulative incidence of second relapse were 68% and 41% in hematological relapse, 66% and 48% in molecular relapse and 90 and 11% in extramedullary relapse, respectively. After allogeneic or autologous transplantation in second CR (n=93), the 3-year OS was 80% compared with 59% without transplantation (n=55) (P=0.03). Multivariable analysis demonstrated the favorable prognostic impact of first remission duration ⩾1.5 years, achievement of mCR and allogeneic or autologous transplantation on OS of patients alive after induction (P=0.03, P=0.01, P=0.01) and on leukemia-free survival (P=0.006, P<0.0001, P=0.003), respectively. PMID:25627637

  2. Acute promyelocytic leukemia: a 5-year experience with new antileukemic agents and a new approach to preventing fatal hemorrhage.

    PubMed

    Feldman, E J; Arlin, Z A; Ahmed, T; Mittelman, A; Ascensao, J L; Puccio, C A; Coombe, N; Baskind, P

    1989-01-01

    Forty-six induction courses were administered to 32 patients with acute promyelocytic leukemia. There were 28 males and 18 females with a median age of 39.5 (range 19-68). Twelve patients were previously untreated, 32 were in relapse, and 2 were refractory to primary induction chemotherapy. Heparin 7.5-10 units/kg/h by continuous infusion, 4-6 units of platelets and 1-2 units of fresh-frozen plasma (FFP) every 12 h were given to all patients. Previously untreated patients received either daunorubicin, idarubicin or mitoxantrone in combination with cytarabine (Ara-C). For relapsed and refractory patients, regimens included amsacrine with high-dose cytarabine (Amsa/HiDac), homoharringtonine (HHT) alone, or with Ara-C, mitoxantrone and bisantrene. Hemorrhagic complications occurred in only 1 out of 46 courses (2%). Complete remission rates (CR) were as follows: previously untreated 83% (10/12), relapsed 66% (21/32), primary refractory 50% (1/2). Amsa/HiDac resulted in a 71% (10/14) CR and HHT-based regimens achieved a 46% (6/13) CR. These regimens are effective and the value of their incorporation into primary therapy should be studied. The use of heparin with platelet and FFP transfusions every 12 h reduces the risk of hemorrhage during induction therapy.

  3. Retinoid-dependent growth inhibition, differentiation and apoptosis in acute promyelocytic leukemia cells. Expression and activation of caspases.

    PubMed

    Gianni, M; Ponzanelli, I; Mologni, L; Reichert, U; Rambaldi, A; Terao, M; Garattini, E

    2000-05-01

    In the NB4 model of acute promyelocytic leukemia (APL), ATRA, 9-cis retinoic acid (9-cis RA), the pan-RAR and RARalpha-selective agonists, TTNPB and AM580, induce growth inhibition, granulocytic differentiation and apoptosis. By contrast, two RXR agonists, a RARbeta agonist and an anti-AP1 retinoid have very limited activity, ATRA- and AM580-dependent effects are completely inhibited by RAR antagonistic blockade, while 9-cis RA-induced cell-growth-inhibition and apoptosis are equally inhibited by RAR and RXR antagonists. ATRA, 9-cis RA and AM580 cause upregulation of the mRNAs coding for pro-caspase-1, -7, -8, and -9, which, however, results in increased synthesis of only pro-caspase-1 and -7 proteins. These phenomena are associated with activation of pro-caspase-6, -7 and -8, cytochrome c release from the mitochondria, inversion of Bcl-2/Bax ratio and degradation of PML-RARalpha. Caspase activation is fundamental for retinoid-induced apoptosis, which is suppressed by the caspase-inhibitor z-VAD.

  4. Altered nuclear co-factor switching in retinoic resistant variants of the PML-RARα oncoprotein of acute promyelocytic leukemia†

    PubMed Central

    Farris, Mindy; Lague, Astrid; Manuelyan, Zara; Statnekov, Jacob; Francklyn, Christopher

    2011-01-01

    Acute Promyelocytic Leukemia (APL) results from a reciprocal translocation that fuses the gene for the PML tumor suppressor to that encoding the retinoic acid receptor alpha (RARα). The resulting PML-RARα oncogene product interferes with multiple regulatory pathways associated with myeloid differentiation, including normal PML and RARα functions. The standard treatment for APL includes anthracycline-based chemotherapeutic agents plus the RARα agonist all-trans retinoic acid (ATRA). Relapse, which is often accompanied by ATRA resistance, occurs in an appreciable frequency of treated patients. One potential mechanism suggested by model experiments featuring the selection of ATRA resistant APL cell lines involves ATRA resistant versions of the PML-RARα oncogene, where the relevant mutations localize to the RARα ligand-binding domain (LBD). Such mutations may act by compromising agonist binding, but other mechanisms are possible. Here, we studied the molecular consequence of ATRA resistance by use of circular dichroism, protease resistance, and fluorescence anisotropy assays employing peptides derived from the NCOR nuclear co-repressor and the ACTR nuclear co-activator. The consequences of the mutations on global structure and co-factor interaction functions were assessed quantitatively, providing insights into the basis of agonist resistance. Attenuated co-factor switching and increased protease resistance represent features of the LBDs of ATRA-resistant PML-RARα, and these properties may be recapitulated in the full-length oncoproteins. PMID:22228505

  5. Recurrent Arterial Thrombosis as a Presenting Feature of a Variant M3-Acute Promyelocytic Leukemia

    PubMed Central

    Chotai, Pranit N.; Kasangana, Kalenda; Chandra, Abhinav B.; Rao, Atul S.

    2016-01-01

    Acute limb ischemia (ALI) is a common vascular emergency. Hematologic malignancies are commonly associated with derangement of normal hemostasis and thrombo-hemorrhagic symptoms during the course of the disease are common. However, ALI as an initial presenting feature of acute leukemia is rare. Due to the rarity of this presentation, there is a scarcity of prospective randomized data to optimally guide the management of these patients. Current knowledge is mainly based on isolated cases. We report our experience managing a patient who presented with ALI and was found to have occult leukemia. A review of all cases with ALI as a presenting feature of acute leukemia is also presented. PMID:27386455

  6. Recurrent Arterial Thrombosis as a Presenting Feature of a Variant M3-Acute Promyelocytic Leukemia.

    PubMed

    Chotai, Pranit N; Kasangana, Kalenda; Chandra, Abhinav B; Rao, Atul S

    2016-06-01

    Acute limb ischemia (ALI) is a common vascular emergency. Hematologic malignancies are commonly associated with derangement of normal hemostasis and thrombo-hemorrhagic symptoms during the course of the disease are common. However, ALI as an initial presenting feature of acute leukemia is rare. Due to the rarity of this presentation, there is a scarcity of prospective randomized data to optimally guide the management of these patients. Current knowledge is mainly based on isolated cases. We report our experience managing a patient who presented with ALI and was found to have occult leukemia. A review of all cases with ALI as a presenting feature of acute leukemia is also presented. PMID:27386455

  7. Recurrent Arterial Thrombosis as a Presenting Feature of a Variant M3-Acute Promyelocytic Leukemia.

    PubMed

    Chotai, Pranit N; Kasangana, Kalenda; Chandra, Abhinav B; Rao, Atul S

    2016-06-01

    Acute limb ischemia (ALI) is a common vascular emergency. Hematologic malignancies are commonly associated with derangement of normal hemostasis and thrombo-hemorrhagic symptoms during the course of the disease are common. However, ALI as an initial presenting feature of acute leukemia is rare. Due to the rarity of this presentation, there is a scarcity of prospective randomized data to optimally guide the management of these patients. Current knowledge is mainly based on isolated cases. We report our experience managing a patient who presented with ALI and was found to have occult leukemia. A review of all cases with ALI as a presenting feature of acute leukemia is also presented.

  8. Microgranular variant of acute promyelocytic leukemia with der(17) ins(17;15): A case report and review of the literature

    PubMed Central

    GUAN, HONGZAI; LIU, JING; GUO, XIAOFANG; WU, CHUNMEI; YU, HUAWEI

    2015-01-01

    Acute promyelocytic leukemia (APL) with variant translocations is rare. The patient of the present case report, a 2-year-old male with a microgranular variant of APL carrying der(17) ins(17;15) translocation, exhibited fever and epistaxis. The complete blood count showed marked leukocytosis with 72% atypical promyelocytes, anemia and thrombocytopenia. Conventional cytogenetic analysis of the bone marrow cells revealed a karyotype of 47, XY, add(3)(q29), −7, ins(17;15)(q12;q14q22),+21,+mar. The promyelocytic leukemia/retinoic acid receptor α (PML/RARα) rearrangement and insertion were confirmed by fluorescence in situ hybridization. The PML/RARα transcripts were not detected by the reverse transcription polymerase chain reaction, and the patient was diagnosed with microgranular variant M3 APL. The patient achieved remission after a 30-day treatment and was still in remission during a recent follow-up. The present findings suggest that the ins(17;15) variant in APL may not be associated with an unfavorable prognosis. In summary, we reported an extremely rare case of APL with der(17) ins(17;15) abnormality in a pediatric patient and reviewed the literature. PMID:26622430

  9. All-Trans Retinoic Acid plus Arsenic Trioxide versus All-Trans Retinoic Acid plus Chemotherapy for Newly Diagnosed Acute Promyelocytic Leukemia: A Meta-Analysis

    PubMed Central

    Ma, Yafang; Liu, Lu; Jin, Jie; Lou, Yinjun

    2016-01-01

    Background Recently, the all-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) protocol has become a promising first-line therapeutic approach in patients with newly diagnosed acute promyelocytic leukemia (APL), but its benefits compared with standard ATRA plus chemotherapy regimen needs to be proven. Herein, we conducted a meta-analysis comparing the efficacy of ATRA plus ATO with ATRA plus chemotherapy for adult patients with newly diagnosed APL. Methods We systematically searched biomedical electronic databases and conference proceedings through February 2016. Two reviewers independently assessed all studies for relevance and validity. Results Overall, three studies were eligible for inclusion in this meta-analysis, which included a total of 585 patients, with 317 in ATRA plus ATO group and 268 in ATRA plus chemotherapy group. Compared with patients who received ATRA and chemotherapy, patients who received ATRA plus ATO had a significantly better event-free survival (hazard ratio [HR] = 0.38, 95% confidence interval [CI]: 0.22–0.67, p = 0.009), overall survival (HR = 0.44, 95% CI: 0.24–0.82, p = 0.009), complete remission rate (relative risk [RR] = 1.05; 95% CI: 1.01–1.10; p = 0.03). There were no significant differences in early mortality (RR = 0.48; 95% CI: 0.22–1.05; p = 0.07). Conclusion Thus, this analysis indicated that ATRA plus ATO protocol may be preferred to standard ATRA plus chemotherapy protocol, particularly in low-to-intermediate risk APL patients. Further larger trials were needed to provide more evidence in high-risk APL patients. PMID:27391027

  10. BMS-214662 in Treating Patients With Acute Leukemia, Myelodysplastic Syndrome, or Chronic Myeloid Leukemia

    ClinicalTrials.gov

    2013-01-22

    Adult Acute Promyelocytic Leukemia (M3); Blastic Phase Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; 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

  11. Asthma in adults (acute)

    PubMed Central

    2011-01-01

    Introduction About 10% of adults have suffered an attack of asthma, and up to 5% of these have severe disease that responds poorly to treatment. Patients with severe disease have an increased risk of death, but patients with mild to moderate disease are also at risk of exacerbations. Most guidelines about the management of asthma follow stepwise protocols. This review does not endorse or follow any particular protocol, but presents the evidence about specific interventions. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for acute asthma? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 100 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: beta2 agonists (plus ipratropium bromide, pressured metered-dose inhalers, short-acting continuous nebulised, short-acting intermittent nebulised, short-acting iv, and inhaled formoterol); corticosteroids (inhaled); corticosteroids (single oral, combined inhaled, and short courses); education about acute asthma; generalist care; helium–oxygen mixture (heliox); magnesium sulphate (iv and adding isotonic nebulised magnesium to inhaled beta2 agonists); mechanical ventilation; oxygen supplementation (controlled 28% oxygen and controlled 100% oxygen); and specialist care. PMID:21463536

  12. Establishment of two-dimensional gel electrophoresis profiles of the human acute promyelocytic leukemia cell line NB4.

    PubMed

    He, Pengcheng; Liu, Yanfeng; Zhang, Mei; Wang, Xiaoning; Wang, Huaiyu; Xi, Jieying; Wei, Kaihua; Wang, Hongli; Zhao, Jing

    2012-09-01

    To explore optimum conditions for establishing a two‑dimensional gel electrophoresis (2-DE) map of the human acute promyelocytic leukemia (APL) cell line NB4 and to analyze its protein profiles, we extracted total proteins from NB4 cells using cell disruption, liquid nitrogen freeze-thawing and fracturing by ultrasound, and quantified the extracted protein samples using Bradford's method. 2-DE was applied to separate the proteins, which were silver-stained in the gel. Well‑separated protein spots were selected from the gel using the ImageMaster™ 2D Platinum analysis system. Moreover, the effects of various protein sample sizes (140, 160 and 180 µg) on the 2-DE maps of the NB4 cells were determined and compared. Matrix-assisted laser desorption/ionization time of flight-mass spectrometry (MALDI-TOF-MS), peptide mass fingerprinting (PMF) and database searching were used to identify the proteins. When the quantity of loading proteins was 160 µg, clear, well-resolved, reproducible 2-DE proteomic profiles of the NB4 cells were obtained. The average number of protein spots in 3 gels was 1160±51 with an average matching rate of 81%. A total of 10 proteins were identified by mass spectrometry and database queries, certain proteins were products of oncogenes and others were involved in cell cycle regulation and signal transduction. In summary, 2-DE profiles of the proteome of NB4 cells were established and certain proteins were identified by MALDI-TOF-MS and PMF which lay the foundation of further proteomic research of NB4 cells. These data should be useful for establishing a human APL proteome database. PMID:22736039

  13. Absolute quantification of the pretreatment PML-RARA transcript defines the relapse risk in acute promyelocytic leukemia.

    PubMed

    Albano, Francesco; Zagaria, Antonella; Anelli, Luisa; Coccaro, Nicoletta; Tota, Giuseppina; Brunetti, Claudia; Minervini, Crescenzio Francesco; Impera, Luciana; Minervini, Angela; Cellamare, Angelo; Orsini, Paola; Cumbo, Cosimo; Casieri, Paola; Specchia, Giorgina

    2015-05-30

    In this study we performed absolute quantification of the PML-RARA transcript by droplet digital polymerase chain reaction (ddPCR) in 76 newly diagnosed acute promyelocytic leukemia (APL) cases to verify the prognostic impact of the PML-RARA initial molecular burden. ddPCR analysis revealed that the amount of PML-RARA transcript at diagnosis in the group of patients who relapsed was higher than in that with continuous complete remission (CCR) (272 vs 89.2 PML-RARA copies/ng, p = 0.0004, respectively). Receiver operating characteristic analysis detected the optimal PML-RARA concentration threshold as 209.6 PML-RARA/ng (AUC 0.78; p < 0.0001) for discriminating between outcomes (CCR versus relapse). Among the 67 APL cases who achieved complete remission after the induction treatment, those with >209.6 PML-RARA/ng had a worse relapse-free survival (p = 0.0006). At 5-year follow-up, patients with >209.6 PML-RARA/ng had a cumulative incidence of relapse of 50.3% whereas 7.5% of the patients with suffered a relapse (p < 0.0001). Multivariate analysis identified the amount of PML-RARA before induction treatment as the sole independent prognostic factor for APL relapse.Our results show that the pretreatment PML-RARA molecular burden could therefore be used to improve risk stratification in order to develop more individualized treatment regimens for high-risk APL cases. PMID:25944686

  14. Comparison of Newly Diagnosed and Relapsed Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide: Insight into Mechanisms of Resistance

    PubMed Central

    Chendamarai, Ezhilarasi; Ganesan, Saravanan; Alex, Ansu Abu; Kamath, Vandana; Nair, Sukesh C.; Nellickal, Arun Jose; Janet, Nancy Beryl; Srivastava, Vivi; Lakshmi, Kavitha M.; Viswabandya, Auro; Abraham, Aby; Aiyaz, Mohammed; Mullapudi, Nandita; Mugasimangalam, Raja; Padua, Rose Ann; Chomienne, Christine; Chandy, Mammen; Srivastava, Alok; George, Biju; Balasubramanian, Poonkuzhali; Mathews, Vikram

    2015-01-01

    There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens. PMID:25822503

  15. A drug from poison: how the therapeutic effect of arsenic trioxide on acute promyelocytic leukemia was discovered.

    PubMed

    Rao, Yi; Li, Runhong; Zhang, Daqing

    2013-06-01

    It is surprising that, while arsenic trioxide (ATO) is now considered as "the single most active agent in patients with acute promyelocytic leukemia (APL)", the most important discoverer remains obscure and his original papers have not been cited by a single English paper. The discovery was made during the Cultural Revolution when most Chinese scientists and doctors struggled to survive. Beginning with recipes from a countryside practitioner that were vague in applicable diseases, Zhang TingDong and colleagues proposed in the 1970s that a single chemical in the recipe is most effective and that its target is APL. More than 20 years of work by Zhang and colleagues eliminated the confusions about whether and how ATO can be used effectively. Other researchers, first in China and then in the West, followed his lead. Retrospective analysis of data from his own group proved that APL was indeed the most sensitive target. Removal of a trace amount of mercury chloride from the recipe by another group in his hospital proved that only ATO was required. Publication of Western replication in 1998 made the therapy widely accepted, though neither Western, nor Chinese authors of English papers on ATO cited Zhang's papers in the 1970s. This article focuses on the early papers of Zhang, but also suggests it worth further work to validate Chinese reports of ATO treatment of other cancers, and infers that some findings published in Chinese journals are of considerable value to patients and that doctors from other countries can benefit from the clinical experience of Chinese doctors with the largest population of patients.

  16. A drug from poison: how the therapeutic effect of arsenic trioxide on acute promyelocytic leukemia was discovered.

    PubMed

    Rao, Yi; Li, Runhong; Zhang, Daqing

    2013-06-01

    It is surprising that, while arsenic trioxide (ATO) is now considered as "the single most active agent in patients with acute promyelocytic leukemia (APL)", the most important discoverer remains obscure and his original papers have not been cited by a single English paper. The discovery was made during the Cultural Revolution when most Chinese scientists and doctors struggled to survive. Beginning with recipes from a countryside practitioner that were vague in applicable diseases, Zhang TingDong and colleagues proposed in the 1970s that a single chemical in the recipe is most effective and that its target is APL. More than 20 years of work by Zhang and colleagues eliminated the confusions about whether and how ATO can be used effectively. Other researchers, first in China and then in the West, followed his lead. Retrospective analysis of data from his own group proved that APL was indeed the most sensitive target. Removal of a trace amount of mercury chloride from the recipe by another group in his hospital proved that only ATO was required. Publication of Western replication in 1998 made the therapy widely accepted, though neither Western, nor Chinese authors of English papers on ATO cited Zhang's papers in the 1970s. This article focuses on the early papers of Zhang, but also suggests it worth further work to validate Chinese reports of ATO treatment of other cancers, and infers that some findings published in Chinese journals are of considerable value to patients and that doctors from other countries can benefit from the clinical experience of Chinese doctors with the largest population of patients. PMID:23645104

  17. Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis

    PubMed Central

    Montesinos, Pau; Díaz-Mediavilla, Joaquín; Debén, Guillermo; Prates, Virginia; Tormo, Mar; Rubio, Vicente; Pérez, Inmaculada; Fernández, Isolda; Viguria, Maricruz; Rayón, Chelo; González, José; de la Serna, Javier; Esteve, Jordi; Bergua, Juan M.; Rivas, Concha; González, Marcos; González, Jose D.; Negri, Silvia; Brunet, Salut; Lowenberg, Bob; Sanz, Miguel A.

    2009-01-01

    Background The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter. Design and Methods Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given. Results Central nervous system relapse was documented in 11 patients. The 5-year cumulative incidence of central nervous system relapse was 1.7% (LPA96 3.2% and LPA99 1.2%; p=0.09). The cumulative incidence was 0%, 0.8%, and 5.5% in low-, intermediate-, and high-risk patients, respectively. Relapse risk score (p=0.0001) and the occurrence of central nervous system hemorrhage during induction (5-year cumulative incidence 18.7%, p=0.006) were independent risk factors for central nervous system relapse. Conclusions This study shows a low incidence of central nervous system relapse in patients with acute promyelocytic leukemia following therapy with all-trans retinoic acid and anthracycline without specific central nervous system prophylaxis. Central nervous system relapse was significantly associated with high white blood cell counts and prior central nervous system hemorrhage, which emerged as independent prognostic factors. PMID:19608685

  18. Misfolded N-CoR is Linked to the Ectopic Reactivation of CD34/Flt3-Based Stem-Cell Phenotype in Promyelocytic and Monocytic Acute Myeloid Leukemia

    PubMed Central

    Nin, Dawn Sijin; Li, Feng; Visvanathan, Sridevi; Khan, Matiullah

    2015-01-01

    Nuclear receptor co-repressor (N-CoR) is the key component of generic co-repressor complex essential for the transcriptional control of genes involved in cellular hemostasis. We have recently reported that N-CoR actively represses Flt3, a key factor of hematopoietic stem cells (HSC) self-renewal and growth, and that de-repression of Flt3 by the misfolded N-CoR plays an important role in the pathogenesis of promyelocytic and monocytic acute myeloid leukemia (AML). The leukemic cells derived from the promyelocytic and monocytic AML are distinctly characterized by the ectopic reactivation of stem cell phenotypes in relatively committed myeloid compartment. However, the molecular mechanism underlying this phenomenon is not known. Here, we report that N-CoR function is essential for the commitment of primitive hematopoietic cells to the cells of myeloid lineage and that loss of N-CoR function due to misfolding is linked to the ectopic reactivation of generic stem cell phenotypes in promyelocytic and monocytic AML. Analysis of N-CoR and Flt3 transcripts in mouse hematopoietic cells revealed a positive correlation between N-CoR level and the commitment of myeloid cells and an inverse correlation between N-CoR and Flt3 levels in primitive as well as committed myeloid cells. Enforced N-CoR expression in mouse HSCs inhibited their growth and self-renewal potentials and promoted maturation toward cells of myeloid lineage, suggesting a role of N-CoR in the commitment of cells of myeloid lineage. In contrast to AML cells with natively folded N-CoR, primary and secondary promyelocytic and monocytic AML cells harboring the misfolded N-CoR were highly positive for Flt3 and myeloid antigen-based HSC marker CD34. Genetic and therapeutic restoration of N-CoR conformation significantly down-regulated the CD34 levels in monocytic AML cells, suggesting an important role of N-CoR in the suppression of CD34-based HSC phenotypes. These findings collectively suggest that N-CoR is crucial

  19. Treatment Options for Adult Acute Myeloid Leukemia

    MedlinePlus

    ... Treatment Childhood AML Treatment Research Adult Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Myeloid Leukemia Go to Health Professional Version Key Points Adult ...

  20. Stages of Adult Acute Myeloid Leukemia

    MedlinePlus

    ... Treatment Childhood AML Treatment Research Adult Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Myeloid Leukemia Go to Health Professional Version Key Points Adult ...

  1. Treatment Option Overview (Adult Acute Myeloid Leukemia)

    MedlinePlus

    ... Treatment Childhood AML Treatment Research Adult Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Myeloid Leukemia Go to Health Professional Version Key Points Adult ...

  2. Retinoid-induced differentiation of acute promyelocytic leukemia involves PML-RARalpha-mediated increase of type II transglutaminase.

    PubMed

    Benedetti, L; Grignani, F; Scicchitano, B M; Jetten, A M; Diverio, D; Lo Coco, F; Avvisati, G; Gambacorti-Passerini, C; Adamo, S; Levin, A A; Pelicci, P G; Nervi, C

    1996-03-01

    All-trans retinoic acid (t-RA) administration leads to complete remission in acute promyelocytic leukemia (APL) patients by inducing growth arrest and differentiation of the leukemic clone. In the present study, we show that t-RA treatment dramatically induced type II transglutaminase (type II TGase) expression in cells carrying the t(15;17) translocation and expressing the PML-RARalpha product such as the APL-derived NB4 cell line and fresh leukemic cells from APL patients. This induction correlated with t-RA-induced growth arrest, granulocytic differentiation, and upregulation of the leukocyte adherence receptor beta subunit (CD18) gene expression. The increase in type II TGase was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate was not required for the induction. t-RA did not significantly alter the rate of growth arrest and did not stimulate differentiation and type II TGase activity in NB4.306 cells, a t-RA-resistant subclone of the NB4 cell line, or in leukemic cells derived from two patients morphologically defined as APL but lacking the t(15;17). However, in NB4.306 cells, t-RA treatment was able to increase CD18 mRNA expression in a manner similar to NB4 cells. The molecular mechanisms involved in the induction of these genes were investigated. In NB4 cells, using novel receptor-selective ligands such as 9-cis-RA, TTNPB, AM580, and SR11217, we found that RAR- and RARalpha-selective retinoids were able to induce growth arrest, granulocytic differentiation, and type II TGase, whereas the RXR-selective retinoid SR11217 was inactive. Moreover, an RAR alpha-antagonist completely inhibited the expression of type II TGase and CD18 induced by these selective retinoids in NB4 cells. In NB4.306 cells, an RARalpha-dependent signaling pathway was found involved in the modulation of CD18 expression. In addition, expression of the PML-RARalpha gene in myeloid U937 precursor cells resulted in the ability of these cells to

  3. Bortezomib in Treating Patients With High-Risk Acute Myeloid Leukemia in Remission

    ClinicalTrials.gov

    2014-10-30

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia

  4. A Rare Occurrence of Simultaneous Venous and Arterial Thromboembolic Events – Lower Limb Deep Venous Thrombosis and Pulmonary Thromboembolism as Initial Presentation in Acute Promyelocytic Leukemia

    PubMed Central

    Kutiyal, Aditya S.; Dharmshaktu, Pramila; Kataria, Babita; Garg, Abhilasha

    2016-01-01

    The development of acute myeloid leukemia has been attributed to various factors, including hereditary, radiation, drugs, and certain occupational exposures. The association between malignancy and venous thromboembolism events is well established. Here, we present a case of a 70-year-old Indian man who had presented with arterial and venous thrombosis, and the patient was later diagnosed with acute promyelocytic leukemia (APL). In our case, the patient presented with right lower limb deep venous thrombosis and pulmonary thromboembolism four months prior to the diagnosis of APL. Although thromboembolic event subsequent to the diagnosis of malignancy, and especially during the chemotherapy has been widely reported, this prior presentation with simultaneous occurrence of both venous and arterial thromboembolism has rarely been reported. We take this opportunity to state the significance of a complete medical evaluation in cases of recurrent or unusual thrombotic events. PMID:26949347

  5. BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia.

    PubMed

    Yamamoto, Yukiya; Tsuzuki, Sachiko; Tsuzuki, Motohiro; Handa, Kousuke; Inaguma, Yoko; Emi, Nobuhiko

    2010-11-18

    The majority of acute promyelocytic leukemia (APL) cases are characterized by the presence of a promyelocytic leukemia-retinoic acid receptor alpha(RARA) fusion gene. In a small subset, RARA is fused to a different partner, usually involved in regulating cell growth and differentiation. Here, we identified a novel RARA fusion transcript, BCOR-RARA, in a t(X;17)(p11;q12) variant of APL with unique morphologic features, including rectangular and round cytoplasmic inclusion bodies. Although the patient was clinically responsive to all-trans retinoic acid, several relapses occurred with standard chemotherapy and all-trans retinoic acid. BCOR is a transcriptional corepressor through the proto-oncoprotein, BCL6, recruiting histone deacetylases and polycomb repressive complex 1 components. BCOR-RARA was found to possess common features with other RARA fusion proteins. These included: (1) the same break point in RARA cDNA; (2) self-association; (3) retinoid X receptor alpha is necessary for BCOR-RARA to associate with the RARA responsive element; (4) action in a dominant-negative manner on RARA transcriptional activation; and (5) aberrant subcellular relocalization. It should be noted that there was no intact BCOR found in the 45,-Y,t(X;17)(p11;q12) APL cells because they featured only a rearranged X chromosome. These results highlight essential features of pathogenesis in APL in more detail. BCOR appears to be involved not only in human congenital diseases, but also in a human cancer. PMID:20807888

  6. Matrine cooperates with all-trans retinoic acid on differentiation induction of all-trans retinoic acid-resistant acute promyelocytic leukemia cells (NB4-LR1): possible mechanisms.

    PubMed

    Wu, Dijiong; Shao, Keding; Sun, Jie; Zhu, Fuyun; Ye, Baodong; Liu, Tingting; Shen, Yiping; Huang, He; Zhou, Yuhong

    2014-03-01

    Retinoic acid resistance results in refractory disease, and recovery in acute promyelocytic leukemia remains a challenge in clinical practice, with no ideal chemotherapeutic drug currently available. Here we report on the effect of an active compound of Sophora flavescens called matrine (0.1 mmol/L) combined with all-trans retinoic acid (1 µmol/L) in alleviating retinoic acid resistance in acute promyelocytic leukemia-derived NB4-LR1 cells by differentiation induction, as can be seen by an induced morphology change, increased CD11b expression, and nitro blue tetrazolium reduction activity, and a decreased expression of the promyelocytic leukemia-retinoic acid receptor α fusion gene and protein product. We further explored the probable mechanism of how matrine promotes the recovery of differentiation ability in NB4-LR1 cells when exposed to all-trans retinoic acid. We observed that the combination of all-trans retinoic acid and matrine can increase the level of cyclic adenosine monophosphate and protein kinase A activity, reduce telomerase activity, and downregulate the protein expression of topoisomerase II beta in NB4-LR1 cells. The results of this study suggest the possible clinical utility of matrine in the treatment of retinoic acid-resistant acute promyelocytic leukemia.

  7. General Information about Adult Acute Lymphoblastic Leukemia

    MedlinePlus

    ... Acute Lymphoblastic Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Lymphoblastic Leukemia Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  8. General Information about Adult Acute Myeloid Leukemia

    MedlinePlus

    ... Acute Myeloid Leukemia Treatment (PDQ®)–Patient Version General Information About Adult Acute Myeloid Leukemia Go to Health ... the PDQ Adult Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  9. NPM-RAR, not the RAR-NPM reciprocal t(5;17)(q35;q21) acute promyelocytic leukemia fusion protein, inhibits myeloid differentiation.

    PubMed

    Pollock, Sheri L; Rush, Elizabeth A; Redner, Robert L

    2014-06-01

    The t(5;17) variant of acute promyelocytic leukemia (APL) fuses the nucleophosmin (NPM) gene at 5q35 with the retinoic acid receptor alpha (RARA) at 17q12-22. We have previously shown that leukemic cells express both NPM-RAR and RAR- NPM reciprocal translocation products. In this study we investigated the potential role of both proteins in modulating myeloid differentiation. Expression of NPM-RAR inhibited vitamin D3/transforming growth factor β (TGFβ)-mediated differentiation of U937 cells by more than 50%. In contrast, RAR-NPM expression did not alter vitamin D3/TGFβ-induced differentiation of U937 clones. These results indicate that NPM-RAR, not RAR-NPM, is the prime mediator of myeloid differentiation arrest in t(5;17) APL.

  10. Acute promyelocytic leukaemia (APL) in a patient with Crohn's disease and exposure to infliximab: a rare clinical presentation and review of the literature.

    PubMed

    Mohammad, Farhan; Vivekanandarajah, Abhirami; Haddad, Housam; Shutty, Christopher M; Hurford, Matthew T; Dai, Qun

    2014-01-01

    With the introduction of potent immunosuppressive and chemotherapeutic medications for various diseases, there is an increased incidence of therapy-related myeloid neoplasms. They are the result of mutational rearrangement and historically, have a grave prognosis compared with de novo myeloid neoplasms. We did a short review on various types of myeloid leukaemias reported after therapy with antitumour necrosis factor and also report, to the best of our knowledge, one among the very few cases of therapy-related acute promyelocytic leukaemia in a patient on infliximab therapy for refractory Crohn's disease. The patient responded well to the traditional treatment and is in complete remission for more than 5 years. PMID:24842356

  11. The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy.

    PubMed

    Falchi, Lorenzo; Verstovsek, Srdan; Ravandi-Kashani, Farhad; Kantarjian, Hagop M

    2016-04-15

    The therapeutic potential of arsenic derivatives has long been recognized and was recently rediscovered in modern literature. Early studies demonstrated impressive activity of this compound in patients with relapsed acute promyelocytic leukemia (APL). Over the last 2 decades, intravenous arsenic trioxide has been used successfully, both alone and in combination with other agents, for the treatment of APL and, with some success, of other myeloid neoplasms. Arsenic trioxide is currently part the standard of care for patients with APL. More recently, oral formulations of this compound have been developed and are entering clinical practice. In this review, the authors discuss the evolution of arsenic in the treatment of APL and other myeloid neoplasms. PMID:26716387

  12. Extramedullary relapse in lumbar spine of patient with acute promyelocytic leukemia after remission for 16 years: a case report and literature review.

    PubMed

    He, Zhengmei; Tao, Shandong; Deng, Yuan; Chen, Yue; Song, Lixiao; Ding, Banghe; Chen, Kankan; Yu, Liang; Wang, Chunling

    2015-01-01

    Acute promyelocytic leukemia (APL) is a common myeloid leukemia. At the newly diagnosed stage, it can be fatal because of the serious complication-disseminated intravascular coagulation. With the advent and early application of all-trans retinoic acid, most APL patients can achieve a long-term survival, and only a minority of patients will develop extramedullary relapse after remission. The most common site of extramedullary relapse is central nervous system, while other sites are relatively rare. Here, we report a particularly rare APL patient who experienced extramedullary relapse with lumbar spine as the isolated site after a rather long time of remission for 16 years. At the time of relapse, the main clinical manifestations of the patient are obvious low back pain, weakness in lower limbs and limitation of activity. After treatment of local radiotherapy combined with ATRA and arsenic trioxide, the patient achieved and maintained a second complete remission by now. PMID:26885224

  13. Extramedullary relapse in lumbar spine of patient with acute promyelocytic leukemia after remission for 16 years: a case report and literature review

    PubMed Central

    He, Zhengmei; Tao, Shandong; Deng, Yuan; Chen, Yue; Song, Lixiao; Ding, Banghe; Chen, Kankan; Yu, Liang; Wang, Chunling

    2015-01-01

    Acute promyelocytic leukemia (APL) is a common myeloid leukemia. At the newly diagnosed stage, it can be fatal because of the serious complication-disseminated intravascular coagulation. With the advent and early application of all-trans retinoic acid, most APL patients can achieve a long-term survival, and only a minority of patients will develop extramedullary relapse after remission. The most common site of extramedullary relapse is central nervous system, while other sites are relatively rare. Here, we report a particularly rare APL patient who experienced extramedullary relapse with lumbar spine as the isolated site after a rather long time of remission for 16 years. At the time of relapse, the main clinical manifestations of the patient are obvious low back pain, weakness in lower limbs and limitation of activity. After treatment of local radiotherapy combined with ATRA and arsenic trioxide, the patient achieved and maintained a second complete remission by now. PMID:26885224

  14. PS-341 in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myeloid Leukemia in Blast Phase, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2013-01-22

    Adult Acute Promyelocytic Leukemia (M3); Blastic Phase Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia

  15. The pleiotropic effects of fisetin and hesperetin on human acute promyelocytic leukemia cells are mediated through apoptosis, cell cycle arrest, and alterations in signaling networks.

    PubMed

    Adan, Aysun; Baran, Yusuf

    2015-11-01

    Fisetin and hesperetin, flavonoids from various plants, have several pharmaceutical activities including antioxidative, anti-inflammatory, and anticancer effects. However, studies elucidating the role and the mechanism(s) of action of fisetin and hesperetin in acute promyelocytic leukemia are absent. In this study, we investigated the mechanism of the antiproliferative and apoptotic actions exerted by fisetin and hesperetin on human HL60 acute promyelocytic leukemia cells. The viability of HL60 cells was evaluated using the MTT assay, apoptosis by annexin V/propidium iodide (PI) staining and cell cycle distribution using flow cytometry, and changes in caspase-3 enzyme activity and mitochondrial transmembrane potential. Moreover, we performed whole-genome microarray gene expression analysis to reveal genes affected by fisetin and hesperetin that can be important for developing of future targeted therapy. Based on data obtained from microarray analysis, we also described biological networks modulated after fisetin and hesperetin treatment by KEGG and IPA analysis. Fisetin and hesperetin treatment showed a concentration- and time-dependent inhibition of proliferation and induced G2/M arrest for both agents and G0/G1 arrest for hesperetin at only the highest concentrations. There was a disruption of mitochondrial membrane potential together with increased caspase-3 activity. Furthermore, fisetin- and hesperetin-triggered apoptosis was confirmed by annexin V/PI analysis. The microarray gene profiling analysis revealed some important biological pathways including mitogen-activated protein kinases (MAPK) and inhibitor of DNA binding (ID) signaling pathways altered by fisetin and hesperetin treatment as well as gave a list of genes modulated ≥2-fold involved in cell proliferation, cell division, and apoptosis. Altogether, data suggested that fisetin and hesperetin have anticancer properties and deserve further investigation.

  16. Clinical characteristics, outcome and early induction deaths in patients with acute promyelocytic leukaemia: a five-year experience at a tertiary care centre

    PubMed Central

    Karim, Farheen; Shaikh, Usman; Adil, Salman Naseem; Khurshid, Mohammad

    2014-01-01

    INTRODUCTION Acute promyelocytic leukaemia (APL) is a distinct clinical and biological subtype of acute myeloid leukaemia. APL is notorious for causing early death during induction therapy, resulting in induction failure. The aim of our study was to report the clinical characteristics, outcome and early induction deaths with regard to patients with APL seen at our hospital. METHODS This was a retrospective study carried out at Aga Khan University Hospital, Karachi, Pakistan. Patients aged > 15 years diagnosed with APL within the period September 2007–September 2012 were included in the study. RESULTS Within the study period, 26 patients were diagnosed with APL based on morphology and the detection of t(15;17)(q24.1;q21.1) and promyelocytic leukaemia-retinoic acid receptor alpha (PML-RARA). The male to female ratio was 1:1. The median age of the patients was 41 (range 16–72) years. In all, there were 13 (50.0%) high-risk patients, and early induction death rate was 61.5%. Causes of early induction deaths (n = 16) included haemorrhage in 7 (43.8%) patients, differentiation (ATRA) syndrome in 7 (43.8%) and infection in 2 (12.5%). The survival rate among patients who survived the early period was 70% at 42 months. The relapse rate was 30%. CONCLUSION Early induction death rate was very high in patients with APL. The most common cause of early induction death in our study was haemorrhage. Outcome among patients with APL was found to be better among those who survived the initial period. PMID:25189308

  17. [Acute epiglottitis in adults].

    PubMed

    Castillo, A

    1992-09-01

    The author presents the clinical history of 14 patients, from 21 to 48 years of age, 10 men and 4 women, with a final diagnosis of acute epiglottitis who were hospitalized at Gorgas Army Hospital or at the San Fernando Clinic. All the patients had pharyngitis and dysphagia, a few with nasal voice, stridor and difficulty breathing, as the chief complaint. All the patients were initially intubated orally for diagnostic purposes and immediately after nasotracheal intubation was done until the patient improved in 2 or 3 days (one patient remained intubated for 5 days). All patients were kept in the Intensive Care Unit and were treated with Ampicillin and Chloramphenicol IV and lately with a second generation cephalosporin (Cefamandole). The patients allergic to Penicillin were treated with Clindamycin and Chloramphenicol. Corticosteroids were not used in any of the patients. There were no sequelae and none of the patients expired. PMID:1439005

  18. A Multicenter Experience from Lebanon in Childhood and Adolescent Acute Myeloid Leukemia: High rate of Early Death in Childhood Acute Promyelocytic Leukemia

    PubMed Central

    Farah, Roula A.; Horkos, Jessy G.; Bustros, Youssef D.; Farhat, Hussein Z.; Abla, Oussama

    2015-01-01

    Background Acute myeloid leukemia (AML) is a disease with marked heterogeneity. Despite major improvement in outcome, it remains a life-threatening malignancy. Demographic and clinical data on pediatric AML is lacking among the Lebanese population. Purpose We aimed to identify clinical, molecular and outcome data in children with AML in Lebanon. Methods A retrospective chart review of children with AML diagnosed in three Lebanese hospitals during the past 8 years was conducted. Results From May 2002 through March 2010, we identified 24 children with AML in Saint George Hospital University Medical Center, University Medical Center Rizk Hospital, and Abou-Jaoude Hospital. Males and females were equally represented; median age at diagnosis was 9 years (range 1–24) and median WBC at diagnosis was 31 × 109/L (range: 2.1–376 × 109/L). Twenty five percent of patients (6 out of 24) had acute promyelocytic leukemia (APL). Karyotype was normal in 33% of patients; t(8;21), inv (16), t(8;9), t(7;11), t(9;11), complex chromosomal abnormality, monosomy 7 and trisomy 8 were the most common cytogenetic abnormalities encountered. Patients were treated on different European and North American protocols. Twelve patients (50%) achieved morphologic CR after cycle 1, 6 of them (50%) had bone marrow relapse within 11 months from diagnosis. Nine patients underwent allogeneic stem cell transplant, and 3 of them are alive at 5 years post-transplant. Early death rate was 16.6% of patients, mainly those with APL and a presenting WBC > 10 × 109/L. Fifty per cent of APL patients had an early death due to DIC despite starting ATRA therapy. Overall, median survival for AML patients who died from disease progression was 25.8 months (range: 1–60 months). Overall disease-free survival was 30.4%. Patients < 10 years of age had a 50% survival rate compared to 0% in patients > 10 years. Conclusions Our report highlights the needs in Lebanon for better supportive care of children with APL

  19. Clofarabine, Cytarabine, and Filgrastim Followed by Infusion of Non-HLA Matched Ex Vivo Expanded Cord Blood Progenitors in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-08-13

    Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); 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 Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  20. Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens.

    PubMed

    Montesinos, Pau; Rayón, Chelo; Vellenga, Edo; Brunet, Salut; González, José; González, Marcos; Holowiecka, Aleksandra; Esteve, Jordi; Bergua, Juan; González, José D; Rivas, Concha; Tormo, Mar; Rubio, Vicente; Bueno, Javier; Manso, Félix; Milone, Gustavo; de la Serna, Javier; Pérez, Inmaculada; Pérez-Encinas, Manuel; Krsnik, Isabel; Ribera, Josep M; Escoda, Lourdes; Lowenberg, Bob; Sanz, Miguel A

    2011-02-10

    The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthracycline-based regimens. Between 1996 and 2009, 651 APL patients with available data on CD56 expression were included in 3 subsequent trials (PETHEMA LPA96 and LPA99 and PETHEMA/HOVON LPA2005). Seventy-two patients (11%) were CD56(+) (expression of CD56 in ≥ 20% leukemic promyelocytes). CD56(+) APL was significantly associated with high white blood cell counts; low albumin levels; BCR3 isoform; and the coexpression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. For CD56(+) APL, the 5-year relapse rate was 22%, compared with a 10% relapse rate for CD56(-) APL (P = .006). In the multivariate analysis, CD56 expression retained the statistical significance together with the relapse-risk score. CD56(+) APL also showed a greater risk of extramedullary relapse (P < .001). In summary, CD56 expression is associated with the coexpression of immaturity-associated and T-cell antigens and is an independent adverse prognostic factor for relapse in patients with APL treated with all-trans-retinoic acid plus idarubicin-derived regimens. This marker may be considered for implementing risk-adapted therapeutic strategies in APL. The LPA2005 trial is registered at http://www.clinicaltrials.gov as NCT00408278.

  1. Acute Migraine Treatment in Adults.

    PubMed

    Becker, Werner J

    2015-06-01

    There are many options for acute migraine attack treatment, but none is ideal for all patients. This study aims to review current medical office-based acute migraine therapy in adults and provides readers with an organized approach to this important facet of migraine treatment. A general literature review includes a review of several recent published guidelines. Acetaminophen, 4 nonsteroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, acetylsalicylic acid [ASA], naproxen sodium, and diclofenac potassium), and 7 triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) have good evidence for efficacy and form the core of acute migraine treatment. NSAID-triptan combinations, dihydroergotamine, non-opioid combination analgesics (acetaminophen, ASA, and caffeine), and several anti-emetics (metoclopramide, domperidone, and prochlorperazine) are additional evidence-based options. Opioid containing combination analgesics may be helpful in specific patients, but should not be used routinely. Clinical features to be considered when choosing an acute migraine medication include usual headache intensity, usual rapidity of pain intensity increase, nausea, vomiting, degree of disability, patient response to previously used medications, history of headache recurrence with previous attacks, and the presence of contraindications to specific acute medications. Available acute medications can be organized into 4 treatment strategies, including a strategy for attacks of mild to moderate severity (strategy one: acetaminophen and/or NSAIDs), a triptan strategy for patients with severe attacks and for attacks not responding to strategy one, a refractory attack strategy, and a strategy for patients with contraindications to vasoconstricting drugs. Acute treatment of migraine attacks during pregnancy, lactation, and for patients with chronic migraine is also discussed. In chronic migraine, it is particularly important that medication

  2. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study.

    PubMed

    Avvisati, G; Lo Coco, F; Diverio, D; Falda, M; Ferrara, F; Lazzarino, M; Russo, D; Petti, M C; Mandelli, F

    1996-08-15

    From March 1993 to October 1993, 20 consecutive, newly diagnosed acute promyelocytic leukemia (APL) patients from 13 Italian institutions entered in a pilot study named AIDA, combining all-trans retinoic acid (ATRA) with idarubicin (IDA). ATRA was administered orally beginning on the first day of induction at the dosage of 45 mg/m2/d until complete remission (CR), whereas IDA was administered intravenously at the dosage of 12 mg/m2/d on days 2, 4, 6, and 8 of the induction. Patients who achieved CR were consolidated with 3 courses of chemotherapy without ATRA; thereafter, they were followed up for molecular and hematologic CR. The median age was 35.3 years (range, 6.5 to 67.6 years); 8 patients were males and 12 females; 4 had the hypogranular variant of APL (M3v), and 4 (2 with M3v) presented with leukocyte counts > or = 10,000/microL. Molecular analysis for the promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) hybrid gene at diagnosis was performed in 16 patients by means of reverse transcription-polymerase chain reaction (RT-PCR) analysis, and all were RT-PCR+ for the hybrid gene. In the remaining 4 patients, the cytogenetic study showed the presence of the t(15;17). After a median time of 36 days (range, 28 to 52 days) 18 (90%) patients achieved CR; the remaining 2 patients died 12 and 34 days after diagnosis from myocardial infarction caused by fungal myocarditis and from massive hemoptysis, respectively. ATRA syndrome was observed in only 2 patients, and, after the prompt discontinuation of ATRA and initiation of dexamethasone, both recovered from the syndrome. However, after recovering, 1 patient achieved CR, whereas the other died at day 34 because of massive hemoptysis; other side effects were very limited. At recovery from the third consolidation course, only 3 of 14 (21.4%) tested patients were RT-PCR+ for the PML-RAR alpha hybrid gene. Of these, 2 relapsed shortly afterwards; however, in the last patient, the PML-RAR alpha disappeared

  3. Quantitation of minimal residual disease in acute promyelocytic leukemia patients with t(15;17) translocation using real-time RT-PCR.

    PubMed

    Cassinat, B; Zassadowski, F; Balitrand, N; Barbey, C; Rain, J D; Fenaux, P; Degos, L; Vidaud, M; Chomienne, C

    2000-02-01

    We took advantage of a recently developed system allowing performance of real-time quantitation of polymerase chain reaction to develop a quantitative method of measurement of PML-RARalpha transcripts which are hallmarks of acute promyelocytic leukemia (APL) with t(15;17) translocation. Indeed, although quantitation of minimal residual disease has proved to be useful in predicting clinical outcome in other leukemias such as chronic myeloid leukemia or acute lymphoblastic leukemia, no quantitative data have been provided in the case of APL. We present here a method for quantitation of the most frequent subtypes of t(15;17) transcripts (namely bcr1 and bcr3). One specific forward primer is used for each subtype in order to keep amplicon length under 200 bp. The expression of PML-RARalpha transcripts is normalized using the housekeeping porphobilinogen deaminase (PBGD) gene. This technique allows detection of 10 copies of PML-RARalpha or PBGD plasmids, and quantitation was efficient up to 100 copies. One t(15;17)-positive NB4 cell could be detected among 106 HL60 cells, although quantitation was efficient up to one cell among 105. Repeatability and reproducibility of the method were satisfying as intra- and inter-assay variation coefficients were not higher than 15%. The efficiency of the method was finally tested in patient samples, showing a decrease of the PML-RARalpha copy number during therapy, and an increase at the time of relapse.

  4. Herbo-mineral ayurvedic treatment in a high risk acute promyelocytic leukemia patient with second relapse: 12 years follow up

    PubMed Central

    Prakash, Balendu; Parikh, Purvish M.; Pal, Sanjoy K.

    2010-01-01

    A 47 year old diabetic male patient was diagnosed and treated for high risk AML-M3 at Tata Memorial Hospital (BJ 17572), Mumbai in September 1995. His bone marrow aspiration cytology indicated 96% promyelocytes with abnormal forms, absence of lymphocytic series and myeloperoxide test 100% positive. Initially treated with ATRA, he achieved hematological remission on day 60, but cytogenetically the disease persisted. The patient received induction and consolidated chemotherapy with Daunorubicin and Cytarabine combination from 12.01.96 to 14.05.96, following which he achieved remission. However, his disease relapsed in February 97. The patient was given two cycles of chemotherapy with Idarubicine and Etoposide, after which he achieved remission. His disease again relapsed in December 97. The patient then refused more chemotherapy and volunteered for a pilot Ayurvedic study conducted by the Central Council for Research in Ayurveda and Siddha, New Delhi. The patient was treated with a proprietary Ayurvedic medicine Navajeevan, Kamadudha Rasa and Keharuba Pisti for one year. For the subsequent 5 years the patient received three months of intermittent Ayurvedic treatment every year. The patient achieved complete disease remission with the alternative treatment without any adverse side effects. The patient has so far completed 13 years of survival after the start of Ayurvedic therapy. PMID:21547051

  5. Herbo-mineral ayurvedic treatment in a high risk acute promyelocytic leukemia patient with second relapse: 12 years follow up.

    PubMed

    Prakash, Balendu; Parikh, Purvish M; Pal, Sanjoy K

    2010-07-01

    A 47 year old diabetic male patient was diagnosed and treated for high risk AML-M3 at Tata Memorial Hospital (BJ 17572), Mumbai in September 1995. His bone marrow aspiration cytology indicated 96% promyelocytes with abnormal forms, absence of lymphocytic series and myeloperoxide test 100% positive. Initially treated with ATRA, he achieved hematological remission on day 60, but cytogenetically the disease persisted. The patient received induction and consolidated chemotherapy with Daunorubicin and Cytarabine combination from 12.01.96 to 14.05.96, following which he achieved remission. However, his disease relapsed in February 97. The patient was given two cycles of chemotherapy with Idarubicine and Etoposide, after which he achieved remission. His disease again relapsed in December 97. The patient then refused more chemotherapy and volunteered for a pilot Ayurvedic study conducted by the Central Council for Research in Ayurveda and Siddha, New Delhi. The patient was treated with a proprietary Ayurvedic medicine Navajeevan, Kamadudha Rasa and Keharuba Pisti for one year. For the subsequent 5 years the patient received three months of intermittent Ayurvedic treatment every year. The patient achieved complete disease remission with the alternative treatment without any adverse side effects. The patient has so far completed 13 years of survival after the start of Ayurvedic therapy. PMID:21547051

  6. miR-299-5p promotes cell growth and regulates G1/S transition by targeting p21Cip1/Waf1 in acute promyelocytic leukemia

    PubMed Central

    WU, SHUN-QUAN; ZHANG, LANG-HUI; HUANG, HAO-BO; LI, YA-PING; NIU, WEN-YAN; ZHAN, RONG

    2016-01-01

    MicroRNAs (miRs) are often located in genomic breakpoint regions and are hypothesized to be important regulators involved in the regulation of critical cell processes, including cell apoptosis, proliferation and differentiation. miR-299 has been reported to be upregulated in acute promyelocytic leukemia (APL); however, the function and mechanistic role of miR-299 in APL remains unknown. The present study demonstrated mir-299 significantly induced cell growth and cell cycle progression at the G1/S transition in APL cells. Notably, the present study revealed that miR-299-5p induces these effects, whereas miR-299-3p does not. Additional studies demonstrated that in APL cells the tumor suppressor p21Cip1/Waf1 is a downstream target of miR-299; miR-299 binds directly to the 3′ untranslated region of p21Cip1/Waf1, and reduces protein, but not mRNA, levels of p21Cip1/Waf1. The present findings demonstrate that miR-299 exerts growth-promoting effects in APL cells through the suppression of p21Cip1/Waf1. Overall, the present study demonstrates that p21Cip1/Waf1 is a direct functional target of miR-299 in APL. PMID:27347210

  7. Clinical Study on Prospective Efficacy of All-Trans Acid, Realgar-Indigo Naturalis Formula Combined with Chemotherapy as Maintenance Treatment of Acute Promyelocytic Leukemia

    PubMed Central

    Lu-Qun, Wang; Hao, Li; Xiao-Peng, He; Fang-Lin, Li; Ling-Ling, Wang; Xue-Liang, Chen; Ming, Hou

    2014-01-01

    Objectives. To test the efficiency and safety of sequential application of retinoic acid (ATRA), Realgar-Indigo naturalis formula (RIF) and chemotherapy (CT) were used as the maintenance treatment in patients with acute promyelocytic leukemia (APL). Methods. This was a retrospective study of 98 patients with newly diagnosed APL who accepted two different maintenance treatments. After remission induction and consolidation chemotherapy according to their Sanz scores, patients received two different kinds of maintenance scheme. The first regimen was using ATRA, RIF, and standard dose of CT sequentially (ATRA/RIF/CT regimen), while the second one was using ATRA and low dose of chemotherapy with methotrexate (MTX) plus 6-mercaptopurine (6-MP) alternately (ATRA/CTlow regimen). The OS, DFS, relapse rate, minimal residual disease, and adverse reactions in two groups were monitored and evaluated. Results. ATRA/RIF/CT regimen could effectively reduce the chance of relapse in different risk stratification of patients, but there was no significant difference in 5-year DFS rate and OS rate between the two groups. Besides, the patients in the experimental group suffered less severe adverse reactions than those in the control group. Conclusions. The repeated sequential therapeutic regimen to APL with ATRA, RIF, and chemotherapy is worth popularizing for its high effectiveness and low toxicity. PMID:24963332

  8. Design and stereoselective synthesis of retinoids with ferrocene or N-butylcarbazole pharmacophores that induce post-differentiation apoptosis in acute promyelocytic leukemia cells.

    PubMed

    Ivanova, Diana; Gronemeyer, Hinrich; de Lera, Angel R

    2011-08-01

    New ferrocene and N-alkylcarbazole retinoids were designed and synthesized stereoselectively in good yields. A number of these synthesized ligands, in particular 2, 3, and 11, were found to exhibit a high RARα activation potential and to effectively induce post-differentiation apoptosis in NB4 acute promyelocytic leukemia (APL) cells. Increasing the length of the side chain attached to the heterocycle of the carbazole arotinoids creates new opportunities for altered compound catabolism and for fine-tuning of the apoptosis-inducing potential of the ligand. In the carbazole series of new retinoids, maximal activity was established for N-butylcarbazole analogue 11 in all assays (i.e., RARα activation, differentiation induction, and apoptosis induction). Study of the mechanism of apoptosis revealed an activation of initiator caspases-8 and -9, followed by efficient cleavage of effector caspase-3 on day 6 of treatment. Subsequent induction of a caspase cascade in NB4 cells triggered ultimate leukemic cell death. The selected ligands 2, 3, and 11 may provide alternate options for the treatment of APL in cases of life-threatening ATRA syndrome, resistance, and high toxicity to conventionally used retinoids.

  9. The influence of joint application of arsenic trioxide and daunorubicin on primary acute promyelocytic leukaemia cells and apoptosis and blood coagulation of cell strain.

    PubMed

    Zhang, Xiaojuan; Qin, Na; Chen, Xinghua; Guo, Shuxia

    2015-05-01

    This test cultivated three groups of acute promyelocytic leukemia (APL) and NB4 cells in liquid in vitro, processed them with arsenic trioxide (ATO), daunorubicin (DNR), ATO+DNR respectively, and then set up blank control group. Apoptosis of cells in each group was observed using flow cytometry, procoagulant activity of APL and NB4 cells in each group was detected with recalcification time, and expressions of tissue factor (TF), thrombomodulin and annexin II of NB4 cells in each group were measured using ELISA method. The results showed that the apoptosis rate increased 4-8 times compared with blank control group after processing APL and NB4 cells with ATO and DNR; procoagulant activity decreased obviously; and expression of TF and annexin II of NB4 cells reduced significantly (P<0.05). We concluded that combination of ATO and DNR could promote APL and NB4 cell apoptosis effectively without aggravating blood coagulation disorders, which might improve coagulation function of APL by inhibiting coagulation and hyperfibrinolysis through reducing expression of TF and annexin II. This drug combination may be a safe and effective method in the treatment of APL of primary high white blood cells type.

  10. A novel PAD4/SOX4/PU.1 signaling pathway is involved in the committed differentiation of acute promyelocytic leukemia cells into granulocytic cells

    PubMed Central

    Song, Guanhua; Shi, Lulu; Guo, Yuqi; Yu, Linchang; Wang, Lin; Zhang, Xiaoyu; Li, Lianlian; Han, Yang; Ren, Xia; Guo, Qiang; Bi, Kehong; Jiang, Guosheng

    2016-01-01

    All-trans retinoic acid (ATRA) treatment yields cure rates > 80% through proteasomal degradation of the PML-RARα fusion protein that typically promotes acute promyelocytic leukemia (APL). However, recent evidence indicates that ATRA can also promote differentiation of leukemia cells that are PML-RARα negative, such as HL-60 cells. Here, gene expression profiling of HL-60 cells was used to investigate the alternative mechanism of impaired differentiation in APL. The expression of peptidylarginine deiminase 4 (PADI4), encoding PAD4, a protein that post-translationally converts arginine into citrulline, was restored during ATRA-induced differentiation. We further identified that hypermethylation in the PADI4 promoter was associated with its transcriptional repression in HL-60 and NB4 (PML-RARα positive) cells. Functionally, PAD4 translocated into the nucleus upon ATRA exposure and promoted ATRA-mediated differentiation. Mechanistic studies using RNAi knockdown or electroporation-mediated delivery of PADI4, along with chromatin immunoprecipitation, helped identify PU.1 as an indirect target and SOX4 as a direct target of PAD4 regulation. Indeed, PAD4 regulates SOX4-mediated PU.1 expression, and thereby the differentiation process, in a SOX4-dependent manner. Taken together, our results highlight an association between PAD4 and DNA hypermethylation in APL and demonstrate that targeting PAD4 or regulating its downstream effectors may be a promising strategy to control differentiation in the clinic. PMID:26673819

  11. Influence of time to complete remission and duration of all-trans retinoic acid therapy on the relapse risk in patients with acute promyelocytic leukemia receiving AIDA protocols.

    PubMed

    Breccia, Massimo; Minotti, Clara; Latagliata, Roberto; Loglisci, Giuseppina; Salaroli, Adriano; Loglisci, Maria Giovanna; Lo-Coco, Francesco

    2013-04-01

    Despite the impressive results obtained with standard chemotherapy, approximately 20% of acute promyelocytic leukemia (APL) patients undergo disease relapse thereby requiring salvage therapy. Few data is available on long-term prognosis in relation to time to complete remission (CR): we reviewed 142 patients treated with AIDA protocols and we found that 42 out of 142 (29.6%) patients achieved CR after 35 days (median time, 42 days). No significant differences in presenting features, including FAB subtype, type of PML/RARA transcript and relapse risk at presentation between the two patient groups achieving CR > or <35 days were revealed, except for male sex and older age that were significantly associated with delayed CR. Rate of relapse was 31% in patients with delayed CR compared to 17% in the group of patients who achieved CR<35 days (p=0.001), with a 5-year CIR of 29.6% compared to 12% (p=0.03). APL patients with delayed CR should be more closely monitored during follow-up for early identification of relapse and prompt administration of pre-emptive salvage therapy.

  12. Increased BMI correlates with higher risk of disease relapse and differentiation syndrome in patients with acute promyelocytic leukemia treated with the AIDA protocols.

    PubMed

    Breccia, Massimo; Mazzarella, Luca; Bagnardi, Vincenzo; Disalvatore, Davide; Loglisci, Giuseppina; Cimino, Giuseppe; Testi, Anna Maria; Avvisati, Giuseppe; Petti, Maria Concetta; Minotti, Clara; Latagliata, Roberto; Foà, Robin; Pelicci, Pier Giuseppe; Lo-Coco, Francesco

    2012-01-01

    We investigated whether body mass index (BMI) correlates with distinct outcomes in newly diagnosed acute promyelocytic leukemia (APL). The study population included 144 patients with newly diagnosed and genetically confirmed APL consecutively treated at a single institution. All patients received All-trans retinoic acid and idarubicin according to the GIMEMA protocols AIDA-0493 and AIDA-2000. Outcome estimates according to the BMI were carried out together with multivariable analysis for the risk of relapse and differentiation syndrome. Fifty-four (37.5%) were under/normal weight (BMI < 25), whereas 90 (62.5%) patients were overweight/obese (BMI ≥ 25). An increased BMI was associated with older age (P < .0001) and male sex (P = .02). BMI was the most powerful predictor of differentiation syndrome in multivariable analysis (odds ratio = 7.24; 95% CI, 1.50-34; P = .014). After a median follow-up of 6 years, the estimated cumulative incidence of relapse at 5 years was 31.6% (95% CI, 22.7%-43.8%) in overweight/obese and 11.2% (95% CI, 5.3%-23.8%) in underweight/normal weight patients (P = .029). Multivariable analysis showed that BMI was an independent predictor of relapse (hazard ratio = 2.45, 95% CI, 1.00-5.99, in overweight/obese vs under/normal weight patients, P = .049). An increased BMI at diagnosis is associated with a higher risk of developing differentiation syndrome and disease relapse in APL patients treated with AIDA protocols.

  13. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors.

    PubMed

    Montesinos, Pau; Bergua, Juan M; Vellenga, Edo; Rayón, Chelo; Parody, Ricardo; de la Serna, Javier; León, Angel; Esteve, Jordi; Milone, Gustavo; Debén, Guillermo; Rivas, Concha; González, Marcos; Tormo, Mar; Díaz-Mediavilla, Joaquín; González, Jose D; Negri, Silvia; Amutio, Elena; Brunet, Salut; Lowenberg, Bob; Sanz, Miguel A

    2009-01-22

    Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid (ATRA). Detailed knowledge about DS has remained limited. We present an analysis of the incidence, characteristics, prognostic factors, and outcome of 739 APL patients treated with ATRA plus idarubicin in 2 consecutive trials (Programa Español de Tratamientos en Hematología [PETHEMA] LPA96 and LPA99). Overall, 183 patients (24.8%) experienced DS, 93 with a severe form (12.6%) and 90 with a moderate form (12.2%). Severe but not moderate DS was associated with an increase in mortality. A bimodal incidence of DS was observed, with peaks occurring in the first and third weeks after the start of ATRA therapy. A multivariate analysis indicated that a WBC count greater than 5 x 10(9)/L and an abnormal serum creatinine level correlated with an increased risk of developing severe DS. Patients receiving systematic prednisone prophylaxis (LPA99 trial) in contrast to those receiving selective prophylaxis with dexamethasone (LPA96 trial) had a lower incidence of severe DS. Patients developing severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003), but this difference was not apparent in the LPA99 trial (86% vs 88%).

  14. International Society of Thrombosis and Hemostasis Scoring System for disseminated intravascular coagulation ≥ 6: a new predictor of hemorrhagic early death in acute promyelocytic leukemia.

    PubMed

    Mitrovic, Mirjana; Suvajdzic, Nada; Bogdanovic, Andrija; Kurtovic, Nada Kraguljac; Sretenovic, Aleksandra; Elezovic, Ivo; Tomin, Dragica

    2013-03-01

    High-hemorrhagic early death (ED) rate is a major impediment in the managing of acute promyelocytic leukemia (APL). In our group of 56 newly diagnosed APL patients, ED occurred in 12 subjects, due to endocranial bleeding (8/12), differentiation syndrome (2/12), or infection (2/12). Predictors of hemorrhagic ED were as follows: white blood cells count ≥ 20 × 10(9)/L (P = 0.002337), Eastern cooperative oncology group performance status ≥ 3 (P = 0.00173), fibrinogen level <2 g/L (P = 0.004907), prothrombin time <50% (P = 0.0124), and International Society of Thrombosis and Hemostasis Scoring System for disseminated intravascular coagulation (ISTH DIC score) ≥ 6 (P = 0.00741). Multivariate analysis indicated ISTH DIC score ≥ 6 to be the most significant predictor for hemorrhagic ED (P = 0.008). The main finding of this study is that simple coagulation-related tests, performed on hospital admission and combined in the ISTH DIC score, might help to identify patients at high risk for fatal bleeding needing more aggressive supportive measures.

  15. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia.

    PubMed

    Hu, Jiong; Liu, Yuan-Fang; Wu, Chuan-Feng; Xu, Fang; Shen, Zhi-Xiang; Zhu, Yong-Mei; Li, Jun-Min; Tang, Wei; Zhao, Wei-Li; Wu, Wen; Sun, Hui-Ping; Chen, Qiu-Sheng; Chen, Bing; Zhou, Guang-Biao; Zelent, Arthur; Waxman, Samuel; Wang, Zhen-Yi; Chen, Sai-Juan; Chen, Zhu

    2009-03-01

    All-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combination-based therapy has benefitted newly diagnosed acute promyelocytic leukemia (APL) in short-term studies, but the long-term efficacy and safety remained unclear. From April 2001, we have followed 85 patients administrated ATRA/ATO with a median follow-up of 70 months. Eighty patients (94.1%) entered complete remission (CR). Kaplan-Meier estimates of the 5-year event-free survival (EFS) and overall survival (OS) for all patients were 89.2% +/- 3.4% and 91.7% +/- 3.0%, respectively, and the 5-year relapse-free survival (RFS) and OS for patients who achieved CR (n = 80) were 94.8% +/- 2.5% and 97.4% +/- 1.8%, respectively. Upon ATRA/ATO, prognosis was not influenced by initial white blood cell count, distinct PML-RARalpha types, or FLT3 mutations. The toxicity profile was mild and reversible. No secondary carcinoma was observed, and 24 months after the last dose of ATRA/ATO, patients had urine arsenic concentrations well below the safety limit. These results demonstrate the high efficacy and minimal toxicity of ATRA/ATO treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for de novo APL.

  16. Severe stomatitis and ileocecal perforation developed after all-trans retinoic acid monotherapy in an HLA-B51-positive patient with acute promyelocytic leukemia.

    PubMed

    Kimura, Kenji; Takeuchi, Masahiro; Hasegawa, Nagisa; Togasaki, Emi; Shimizu, Ryoh; Kawajiri, Chika; Muto, Tomoya; Tsukamoto, Shokichi; Takeda, Yusuke; Ohwada, Chikako; Sakaida, Emiko; Sakai, Shio; Mimura, Naoya; Ota, Satoshi; Iseki, Tohru; Nakaseko, Chiaki

    2016-06-01

    A 34-year-old man who had been referred to our hospital was diagnosed with acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA), oral administration, was initiated. On day 25, he developed fever and respiratory distress with bilateral pulmonary infiltrates, suggesting differentiation syndrome (DS) caused by ATRA. These symptoms showed amelioration after discontinuing ATRA and initiating methylprednisolone. ATRA was re-started on day 29 at half the original dose because of residual APL blasts. The patient subsequently developed fever, severe stomatitis, and oropharyngeal ulcers, which persisted even after discontinuing ATRA. On day 48, he suddenly developed severe abdominal pain with free air, observable on an abdominal X-ray, and underwent emergency ileocecal resection. Pathological examination of the resected ileocecal intestines revealed multiple ulcers and perforations. No leukemic cell infiltration was observed. In this case, only ATRA was administered for APL treatment. These findings suggest that ileocecal ulcerations and perforations, as well as oropharyngeal ulcers, might have been caused by DS or ATRA. Furthermore, DNA typing of the HLA-B locus revealed that the patient had HLA-B51 associated with Behçet's disease. Therefore, hypercytokinemia with DS might have induced Behçet's disease-like symptoms, including stomatitis and ileocecal perforation, complications that are particularly observed in patients with HLA-B51. PMID:27384858

  17. Coexistence of tetrasomy 8 and trisomy 8 in acute promyelocytic leukemia (AML-M3) with t(15;17)(q22;q12).

    PubMed

    Wang, Hui-Ping; Li, Guo-Xia; Qiao, Zhen-Hua; Ren, Wen-Ying; Wang, Hong-Wei

    2004-08-01

    This study was purposed to characterize the first case of acute promyelocitic leukemia (AML-M(3a)) with t(15;17), trisomy 8 and tetrasomy 8, and explore its characteristics of morphology, cytogenetics, molecular biology, immunology and clinical features. Morphological changes of peripheral blood and bone marrow smears were observed under microscope. Chromosome specimen was prepared by 24 h short-term culture of bone marrow cell, RHG-banding technique was used for karyotypic analysis. PML-RARa fusion gene transcript was detected by nested-reverse transcription-polymerase chain reaction (nested RT-PCR). Interphase fluorescence in situ hybridization (FISH) using chromosome 8 centromere specific probe were carried out to detect abnormal numbers of chromosome 8. Immunophenotypic analysis was performed by flow cytometry. The results showed that peripheral blood smear revealed 65% promyelocyte, and bone marrow aspirate was hypercellular with 72.4% promyelocyte, moderately basophilic cytoplasm with numerous azurophilic granules. Karyotype analysis demonstrated 48, XY, +8, +8, t(15;17)(q22;q12) [16]/47, XY, +8, t(15;17)(q22;q12) [3]/46, XY, t(15;17)(q22;q12) [1]. RT-PCR assay revealed PML-RARa fusion gene transcript (+). FISH showed that the percentages of cells exhibiting 1, 2, 3, 4, 5, 6 green fluorescence signals were 0.5, 7, 19, 55, 18 and 0.5, respectively. This confirmed the presence of tetrasomy 8 and trisomy 8 and also revealed a low percentage of a pentasomy 8 clone. Immunophenotypes of the blasts displayed that CD13 (96.2%), CD33 (55.9%), CYMPO (93.5%) were positive. All the lymphoid markers tested were negative. The patient survival time was just 10 days. It is concluded that tetrasomy 8 is secondary cytogenetic event after t(15;17) in this case. It may be a consequence of clonal evolution of trisomy 8. t(15;17) AML-M(3) with tetrasomy 8 heralds a poor prognosis. PMID:15363120

  18. Cancer procoagulant and tissue factor are differently modulated by all-trans-retinoic acid in acute promyelocytic leukemia cells.

    PubMed

    Falanga, A; Consonni, R; Marchetti, M; Locatelli, G; Garattini, E; Passerini, C G; Gordon, S G; Barbui, T

    1998-07-01

    All-trans-retinoic acid (ATRA) downregulates the expression of two cellular procoagulants, tissue factor (TF) and cancer procoagulant (CP), in human promyelocytic leukemia cells. To evaluate whether or not changes of the procoagulant activities (PCAs) may share mechanisms with the ATRA-induced cyto-differentiation process, we have characterized the effect of ATRA on the TF and CP expression by NB4 cells, an ATRA maturation-inducible cell line, and two NB4-derived cell lines resistant to ATRA-induced maturation, the NB4. 306 and NB4.007/6 cells. Next, we evaluated the effect on the PCAs of the NB4 parental cells of three synthetic retinoid analogues, ie: AM580 (selective for the retinoic acid receptor [RAR] alpha), capable to induce the granulocytic differentiation of NB4 cells; and CD2019 (selective for RARbeta) and CD437 (selective for RARgamma), both lacking this capability. Cells were treated with either ATRA or the analogues (10(-6) to 10(-8) mol/L) for 96 hours. The effect on cell differentiation was evaluated by morphologic changes, cell proliferation, nitro blue tetrazolium reduction assay, and flow cytometry analysis of the CD33 and CD11b surface-antigen expression. PCA was first measured in 20 mmol/L Veronal Buffer cell extracts by the one-stage clotting assay of normal and FVII-deficient plasmas. Further TF and CP have been characterized and quantified in cell-sample preparations by chromogenic and immunological assays. In the first series of experiments, ATRA downregulates both TF and CP in NB4 parental cells, as expected. However, in the differentiation-resistant cell lines, it induced a significant loss of TF but had little or no effect on CP. In a second series of experiments, in the NB4 parental cells, the RARalpha agonist (AM580) induced cell maturation and reduced 91% CP expression, whereas CD437 and CD2019 had no cyto-differentiating effects and did not affect CP levels. On the other hand, in the same cells the TF expression was reduced by ATRA

  19. Decitabine, Vorinostat, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-12-19

    Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  20. Azidothymidine hinders arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells by induction of p21 and attenuation of G2/M arrest.

    PubMed

    Hassani, Saeed; Ghaffari, Seyed H; Zaker, Farhad; Mirzaee, Rohellah; Mardani, Hajar; Bashash, Davood; Zekri, Ali; Yousefi, Meysam; Zaghal, Azam; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir

    2013-09-01

    To enhance anticancer efficacy of the arsenic trioxide (ATO), the combination of ATO and azidothymidine (AZT), with convergence anti-telomerase activity, were examined on acute promyelocytic leukemia (APL) cell line, NB4. In spite of an induction of apoptosis by both drugs separately and a synergistic effect of them on hTERT down-regulation and telomerase inhibition, the ATO-induced cytotoxicity was reduced when it was used in combination with AZT. AZT attenuated the ATO effects on viability, metabolic activity, DNA synthesis, and apoptosis. These observations, despite the deflection from the main goal of this study, dedicate an especial opportunity to elucidate the importance of some of the mechanisms that have been suggested by which ATO induces apoptosis. Cell cycle distribution, ROS level, and caspase-3 activation analyses suggest that AZT reduced the ATO-induced cytotoxic effect possibly via relative induction and diminution of cells accumulated in (G1, S) and (G2/M) phase, respectively, as well as through attenuation of ROS generation and subsequent caspase-3 inhibition. QRT-PCR assay revealed that induction of p21expression by the combined AZT/ATO compared to ATO alone could be a reason for the relative decline of cells accumulation in G2/M and the increase of cells in G1 and S phases. Therefore, the G2/M arrest and ROS generation are likely principle mediators for the ATO-induced apoptosis and can be used as a guide to design rational combinatorial strategies involving ATO and agents with G2/M arrest or ROS generation capacity to intensify ATO-induced apoptosis.

  1. MIR125B1 represses the degradation of the PML-RARA oncoprotein by an autophagy-lysosomal pathway in acute promyelocytic leukemia.

    PubMed

    Zeng, Cheng-Wu; Chen, Zhen-Hua; Zhang, Xing-Ju; Han, Bo-Wei; Lin, Kang-Yu; Li, Xiao-Juan; Wei, Pan-Pan; Zhang, Hua; Li, Yangqiu; Chen, Yue-Qin

    2014-10-01

    Acute promyelocytic leukemia (APL) is characterized by the t(15;17)-associated PML-RARA fusion gene. We have previously found that MIR125B1 is highly expressed in patients with APL and may be associated with disease pathogenesis; however, the mechanism by which MIR125B1 exerts its oncogenic potential has not been fully elucidated. Here, we demonstrated that MIR125B1 abundance correlates with the PML-RARA status. MIR125B1 overexpression enhanced PML-RARA expression and inhibited the ATRA-induced degradation of the PML-RARA oncoprotein. RNA-seq analysis revealed a direct link between the PML-RARA degradation pathway and MIR125B1-arrested differentiation. We further demonstrated that the MIR125B1-mediated blockade of PML-RARA proteolysis was regulated via an autophagy-lysosomal pathway, contributing to the inhibition of APL differentiation. Furthermore, we identified DRAM2 (DNA-damage regulated autophagy modulator 2), a critical regulator of autophagy, as a novel target that was at least partly responsible for the function of MIR125B1 involved in autophagy. Importantly, the knockdown phenotypes for DRAM2 are similar to the effects of overexpressing MIR125B1 as impairment of PML-RARA degradation, inhibition of autophagy, and myeloid cell differentiation arrest. These effects of MIR125B1 and its target DRAM2 were further confirmed in an APL mouse model. Thus, MIR125B1 dysregulation may interfere with the effectiveness of ATRA-mediated differentiation through an autophagy-dependent pathway, representing a novel potential APL therapeutic target.

  2. Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia

    PubMed Central

    Moser, Barry K.; Racevskis, Janis; Poiré, Xavier; Bloomfield, Clara D.; Carroll, Andrew J.; Ketterling, Rhett P.; Roulston, Diane; Schachter-Tokarz, Esther; Zhou, Da-cheng; Chen, I-Ming L.; Harvey, Richard; Koval, Greg; Sher, Dorie A.; Feusner, James H.; Tallman, Martin S.; Larson, Richard A.; Powell, Bayard L.; Appelbaum, Frederick R.; Paietta, Elisabeth; Willman, Cheryl L.; Stock, Wendy

    2012-01-01

    Mutations in the all-trans retinoic acid (ATRA)–targeted ligand binding domain of PML-RARα (PRα/LBD+) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD+ (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD+. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD+), which were differentially associated with PRα/LBD+ depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD+ were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD+, high, S-isoform. These exploratory results suggest that differing PRα/LBD+ activities may interact with FLT3-ITD+ or ACA, that FLT3-ITD+ and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD+ were also associated with reduced postrelapse survival. PMID:22734072

  3. Aquaporin 9, a promising predictor for the cytocidal effects of arsenic trioxide in acute promyelocytic leukemia cell lines and primary blasts.

    PubMed

    Iriyama, Noriyoshi; Yuan, Bo; Yoshino, Yuta; Hatta, Yoshihiro; Horikoshi, Akira; Aizawa, Shin; Takeuchi, Jin; Toyoda, Hiroo

    2013-06-01

    A close correlation between the cytocidal effects of arsenic trioxide (ATO) and aquaporin-9 (AQP9) expression levels has been proposed, yet detailed studies are still needed to confirm this association. Thus, in the present study, the correlation between the expression levels of AQP9 and sensitivity to ATO was investigated using two acute promyelocytic leukemia (APL) cell lines, NB4 and HT93A, as well as primary APL cells from newly diagnosed and relapsed APL patients. A substantially higher sensitivity to ATO-mediated induction of apoptosis was observed in the NB4 cells when compared to that in the HT93A cells. In addition, markedly higher expression levels of AQP9, as assessed using flow cytometry, along with more intracellular arsenic accumulation, were observed in the NB4 cells. More importantly, similar to APL cell lines, the trend of expression levels of AQP9 correlated closely with the differential sensitivity to ATO-mediated induction of apoptosis in primary APL cells. In contrast, no correlation was observed between ATO sensitivity associated with AQP9 expression levels and the expression profiles of cell surface markers as well as chromosomal alterations. These results provide direct evidence that the expression levels of AQP9, rather than other biomarkers such as cell surface markers and chromosomal alterations, correlate closely with the sensitivity to ATO in both APL cell lines and primary blasts. These findings suggest that the AQP9 expression status of APL patients is a predictive marker for the successful outcome of ATO treatment, since AQP9 plays a pivotal role in various arsenite-mediated biological effects on normal and cancer cells. Moreover, flow cytometry may be a new convenient and valuable tool for analyzing the AQP9 status of APL patients compared to current methods such as western blotting.

  4. Acute promyelocytic leukaemia in patients originating in Latin America is associated with an increased frequency of the bcr1 subtype of the PML/RARalpha fusion gene.

    PubMed

    Douer, Dan; Santillana, Sergio; Ramezani, Laleh; Samanez, Cesar; Slovak, Marilyn L; Lee, Ming S; Watkins, Kristy; Williams, Tony; Vallejos, Carlos

    2003-08-01

    The PML/RARalpha fusion gene in acute promyelocytic leukaemia (APL) has three subtypes based on the breakpoint site of the PML gene: long (bcr1), short (bcr3) and variable (bcr2) subtypes. The PML/RARalpha fusion protein is involved in the pathogenesis of APL and the breakpoint site of the PML gene might be associated with aetiological factor(s). Because APL is over-represented in patients that originate in Latin America (Latinos), we evaluated whether the distribution of the PML/RARalpha fusion mRNA in this population is different to that reported in non-Latinos. Among 52 APL patients (28 from Mexico and Central America diagnosed in Los Angeles and 24 from Peru, South America), bcr1, bcr2 and bcr3 expression was 75%, 10% and 15% respectively. However, bcr1 breakpoints were significantly higher compared with non-Latino patients (340/654, 52%) reported in four studies. Often bcr1 and bcr2 are reported together; 862 (60%) of 1429 non-Latino APL patients reported in nine studies were either bcr1 or bcr2, compared with 44 (85%) in our 52 Latino patients. This difference was also statistically significant when our patients were compared to each of the individual studies from USA and Europe, but not for a small series from China and Japan. These results suggest that the overrepresentation of APL among Latin American patients can be accounted for by an increase of a single subtype--bcr1, and the breakage sites in the PML gene may not be random but possibly influenced by genetic and/or environmental factor(s).

  5. PML/RARα-Regulated miR-181a/b Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia.

    PubMed

    Bräuer-Hartmann, Daniela; Hartmann, Jens-Uwe; Wurm, Alexander Arthur; Gerloff, Dennis; Katzerke, Christiane; Verga Falzacappa, Maria Vittoria; Pelicci, Pier Giuseppe; Müller-Tidow, Carsten; Tenen, Daniel G; Niederwieser, Dietger; Behre, Gerhard

    2015-08-15

    In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. microRNAs are known to be critical players in the formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as a key event in the drug response. We found that miR-181a/b expression was activated by the PML/RARα oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNA interference (RNAi)-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony-forming capacity, proliferation, and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3'-untranslated region. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell-cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Finally, RASSF1A levels were reduced in PML/RARα knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RARα-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL. PMID:26041820

  6. Stages of Adult Acute Lymphoblastic Leukemia

    MedlinePlus

    ... recovery) and treatment options. Adult acute lymphoblastic leukemia (ALL) is a type of cancer in which the ... to radiation may increase the risk of developing ALL. Anything that increases your risk of getting a ...

  7. Treatment Options for Adult Acute Lymphoblastic Leukemia

    MedlinePlus

    ... recovery) and treatment options. Adult acute lymphoblastic leukemia (ALL) is a type of cancer in which the ... to radiation may increase the risk of developing ALL. Anything that increases your risk of getting a ...

  8. Treatment Option Overview (Adult Acute Lymphoblastic Leukemia)

    MedlinePlus

    ... recovery) and treatment options. Adult acute lymphoblastic leukemia (ALL) is a type of cancer in which the ... to radiation may increase the risk of developing ALL. Anything that increases your risk of getting a ...

  9. Incorporating measurable ('minimal') residual disease-directed treatment strategies to optimize outcomes in adults with acute myeloid leukemia.

    PubMed

    Pettit, Kristen; Stock, Wendy; Walter, Roland B

    2016-07-01

    Curative-intent therapy leads to complete remissions in many adults with acute myeloid leukemia (AML), but relapse remains common. Numerous studies have unequivocally demonstrated that the persistence of measurable ('minimal') residual disease (MRD) at the submicroscopic level during morphologic remission identifies patients at high risk of disease recurrence and short survival. This association has provided the impetus to customize anti-leukemia therapy based on MRD data, a strategy that is now routinely pursued in acute promyelocytic leukemia (APL). While it is currently uncertain whether this approach will improve outcomes in AML other than APL, randomized studies have validated MRD-based risk-stratified treatment algorithms in acute lymphoblastic leukemia. Here, we review the available studies examining MRD-directed therapy in AML, appraise their strengths and limitations, and discuss avenues for future investigation.

  10. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome.

    PubMed

    Sanz, Miguel A; Montesinos, Pau; Rayón, Chelo; Holowiecka, Alexandra; de la Serna, Javier; Milone, Gustavo; de Lisa, Elena; Brunet, Salut; Rubio, Vicente; Ribera, José M; Rivas, Concha; Krsnik, Isabel; Bergua, Juan; González, José; Díaz-Mediavilla, Joaquín; Rojas, Rafael; Manso, Félix; Ossenkoppele, Gert; González, José D; Lowenberg, Bob

    2010-06-24

    A risk-adapted strategy based on all-trans retinoic acid (ATRA) and anthracycline monochemotherapy (PETHEMA LPA99 trial) has demonstrated a high antileukemic efficacy in acute promyelocytic leukemia. We designed a new trial (LPA2005) with the objective of achieving stepwise improvements in outcome. Between July 2005 and April 2009, low- and intermediate-risk patients (leukocytes < 10 x 10(9)/L) received a reduced dose of mitoxantrone for the second consolidation course, whereas high- risk patients younger than 60 years of age received cytarabine combined with ATRA and idarubicin in the first and third consolidation courses. Of 372 patients attaining complete remission after ATRA plus idarubicin (92.5%), 368 proceeded to consolidation therapy. For low- and intermediate-risk patients, duration of neutropenia and thrombocytopenia and hospital stay were significantly reduced without sacrificing antileukemic efficacy, compared with the previous LPA99 trial. For high-risk patients, the 3-year relapse rate was significantly lower in the LPA2005 trial (11%) than in the LPA99 (26%; P = .03). Overall disease-free survival was also better in the LPA2005 trial (P = .04). In conclusion, the lower dose of mitoxantrone resulted in a significant reduction of toxicity and hospital stay while maintaining the antileukemic activity, and the combination of ATRA, idarubicin, and cytarabine for high-risk acute promyelocytic leukemia significantly reduced the relapse rate in this setting. Registered at http://www.clinicaltrials.gov as NCT00408278.

  11. Azacitidine in Combination With Mitoxantrone, Etoposide Phosphate, and Cytarabine in Treating Patients With Relapsed and Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-08-23

    Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia

  12. Opposite effects of the acute promyelocytic leukemia PML-retinoic acid receptor alpha (RAR alpha) and PLZF-RAR alpha fusion proteins on retinoic acid signalling.

    PubMed Central

    Ruthardt, M; Testa, U; Nervi, C; Ferrucci, P F; Grignani, F; Puccetti, E; Grignani, F; Peschle, C; Pelicci, P G

    1997-01-01

    Fusion proteins involving the retinoic acid receptor alpha (RAR alpha) and the PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemias (APLs). APLs with the PML-RAR alpha or the PLZF-RAR alpha fusion protein are phenotypically indistinguishable except that they differ in their sensitivity to retinoic acid (RA)-induced differentiation: PML-RAR alpha blasts are sensitive to RA and patients enter disease remission after RA treatment, while patients with PLZF-RAR alpha do not. We here report that (i) like PML-RAR alpha expression, PLZF-RAR alpha expression blocks terminal differentiation of hematopoietic precursor cell lines (U937 and HL-60) in response to different stimuli (vitamin D3, transforming growth factor beta1, and dimethyl sulfoxide); (ii) PML-RAR alpha, but not PLZF-RAR alpha, increases RA sensitivity of hematopoietic precursor cells and restores RA sensitivity of RA-resistant hematopoietic cells; (iii) PML-RAR alpha and PLZF-RAR alpha have similar RA binding affinities; and (iv) PML-RAR alpha enhances the RA response of RA target genes (those for RAR beta, RAR gamma, and transglutaminase type II [TGase]) in vivo, while PLZF-RAR alpha expression has either no effect (RAR beta) or an inhibitory activity (RAR gamma and type II TGase). These data demonstrate that PML-RAR alpha and PLZF-RAR alpha have similar (inhibitory) effects on RA-independent differentiation and opposite (stimulatory or inhibitory) effects on RA-dependent differentiation and that they behave in vivo as RA-dependent enhancers or inhibitors of RA-responsive genes, respectively. Their different activities on the RA signalling pathway might underlie the different responses of PML-RAR alpha and PLZF-RAR alpha APLs to RA treatment. The PLZF-RAR alpha fusion protein contains an approximately 120-amino-acid N-terminal motif (called the POZ domain), which is also found in a variety of zinc finger proteins and a group of poxvirus proteins and which mediates protein

  13. Budgetary impact of treating acute promyelocytic leukemia patients with first-line arsenic trioxide and retinoic acid from an Italian payer perspective.

    PubMed

    Kruse, Morgan; Wildner, Rebecca; Barnes, Gisoo; Martin, Monique; Mueller, Udo; Lo-Coco, Francesco; Pathak, Ashutosh

    2015-01-01

    The objective of this study was to estimate the net cost of arsenic trioxide (ATO) added to all-trans retinoic acid (ATRA) compared to ATRA plus chemotherapy when used in first-line acute promyelocytic leukemia (APL) treatment for low to intermediate risk patients from the perspective of the overall Italian healthcare systemA Markov model was developed with 3 health states: stable disease, disease event and death. Each month, patients could move from stable to disease event or die from either state. After a disease event, patients discontinued initial treatment and switched to the other regimen as second-line therapy. Treatment regimens, efficacy and adverse events were derived from published sources and expert opinion; unit costs were collected from standard Italian sources. Clinical outcomes and costs for pre-ATO and post-ATO scenarios were combined with population and product utilization information to calculate the total budgetary impact using a 3-year time horizon; one-way sensitivity analyses were conducted. Three-year cumulative pharmacy costs for ATO+ATRA were €46,700 per-patient versus €6,500 for ATRA+chemotherapy; however, medical costs for ATO+ATRA were €12,300 per-patient versus €30,200 for ATRA+chemotherapy. The total budgetary impact was estimated to be an additional €127,300, €312,500 and €477,800 in the first, second and third years, respectively. The model was most sensitive to changes in the cost of the ATO+ATRA regimen during the consolidation phase. Budgetary impact models are valuable to payers making formulary decisions regarding the access and affordability of new medicines. The cost of treatment analysis showed that pharmacy costs for ATO+ATRA were higher than for ATRA+chemotherapy, while all other evaluated costs were lower for ATO+ATRA treated patients. The average budgetary impact was €305,900 per year overall, representing a 3.5% increase. Further research is needed to determine the cost-effectiveness of ATO+ATRA compared

  14. AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells.

    PubMed

    Gianní, M; Li Calzi, M; Terao, M; Guiso, G; Caccia, S; Barbui, T; Rambaldi, A; Garattini, E

    1996-02-15

    All-trans retinoic acid (ATRA) is successfully used in the cyto-differentiating treatment of acute promyelocytic leukemia (APL). Paradoxically, APL cells express PML-RAR, an aberrant form of the retinoic acid receptor type alpha (RAR alpha) derived from the leukemia-specific t(15;17) chromosomal translocation. We show here that AM580, a stable retinobenzoic derivative originally synthesized as a RAR alpha agonist, is a powerful inducer of granulocytic maturation in NB4, an APL-derived cell line, and in freshly isolated APL blasts. After treatment of APL cells with AM580 either alone or in combination with granulocyte colony-stimulating factor (G-CSF), the compound induces granulocytic maturation, as assessed by determination of the levels of leukocyte alkaline phosphatase, CD11b, CD33, and G-CSF receptor mRNA, at concentrations that are 10- to 100-fold lower than those of ATRA necessary to produce similar effects. By contrast, AM580 is not effective as ATRA in modulating the expression of these differentiation markers in the HL-60 cell line and in freshly isolated granulocytes obtained from the peripheral blood of chronic myelogenous leukemia patients during the stable phase of the disease. In NB4 cells, two other synthetic nonselective RAR ligands are capable of inducing LAP as much as AM580, whereas RAR beta- or RAR gamma-specific ligands are totally ineffective. These results show that AM580 is more powerful than ATRA in modulating the expression of differentiation antigens only in cells in which PML-RAR is present. Binding experiments, using COS-7 cells transiently transfected with PML-RAR and the normal RAR alpha, show that AM580 has a lower affinity than ATRA for both receptors. However, in the presence of PML-RAR, the synthetic retinoid is a much better transactivator of retinoic acid-responsive element-containing promoters than the natural retinoid, whereas, in the presence of RAR alpha, AM580 and ATRA have similar activity. This may explain the strong cyto

  15. Negative prognostic value of CD34 antigen also if expressed on a small population of acute promyelocytic leukemia cells.

    PubMed

    Breccia, Massimo; De Propris, Maria Stefania; Stefanizzi, Caterina; Raponi, Sara; Molica, Matteo; Colafigli, Gioia; Minotti, Clara; Latagliata, Roberto; Diverio, Daniela; Guarini, Anna; Foà, Robin

    2014-11-01

    Potential clinical significance of CD34 expression in acute promyelocitic leukemia (APL) has not been deeply investigated. We hereby analyzed the clinico-biological features and treatment outcome of APL patients in relation to CD34 expression, even when expressed in a small subpopulation: 114 APL patients homogeneously treated with the AIDA schedule were included in the study and prognostic correlation with respect to CD34 expression, both when expressed in association with CD2 and as isolated expression (cutoff ≥2 to <10 % or ≥10 %), were investigated. CD34 was associated to CD2 in 30 patients and was isolated in 19 patients. When compared to the CD34-negative population, CD34/CD2 expression identified a subgroup with characteristic features: M3 variant subtype (26 vs 7 % in the negative group, p = 0.02), bcr3 transcript subtype (73 vs 32 %, p = 0.001), high risk according to the risk of relapse (66 vs 17 %, p = 0.002), high incidence of differentiation syndrome (26 vs 12 %, p = 0.01), lower overall survival (88 vs 95 %), and a significantly higher rate of relapse (22 vs 13.8 %, p = 0.05). We then evaluated the prognostic value of isolated CD34 expression: it was detected in nine patients with a cutoff of expression ≥10 % and in 10 patients with a cutoff ≥2 but <10 %. Isolated CD34 positivity identified a subgroup with a classic morphology (79 %), bcr1 prevalence (53 %), higher rate of relapse (37 vs 13.8 % in the negative group, p = 0.002), higher incidence of differentiation syndrome (55 vs 12 %, p = 0.03), and lower overall survival (60 vs 95 %, p = 0.001). The results of our study confirm that CD34/CD2 expression characterizes a subset of APL with a high WBC count and a variant morphological subtype, associated with an unfavorable clinical course. We also show that the isolated expression of CD34, even at a low cutoff, identifies a group of classic APL with a negative prognosis. Further studies aimed at identifying other

  16. Negative prognostic value of CD34 antigen also if expressed on a small population of acute promyelocytic leukemia cells.

    PubMed

    Breccia, Massimo; De Propris, Maria Stefania; Stefanizzi, Caterina; Raponi, Sara; Molica, Matteo; Colafigli, Gioia; Minotti, Clara; Latagliata, Roberto; Diverio, Daniela; Guarini, Anna; Foà, Robin

    2014-11-01

    Potential clinical significance of CD34 expression in acute promyelocitic leukemia (APL) has not been deeply investigated. We hereby analyzed the clinico-biological features and treatment outcome of APL patients in relation to CD34 expression, even when expressed in a small subpopulation: 114 APL patients homogeneously treated with the AIDA schedule were included in the study and prognostic correlation with respect to CD34 expression, both when expressed in association with CD2 and as isolated expression (cutoff ≥2 to <10 % or ≥10 %), were investigated. CD34 was associated to CD2 in 30 patients and was isolated in 19 patients. When compared to the CD34-negative population, CD34/CD2 expression identified a subgroup with characteristic features: M3 variant subtype (26 vs 7 % in the negative group, p = 0.02), bcr3 transcript subtype (73 vs 32 %, p = 0.001), high risk according to the risk of relapse (66 vs 17 %, p = 0.002), high incidence of differentiation syndrome (26 vs 12 %, p = 0.01), lower overall survival (88 vs 95 %), and a significantly higher rate of relapse (22 vs 13.8 %, p = 0.05). We then evaluated the prognostic value of isolated CD34 expression: it was detected in nine patients with a cutoff of expression ≥10 % and in 10 patients with a cutoff ≥2 but <10 %. Isolated CD34 positivity identified a subgroup with a classic morphology (79 %), bcr1 prevalence (53 %), higher rate of relapse (37 vs 13.8 % in the negative group, p = 0.002), higher incidence of differentiation syndrome (55 vs 12 %, p = 0.03), and lower overall survival (60 vs 95 %, p = 0.001). The results of our study confirm that CD34/CD2 expression characterizes a subset of APL with a high WBC count and a variant morphological subtype, associated with an unfavorable clinical course. We also show that the isolated expression of CD34, even at a low cutoff, identifies a group of classic APL with a negative prognosis. Further studies aimed at identifying other

  17. SB-715992 in Treating Patients With Acute Leukemia, Chronic Myelogenous Leukemia, or Advanced Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-01-10

    Acute Undifferentiated Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); 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); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

  18. Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-03-16

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Alkylating Agent-Related Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

  19. Laboratory-Treated Donor Cord Blood Cell Infusion Following Combination Chemotherapy in Treating Younger Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-09-26

    Acute Leukemia of Ambiguous Lineage; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Alkylating Agent-Related Acute Myeloid Leukemia; Childhood Acute Myeloid Leukemia in Remission; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  20. Acute otitis media in adults: many unknowns.

    PubMed

    2003-06-01

    (1) Acute otitis media is likely in adults with recent-onset otalgia, fever, and a bulging eardrum on otoscopy. Management is similar to that in children: no antibiotics in the first instance, then amoxicillin later if antibiotic therapy is needed. (2) Otitis media with a perforated eardrum, and evidence of pus must be distinguished from external otitis. In patients with otitis media and a perforated eardrum, the commonest bacterial isolates are staphylococci, pseudomonas and pneumococci. (3) If antibiotics are prescribed the choice of agent is based on individual clinical findings and underlying health status.

  1. Cytarabine With or Without SCH 900776 in Treating Adult Patients With Relapsed Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-20

    Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia

  2. Lenalidomide, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-12-22

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Alkylating Agent-Related Acute Myeloid Leukemia; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome; Untreated Adult Acute Myeloid Leukemia

  3. 7-Hydroxystaurosporine and Perifosine in Treating Patients With Relapsed or Refractory Acute Leukemia, Chronic Myelogenous Leukemia or High Risk Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-09-27

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); 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); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Myelodysplastic/Myeloproliferative Neoplasms; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; T-cell Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  4. Sorafenib in Treating Patients With Refractory or Relapsed Acute Leukemia, Myelodysplastic Syndromes, or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-04-27

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Blastic Phase; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome

  5. Vorinostat, Cytarabine, and Etoposide in Treating Patients With Relapsed and/or Refractory Acute Leukemia or Myelodysplastic Syndromes or Myeloproliferative Disorders

    ClinicalTrials.gov

    2013-05-01

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); 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); Adult Acute Myelomonocytic Leukemia (M4); Adult Acute Promyelocytic Leukemia (M3); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; de Novo Myelodysplastic Syndromes; Essential Thrombocythemia; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Polycythemia Vera; Previously Treated Myelodysplastic Syndromes; Primary Myelofibrosis; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  6. Acute necrotising ulcerative gingivitis in an immunocompromised young adult.

    PubMed

    Hu, Jessie; Kent, Paul; Lennon, Joshua M; Logan, Latania K

    2015-01-01

    Acute necrotising ulcerative gingivitis is an acute onset disease characterised by ulceration, necrosis, pain and bleeding in gingival surfaces. It is predominantly seen in severely malnourished children and young adults with advanced HIV infection. We present a unique presentation in a young adult with high-grade osteogenic sarcoma.

  7. Establishment of a retinoic acid-resistant human acute promyelocytic leukaemia (APL) model in human granulocyte-macrophage colony-stimulating factor (hGM-CSF) transgenic severe combined immunodeficiency (SCID) mice.

    PubMed Central

    Fukuchi, Y.; Kizaki, M.; Kinjo, K.; Awaya, N.; Muto, A.; Ito, M.; Kawai, Y.; Umezawa, A.; Hata, J.; Ueyama, Y.; Ikeda, Y.

    1998-01-01

    To understand the mechanisms and identify novel approaches to overcoming retinoic acid (RA) resistance in acute promyelocytic leukaemia (APL), we established the first human RA-resistant APL model in severe combined immunodeficiency (SCID) mice. UF-1 cells, an RA-resistant APL cell line established in our laboratory, were transplanted into human granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing SCID (hGMTg SCID) mice and inoculated cells formed subcutaneous tumours in all hGMTg SCID mice, but not in the non-transgenic control SCID mice. Single-cell suspensions (UF-1/GMTg SCID cells) were similar in morphological, immunological, cytogenetic and molecular genetic features to parental UF-1 cells. All-trans RA did not change the morphological features of cells or their expression of CD11b. RA did not alter the growth curve of cells as determined by MTT assay, suggesting that UF-1/GMTg SCID cells are resistant to RA. These results demonstrate that this is the first RA-resistant APL animal model that may be useful for investigating the biology of this myeloid leukaemia in vivo, as well as for evaluating novel therapeutic approaches including patients with RA-resistant APL. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:9764578

  8. High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese Paediatric Leukaemia/Lymphoma Study Group.

    PubMed

    Takahashi, Hiroyuki; Watanabe, Tomoyuki; Kinoshita, Akitoshi; Yuza, Yuki; Moritake, Hiroshi; Terui, Kiminori; Iwamoto, Shotaro; Nakayama, Hideki; Shimada, Akira; Kudo, Kazuko; Taki, Tomohiko; Yabe, Miharu; Matsushita, Hiromichi; Yamashita, Yuka; Koike, Kazutoshi; Ogawa, Atsushi; Kosaka, Yoshiyuki; Tomizawa, Daisuke; Taga, Takashi; Saito, Akiko M; Horibe, Keizo; Nakahata, Tatsutoshi; Miyachi, Hayato; Tawa, Akio; Adachi, Souichi

    2016-08-01

    We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered.

  9. PLZF-RAR[alpha] fusion proteins generated from the variant t(11; 17)(q23; q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors

    SciTech Connect

    Chen, Zhu; Chen, Sai-Juan; Wang, Zhen-Yi ); Guidez, F.; Rousselot, P.; Agadir, A.; Degos, L.; Chomienne, C. ); Zelent, A. ); Waxman, S. )

    1994-02-01

    Recently, the authors described a recurrent variant translocation, t(11;17)(q23;q21), in acute promyelocytic leukemia (APL) which juxtaposes PLZF, a gene encoding a zinc finger protein, to RARA, encoding retinoic acid receptor [alpha] (RAR[alpha]). They have now cloned cDNAs encoding PLZF-RAR[alpha] chimeric proteins and studied their transactivating activities. In transient-expression assays, both the PLZF(A)-RAR[alpha] and PLZF(B)-RAR[alpha] fusion proteins like the PML-RAR[alpha] protein resulting from the well-known t(15;17) translocation in APL, antagonized endogenous and transfected wild-type RAR[alpha] in the presence of retinoic acid. Cotransfection assays showed that a significant repression of RAR[alpha] transactivation activity was obtained even with a very low PLZF-RAR[alpha]-expressing plasmid concentration. A [open quotes]dominant negative[close quotes] effect was observed with vectors expressing RAR[alpha] and retinoid X receptor [alpha] (RXR[alpha]). These abnormal transactivation properties observed in retinoic acid-sensitive myeloid cells strongly implicate the PLZF-RAR[alpha] fusion proteins in the molecular pathogenesis of APL.

  10. New Role for Granulocyte Colony-Stimulating Factor-Induced Extracellular Signal-Regulated Kinase 1/2 in Histone Modification and Retinoic Acid Receptor α Recruitment to Gene Promoters: Relevance to Acute Promyelocytic Leukemia Cell Differentiation ▿

    PubMed Central

    Cassinat, B.; Zassadowski, F.; Ferry, C.; Llopis, L.; Bruck, N.; Lainey, E.; Duong, V.; Cras, A.; Despouy, G.; Chourbagi, O.; Beinse, G.; Fenaux, P.; Rochette Egly, C.; Chomienne, C.

    2011-01-01

    The induction of the granulocytic differentiation of leukemic cells by all-trans retinoic acid (RA) has been a major breakthrough in terms of survival for acute promyelocytic leukemia (APL) patients. Here we highlight the synergism and the underlying novel mechanism between RA and the granulocyte colony-stimulating factor (G-CSF) to restore differentiation of RA-refractory APL blasts. First, we show that in RA-refractory APL cells (UF-1 cell line), PML-RA receptor alpha (RARα) is not released from target promoters in response to RA, resulting in the maintenance of chromatin repression. Consequently, RARα cannot be recruited, and the RA target genes are not activated. We then deciphered how the combination of G-CSF and RA successfully restored the activation of RA target genes to levels achieved in RA-sensitive APL cells. We demonstrate that G-CSF restores RARα recruitment to target gene promoters through the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the subsequent derepression of chromatin. Thus, combinatorial activation of cytokines and RARs potentiates transcriptional activity through epigenetic modifications induced by specific signaling pathways. PMID:21262770

  11. Veliparib and Temozolomide in Treating Patients With Acute Leukemia

    ClinicalTrials.gov

    2016-07-20

    Accelerated Phase of Disease; Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult B Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1; Adult T Acute Lymphoblastic Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Blastic Phase; Chronic Myelomonocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  12. Topical NSAIDs for acute pain in adults

    PubMed Central

    Massey, Thomas; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Use of topical NSAIDs to treat acute musculoskeletal conditions is widely accepted in some parts of the world, but not in others. Their main attraction is their potential to provide pain relief without associated systemic adverse events. Objectives To review the evidence from randomised, double-blind, controlled trials on the efficacy and safety of topically applied NSAIDs in acute pain. Search methods We searched MEDLINE, EMBASE, The Cochrane Library, and our own in-house database to December 2009. We sought unpublished studies by asking personal contacts and searching on-line clinical trial registers and manufacturers web sites. Selection criteria We included randomised, double-blind, active or placebo (inert carrier)-controlled trials in which treatments were administered to adult patients with acute pain resulting from strains, sprains or sports or overuse-type injuries (twisted ankle, for instance). There had to be at least 10 participants in each treatment arm, with application of treatment at least once daily. Data collection and analysis Two review authors independently assessed trial quality and validity, and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. Main results Forty-seven studies were included; most compared topical NSAIDs in the form of a gel, spray, or cream with a similar placebo, with 3455 participants in the overall analysis of efficacy. For all topical NSAIDs combined, compared with placebo, the number needed to treat to benefit (NNT) for clinical success, equivalent to 50% pain relief, was 4.5 (3.9 to 5.3) for treatment periods of 6 to 14 days. Topical diclofenac, ibuprofen, ketoprofen, and piroxicam were of similar efficacy, but indomethacin and benzydamine were not significantly better than placebo. Local skin reactions were generally mild and transient, and did not differ from

  13. Phase I Dose-Escalation Trial of Clofarabine Followed by Escalating Doses of Fractionated Cyclophosphamide in Children With Relapsed or Refractory Acute Leukemias

    ClinicalTrials.gov

    2010-09-21

    Myelodysplastic Syndrome; Acute Myeloid Leukemia; Myeloproliferative Disorders; Acute Lymphocytic Leukemia; Acute Promyelocytic Leukemia; Acute Leukemia; Chronic Myelogenous Leukemia; Myelofibrosis; Chronic Myelomonocytic Leukemia; Juvenile Myelomonocytic Leukemia

  14. Synergistic decrease of clonal proliferation, induction of differentiation, and apoptosis of acute promyelocytic leukemia cells after combined treatment with novel 20-epi vitamin D3 analogs and 9-cis retinoic acid.

    PubMed Central

    Elstner, E; Linker-Israeli, M; Le, J; Umiel, T; Michl, P; Said, J W; Binderup, L; Reed, J C; Koeffler, H P

    1997-01-01

    Patients with acute promyelocytic leukemia (APL) usually relapse after all-trans retinoic acid (RA) treatment because this therapy fails to eradicate the malignant clone. Our data showed that KH 1060 and other 20-epi vitamin D3 analogs alone were potent inhibitors of clonal growth of NB4 cells, an APL cell line (ED50, approximately 5 x 10(-11) M). The combination of KH 1060 and 9-cis-RA synergistically and irreversibly enhanced this effect. Neither KH 1060 nor 9-cis-RA (10(-6) M, 3 d) were strong inducers of differentiation of NB4 cells. However, 98% of the cells underwent differentiation to a mature phenotype with features of both granulocytes and monocytes after exposure to a combination of both compounds. Apoptosis only increased after incubation of NB4 cells with 9-cis-RA alone (28%) or with a combination of 9-cis-RA plus KH1060 (32%). Immunohistochemistry showed that the bcl-2 protein decreased from nearly 100% of the wild-type NB4 cells to 2% after incubation with a combination of KH 1060 and 9-cis-RA, and the bax protein increased from 50% of wild-type NB4 cells to 92% after culture with both analogs (5 x 10(-7) M, 3 d). Western blot analysis paralleled these results. Studies of APL cells from one untreated individual paralleled our results with NB4 cells. Taken together, the data demonstrated that nearly all of the NB4 cells can be irreversibly induced to differentiate terminally when exposed to the combination of KH 1060 and 9-cis-RA. PMID:9006004

  15. Granulocyte colony-stimulating factor potentiates differentiation induction by all-trans retinoic acid and arsenic trioxide and enhances arsenic uptake in the acute promyelocytic leukemia cell line HT93A.

    PubMed

    Iriyama, Noriyoshi; Yuan, Bo; Hatta, Yoshihiro; Horikoshi, Akira; Yoshino, Yuta; Toyoda, Hiroo; Aizawa, Shin; Takeuchi, Jin

    2012-11-01

    The effects of arsenic trioxide (ATO), all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF), alone or in combination, were investigated by focusing on differentiation, growth inhibition and arsenic uptake in the acute promyelocytic leukemia (APL) cell line HT93A. ATO induced differentiation at low concentrations (0.125 µM) and apoptosis at high concentrations (1-2 µM). Furthermore, ATRA induced greater differentiation than ATO. No synergistic effect of ATRA and ATO was found on differentiation. G-CSF promoted differentiation-inducing activities of both ATO and ATRA. The combination of ATRA and G-CSF showed maximum differentiation and ATO addition was not beneficial. Addition of 1 µM ATRA and/or 50 ng/ml G-CSF to ATO did not affect apoptosis compared to ATO treatment alone. ATRA induced expression of aquaporin-9 (AQP9), a transmembrane transporter recognized as a major pathway of arsenic uptake, in a time- and dose-dependent manner. However, treatment with 1 µM ATRA decreased arsenic uptake by 43.7% compared to control subject. Although G-CSF addition did not enhance AQP9 expression in the cells, the reduced arsenic uptake was recovered to the same level as that in controls. ATRA decreased cell viability and addition of 50 ng/ml G-CSF to ATRA significantly increased the number of viable cells compared with that in ATRA alone treated cells. G-CSF not only promotes differentiation-inducing activities of both ATRA and ATO, but also makes APL cells vulnerable to increased arsenic uptake. These observations provide new insights into combination therapy using these three agents for the treatment of APL.

  16. All-trans retinoic acid with daunorubicin or idarubicin for risk-adapted treatment of acute promyelocytic leukaemia: a matched-pair analysis of the PETHEMA LPA-2005 and IC-APL studies.

    PubMed

    Sanz, Miguel A; Montesinos, Pau; Kim, Haesook T; Ruiz-Argüelles, Guillermo J; Undurraga, María S; Uriarte, María R; Martínez, Lem; Jacomo, Rafael H; Gutiérrez-Aguirre, Homero; Melo, Raul A M; Bittencourt, Rosane; Pasquini, Ricardo; Pagnano, Katia; Fagundes, Evandro M; Vellenga, Edo; Holowiecka, Alexandra; González-Huerta, Ana J; Fernández, Pascual; De la Serna, Javier; Brunet, Salut; De Lisa, Elena; González-Campos, José; Ribera, José M; Krsnik, Isabel; Ganser, Arnold; Berliner, Nancy; Ribeiro, Raul C; Lo-Coco, Francesco; Löwenberg, Bob; Rego, Eduardo M

    2015-08-01

    Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two entire cohorts. Complete remission (CR) rate was significantly higher in the PETHEMA/HOVON (94 %) than in the IC-APL cohort (85 %) (P = 0.002). The distribution of causes of induction failure and the time to achieve CR were similar in both cohorts. Patients who achieved CR had comparable cumulative incidence of relapse and disease-free survival rates, but lower overall and event-free survivals were observed in the IC-APL cohort, which was mainly due to a higher death rate during induction therapy. A higher death rate during consolidation therapy was also observed in the IC-APL. These results show that daunorubicin and idarubicin have similar antileukaemic efficacy in terms of primary resistance, molecular persistence, as well as molecular and haematological relapse rates when combined with ATRA in treatment of APL. However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at www.clinicaltrials.gov as #NCT00408278 [ClinicalTrials.gov]. PMID:25975975

  17. Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group.

    PubMed

    Tallman, Martin S; Kim, Haesook T; Montesinos, Pau; Appelbaum, Frederick R; de la Serna, Javier; Bennett, John M; Deben, Guillermo; Bloomfield, Clara D; Gonzalez, Jose; Feusner, James H; Gonzalez, Marcos; Gallagher, Robert; Miguel, Jose D Gonzalez-San; Larson, Richard A; Milone, Gustavo; Paietta, Elisabeth; Rayon, Chelo; Rowe, Jacob M; Rivas, Concha; Schiffer, Charles A; Vellenga, Edo; Shepherd, Lois; Slack, James L; Wiernik, Peter H; Willman, Cheryl L; Sanz, Miguel A

    2010-12-16

    Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-trans retinoic acid-based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapéutica en Hemopatía Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL.

  18. Agents for refractory/relapsed acute lymphocytic leukemia in adults.

    PubMed

    Qian, L-R; Fu, W; Shen, J-L

    2014-01-01

    Although treatment results for adult acute lymphoblastic leukemia (ALL) have improved considerably in the past decades, treating adult patients with relapsed/refractory acute lymphocytic leukemia (ALL) is still difficult. Adults with refractory/relapsed acute lymphocytic leukemia (ALL) processed to death rapidly associated with chemotherapy resistance, high mortality by reinduction, etc. Only 20% to 30% of those patients acquired complete remission (CR). Those patients are always of short duration unless an allogeneic stem cell transplant is feasible. Median survival is only ranging from 2 to 12 months. Therapeutic strategy on relapsed/refractory acute lymphocytic leukemia (ALL) is always a major therapeutic challenge bothering hematological researchers. Novel agents and unique therapeutic strategies have been developed in recent years. This review focuses on major clinical advances in the agents for refractory/relapsed ALL.

  19. Older adults experiences of rehabilitation in acute health care.

    PubMed

    Atwal, Anita; Tattersall, Kirsty; Murphy, Susana; Davenport, Neil; Craik, Christine; Caldwell, Kay; McIntyre, Anne

    2007-09-01

    Rehabilitation is a key component of nursing and allied healthcare professionals' roles in most health and social care settings. This paper reports on stage 2 of an action research project to ascertain older adult's experience of rehabilitation. Twenty postdischarge interviews were conducted and the interview transcripts were analysed using thematic content analysis. All older adults discharged from an acute older acute rehabilitation ward to their own homes in the community were eligible to participate. The only exclusion criterion was older adults who were thought to be unable to give consent to participate by the nurse in charge and the researcher. Whilst 92 older adults were eligible to participate in this research study, only 20 were interviewed. The findings from this study suggest that older adults valued communication with health professionals but were aware of their time constraints that hindered communication. This study suggests that both nurses and allied health professionals are not actively providing rehabilitative services to promote health and well-being, which contradicts the focus of active ageing. Furthermore, there was evidence of unmet needs on discharge, and older adults unable to recall the professions that were involved in their interventions and the rationale for therapy input. It is suggested that further research is needed to explore the effectiveness of allied health rehabilitation in the acute setting. This study highlights the need for further research into older adults' perceptions of the rehabilitation process in the acute setting.

  20. Restoration of CCAAT enhancer binding protein α P42 induces myeloid differentiation and overcomes all-trans retinoic acid resistance in human acute promyelocytic leukemia NB4-R1 cells

    PubMed Central

    WANG, LIMENGMENG; XIAO, HAOWEN; ZHANG, XING; LIAO, WEICHAO; FU, SHAN; HUANG, HE

    2015-01-01

    All-trans retinoic acid (ATRA) is one of the first line agents in differentiation therapy for acute promyelocytic leukemia (APL). However, drug resistance is a major problem influencing the efficacy of ATRA. Identification of mechanisms of ATRA resistance are urgenly needed. In the present study, we found that expression of C/EBPα, an important transcription factor for myeloid differentiation, was significantly suppressed in ATRA resistant APL cell line NB4-R1 compared with ATRA sensitive NB4 cells. Moreover, two forms of C/EBPα were unequally suppressed in NB4-R1 cells. Suppression of the full-length form P42 was more pronounced than the truncated form P30. Inhibition of PI3K/Akt/mTOR pathway was also observed in NB4-R1 cells. Moreover, C/EBPα expression was reduced by PI3K inhibitor LY294002 and mTOR inhibitor RAD001 in NB4 cells, suggesting that inactivation of the PI3K/Akt/mTOR pathway was responsible for C/EBPα suppression in APL cells. We restored C/EBPα P42 and P30 by lentivirus vectors in NB4-R1 cells, respectively, and found C/EBPα P42, but not P30, could increase CD11b, CD14, G-CSFR and GM-CSFR expression, which indicated the occurrence of myeloid differentiation. Further upregulating of CD11b expression and differential morphological changes were found in NB4-R1 cells with restored C/EBPα P42 after ATRA treatment. However, CD11b expression and differential morphological changes could not be induced by ATRA in NB4-R1 cells infected with P30 expressing or control vector. Thus, we inferred that ATRA sensitivity of NB4-R1 cells was enhanced by restoration of C/EBPα P42. In addition, we used histone deacetylase inhibitor trichostatin (TSA) to restore C/EBPα expression in NB4-R1 cells. Similar enhancement of myeloid differentiation and cell growth arrest were detected. Together, the present study demonstrated that suppression of C/EBPα P42 induced by PI3K/Akt/mTOR inhibition impaired the differentiation and ATRA sensitivity of APL cells. Restoring C

  1. Acute myocardial infarction in young adults: causes and management

    PubMed Central

    Osula, S; Bell, G; Hornung, R

    2002-01-01

    The case report in this review illustrates an acute myocardial infarction in a young adult probably due to arterial thrombosis that can be attributed to a hypercoagulable state resulting from the nephrotic syndrome. Although rare, acute myocardial infarction should be considered in young adults presenting with chest pain. A detailed clinical history may help to identify the aetiology, and guide subsequent management, but diagnostic coronary angiography is essential. Careful risk factor modification and treatment of the underlying cause should reduce the incidence of recurrent cardiac events. PMID:11796868

  2. Acute abdomen in adult Celiac disease: an intestinal intussusception case.

    PubMed

    Makay, Ozer; Kazimi, Mircelal; Doğanavşargil, Başak; Osmanoğlu, Necla; Yilmaz, Mustafa

    2007-06-01

    It is well known that half of the cases admitted to hospital emergency services complain of abdominal pain and that nearly half of these cases are diagnosed with nonspecific abdominal pain. The population of patients with celiac sprue is rarely encountered at the emergency room. Although acute abdominal pain is rarely seen in adult celiac sprue, it should be added to the differential diagnosis. It should also be remembered that acute abdominal pain in these patients could be originating from perforation, intussusceptions and/or intestinal lymphoma. Herein we report a case of adult celiac sprue where successful surgical exploration was carried out because of entero-enteral intussusception. PMID:17602358

  3. Acute moderate exercise enhances compensatory brain activation in older adults.

    PubMed

    Hyodo, Kazuki; Dan, Ippeita; Suwabe, Kazuya; Kyutoku, Yasushi; Yamada, Yuhki; Akahori, Mitsuya; Byun, Kyeongho; Kato, Morimasa; Soya, Hideaki

    2012-11-01

    A growing number of reports state that regular exercise enhances brain function in older adults. Recently a functional near-infrared spectroscopy (fNIRS) study revealed that an acute bout of moderate exercise enhanced activation of the left dorsolateral prefrontal cortex (L-DLPFC) associated with Stroop interference in young adults. Whether this acute effect is also applicable to older adults was examined. Sixteen older adults performed a color-word matching Stroop task before and after 10 minutes of exercise on a cycle ergometer at a moderate intensity. Cortical hemodynamics of the prefrontal area was monitored with a fNIRS during the Stroop task. We analyzed Stroop interference (incongruent-neutral) as Stroop performance. Though activation for Stroop interference was found in the bilateral prefrontal area before the acute bout of exercise, activation of the right frontopolar area (R-FPA) was enhanced after exercise. In the majority of participants, this coincided with improved performance reflected in Stroop interference results. Thus, an acute bout of moderate exercise improved Stroop performance in older adults, and this was associated with contralateral compensatory activation. PMID:22300952

  4. Acute moderate exercise enhances compensatory brain activation in older adults.

    PubMed

    Hyodo, Kazuki; Dan, Ippeita; Suwabe, Kazuya; Kyutoku, Yasushi; Yamada, Yuhki; Akahori, Mitsuya; Byun, Kyeongho; Kato, Morimasa; Soya, Hideaki

    2012-11-01

    A growing number of reports state that regular exercise enhances brain function in older adults. Recently a functional near-infrared spectroscopy (fNIRS) study revealed that an acute bout of moderate exercise enhanced activation of the left dorsolateral prefrontal cortex (L-DLPFC) associated with Stroop interference in young adults. Whether this acute effect is also applicable to older adults was examined. Sixteen older adults performed a color-word matching Stroop task before and after 10 minutes of exercise on a cycle ergometer at a moderate intensity. Cortical hemodynamics of the prefrontal area was monitored with a fNIRS during the Stroop task. We analyzed Stroop interference (incongruent-neutral) as Stroop performance. Though activation for Stroop interference was found in the bilateral prefrontal area before the acute bout of exercise, activation of the right frontopolar area (R-FPA) was enhanced after exercise. In the majority of participants, this coincided with improved performance reflected in Stroop interference results. Thus, an acute bout of moderate exercise improved Stroop performance in older adults, and this was associated with contralateral compensatory activation.

  5. Epidemiology of Acute Symptomatic Seizures among Adult Medical Admissions

    PubMed Central

    Nwani, Paul Osemeke; Nwosu, Maduaburochukwu Cosmas; Nwosu, Monica Nonyelum

    2016-01-01

    Acute symptomatic seizures are seizures occurring in close temporal relationship with an acute central nervous system (CNS) insult. The objective of the study was to determine the frequency of presentation and etiological risk factors of acute symptomatic seizures among adult medical admissions. It was a two-year retrospective study of the medical files of adults patients admitted with acute symptomatic seizures as the first presenting event. There were 94 cases of acute symptomatic seizures accounting for 5.2% (95% CI: 4.17–6.23) of the 1,802 medical admissions during the period under review. There were 49 (52.1%) males and 45 (47.9%) females aged between 18 years and 84 years. The etiological risk factors of acute symptomatic seizures were infections in 36.2% (n = 34) of cases, stroke in 29.8% (n = 28), metabolic in 12.8% (n = 12), toxic in 10.6% (n = 10), and other causes in 10.6% (n = 10). Infective causes were more among those below fifty years while stroke was more in those aged fifty years and above. CNS infections and stroke were the prominent causes of acute symptomatic seizures. This is an evidence of the “double tragedy” facing developing countries, the unresolved threat of infectious diseases on one hand and the increasing impact of noncommunicable diseases on the other one. PMID:26904280

  6. Sex disparity in childhood and young adult acute myeloid leukemia (AML) survival: Evidence from US population data.

    PubMed

    Hossain, Md Jobayer; Xie, Li

    2015-12-01

    Sex variation has been persistently investigated in studies concerning acute myeloid leukemia (AML) survival outcomes but has not been fully explored among pediatric and young adult AML patients. We detected sex difference in the survival of AML patients diagnosed at ages 0-24 years and explored distinct effects of sex across subgroups of age at diagnosis, race-ethnicity and AML subtypes utilizing the United States Surveillance Epidemiology and End Results (SEER) population based dataset of 4865 patients diagnosed with AML between 1973 and 2012. Kaplan-Meier survival function, propensity scores and stratified Cox proportional hazards regression were used for data analyses. After controlling for other prognostic factors, females showed a significant survival advantage over their male counterparts, adjusted hazard ratio (aHR, 95% confidence interval (CI): 1.09, 1.00-1.18). Compared to females, male patients had substantially increased risk of mortality in the following subgroups of: ages 20-24 years at diagnosis (aHR1.30), Caucasian (1.14), acute promyelocytic leukemia (APL) (1.35), acute erythroid leukemia (AEL) (1.39), AML with inv(16)(p13.1q22) (2.57), AML with minimum differentiation (1.47); and had substantially decreased aHR in AML t(9;11)(p22;q23) (0.57) and AML with maturation (0.82). Overall, females demonstrated increased survival over males and this disparity was considerably large in patients ages 20-24 years at diagnosis, Caucasians, and in AML subtypes of AML inv(16), APL and AEL. In contrast, males with AML t(9;11)(p22;q23), AML with maturation and age at diagnosis of 10-14 years showed survival benefit. Further investigations are needed to detect the biological processes influencing the mechanisms of these interactions.

  7. Adult Acute Myeloid Leukemia Long-term Survivors

    PubMed Central

    Cheng, M. Jennifer; Hourigan, Christopher S.; Smith, Thomas J.

    2014-01-01

    The number of leukemia patients and survivors is growing. This review summarizes what is known regarding the health related quality of life (HRQOL) and medical complications associated with acute myeloid leukemia (AML) disease and treatment and highlights understudied aspects of adult AML survivorship care, and potential novel areas for intervention. PMID:25243197

  8. Treatment of Acute Promyelocytic (M3) Leukemia

    MedlinePlus

    ... to give ATRA plus another differentiating drug called arsenic trioxide (Trisenox). This is often used in patients ... anthracycline plus cytarabine for at least 2 cycles Arsenic trioxide for 2 cycles (over about 2½ months), ...

  9. Acute myeloid leukemia in the older adults.

    PubMed

    Almeida, Antonio M; Ramos, Fernando

    2016-01-01

    AML is an aggressive hematological malignancy with highest incidence in the older adults. The adverse features of AML in the elderly, and the frailties and comorbidities frequently present in them, make their management a particularly difficult therapeutic challenge. In this context, it is important to assess carefully patient- as well as disease-associated prognostic features with validated tools. The fittest patients should be considered for curative therapy, such as bone marrow transplantation, whereas low intensity options may be more appropriate for frail patients. Here we review how to assess patients with elderly AML and the treatments options available for them. PMID:27408788

  10. Pericardial Tamponade in an Adult Suffering from Acute Mumps Infection

    PubMed Central

    Flieger, Robert Rainer; Mankertz, Annette; Yilmaz, Kadir; Roepke, Torsten Kai

    2016-01-01

    Here, we report a case of a 51-year-old man with acute pericardial tamponade requiring emergency pericardiocentesis after he suffered from sore throat, headache, malaise, and sweats for two weeks. Serological analyses revealed increased mumps IgM and IgG indicating an acute mumps infection whereas other bacterial and viral infections were excluded. In addition, MRI revealed atypical swelling of the left submandibular gland. Whereas mumps has become a rare entity in children due to comprehensive vaccination regimens in western civilizations, our case highlights mumps as an important differential diagnosis also in adults, where the virus can induce life-threatening complications such as pericardial tamponade.

  11. Acute injuries and specific problems in adult athletes.

    PubMed

    Barry, N N; McGuire, J L

    1996-08-01

    Special considerations need to be given to specific groups of adult athletes. The most common problems and needs of female and older athletes are discussed in the first section of this article. The second section reviews the diagnosis and management of certain acute injuries most frequently encountered in adult athletes. The last section discusses the differentiation between tarsal tunnel syndrome and plantar fasciitis, chronic compartmental pressure syndrome and medial tibial stress syndrome ("shin splints"), and pelvic stress fractures and osteitis pubis, some commonly encountered difficult diagnoses.

  12. Multiple Chronic Conditions in Older Adults with Acute Coronary Syndromes.

    PubMed

    Alfredsson, Joakim; Alexander, Karen P

    2016-05-01

    Older adults presenting with acute coronary syndromes (ACSs) often have multiple chronic conditions (MCCs). In addition to traditional cardiovascular (CV) risk factors (ie, hypertension, hyperlipidemia, and diabetes), common CV comorbidities include heart failure, stroke, and atrial fibrillation, whereas prevalent non-CV comorbidities include chronic kidney disease, anemia, depression, and chronic obstructive pulmonary disease. The presence of MCCs affects the presentation (eg, increased frequency of type 2 myocardial infarctions [MIs]), clinical course, and prognosis of ACS in older adults. In general, higher comorbidity burden increases mortality following MI, reduces utilization of ACS treatments, and increases the importance of developing individualized treatment plans. PMID:27113147

  13. Adult midgut malrotation presented with acute bowel obstruction and ischemia

    PubMed Central

    Zengin, Akile; Uçar, Bercis İmge; Düzgün, Şükrü Aydın; Bayhan, Zülfü; Zeren, Sezgin; Yaylak, Faik; Şanal, Bekir; Bayhan, Nilüfer Araz

    2016-01-01

    Introduction Intestinal malrotation refers to the partial or complete failure of rotation of midgut around the superior mesenteric vessels in embryonic life. Arrested midgut rotation results due to narrow-based mesentery and increases the risk of twisting midgut and subsequent obstruction and necrosis. Presentation of case 40 years old female patient admitted to emergency service with acute abdomen and computerized tomography scan showed dilated large and small intestine segments with air-fluid levels and twisted mesentery around superior mesenteric artery and vein indicating “whirpool sign”. Discussion Malrotation in adults is a rare cause of midgut volvulus as though it should be considered in differential diagnosis in patients presented with acute abdomen and intestinal ischemia. Even though clinical symptoms are obscure, adult patients usually present with vomiting and recurrent abdominal pain due to chronic partial obstruction. Contrast enhanced radiograph has been shown to be the most accurate method. Typical radiological signs are corkscrew sign, which is caused by the dilatation of various duodenal segments at different levels and the relocation of duodenojejunal junction due to jejunum folding. As malrotation commonly causes intestinal obstruction, patients deserve an elective laparotomy. Conclusion Malrotation should be considered in differential diagnosis in patients presented with acute abdomen and intestinal ischemia. Surgical intervention should be prompt to limit morbidity and mortality. PMID:27015011

  14. PHF6 mutations in adult acute myeloid leukemia.

    PubMed

    Van Vlierberghe, P; Patel, J; Abdel-Wahab, O; Lobry, C; Hedvat, C V; Balbin, M; Nicolas, C; Payer, A R; Fernandez, H F; Tallman, M S; Paietta, E; Melnick, A; Vandenberghe, P; Speleman, F; Aifantis, I; Cools, J; Levine, R; Ferrando, A

    2011-01-01

    Loss of function mutations and deletions encompassing the plant homeodomain finger 6 (PHF6) gene are present in about 20% of T-cell acute lymphoblastic leukemias (ALLs). Here, we report the identification of recurrent mutations in PHF6 in 10/353 adult acute myeloid leukemias (AMLs). Genetic lesions in PHF6 found in AMLs are frameshift and nonsense mutations distributed through the gene or point mutations involving the second plant homeodomain (PHD)-like domain of the protein. As in the case of T-ALL, where PHF6 alterations are found almost exclusively in males, mutations in PHF6 were seven times more prevalent in males than in females with AML. Overall, these results identify PHF6 as a tumor suppressor gene mutated in AML and extend the role of this X-linked tumor suppressor gene in the pathogenesis of hematologic tumors.

  15. Acute febrile encephalopathy in adults from Northwest India

    PubMed Central

    Bhalla, Ashish; Suri, Vika; Varma, Subhash; Sharma, Navneet; Mahi, Sushil; Singh, Paramjeet; Khandelwal, Niranjan K

    2010-01-01

    Background: Acute onset fever with altered mentation is a common problem encountered by the physician practicing in tropical countries. Central nervous system (CNS) infections are the most common cause resulting in fever with altered mentation in children. Aim: In this study, we have tried to analyze the cause of encephalopathy following short febrile illness in adults presenting to a tertiary care center in Northwestern part of India. Setting and Design: A prospective observational study carried out in a tertiary care center in the Northwestern India over a period of 1 year. Material and Methods A total of 127 patients with fever of less than 2 weeks duration along with alteration in mentation were studied prospectively over a period of 12 months. The demographic variables were recorded in detail. In addition to routine investigations, cerebrospinal fluid analysis, noncontrast- and contrast-enhanced computed tomography, along with magnetic resonance imaging were performed in all the subjects. Statistical Analysis The results were analyzed using SPSS statistical software. The values were expressed as mean with standard deviation for contiguous variable as percentage for the others. Results and Conclusion Out of these, 70% had primary CNS infection as the etiology. A total of 33% patients had meningitis, 29.9% had evidence of meningoencephalitis, and 12.7% were diagnosed as sepsis-associated encephalopathy. These were followed by cerebral malaria, leptospirosis, and brain abscess as the cause of febrile encephalopathy in adults. Among the noninfectious causes, acute disseminated encephalomyelitis, cortical venous thrombosis, and neuroleptic malignant syndrome were documented in 2.36% each. In 11% of the patients, the final diagnosis could not be made in spite of the extensive investigations. Our study demonstrates that acute febrile encephalopathy in adults is a heterogeneous syndrome with primary CNS infections being the commonest etiology. PMID:20930964

  16. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    PubMed

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL). PMID:27000734

  17. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    PubMed

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL).

  18. [Nursing diagnosis in adult patients with acute myeloid leukemia].

    PubMed

    de Souza, Luccas Melo; Gorini, Maria Isabel Pinto Coelho

    2006-09-01

    This case study aimed at identifying Nursing Diagnosis (ND) in adult patients with Acute Myeloid Leukemia, with the purpose of contributing to the Systematization of Nurse Care. Interviews and observation were used for data collection, in addition to Nursing Process application. During the three months of data collection, other NDs were obtained by searching the files of the 6 patients. The 32 ND found in this study were grouped according to Maslow's hierarchy of needs. Out of these 32 ND, 15 corresponded to changes in Physiological Needs, and 10 to changes in Protection and Safety Needs.

  19. Topical rubefacients for acute and chronic pain in adults

    PubMed Central

    Matthews, Paul; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Rubefacients (containing salicylates or nicotinamides) cause irritation of the skin, and are believed to relieve various musculoskeletal pains. They are available on prescription, and are common components in over-the-counter remedies. A non-Cochrane review in 2004 found limited evidence for efficacy. Objectives To review current evidence for efficacy and safety of topically applied rubefacients in acute and chronic painful musculoskeletal conditions in adults. Search methods Cochrane CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database, and reference lists of articles were searched; last search December 2008. Selection criteria Randomised, double blind, placebo or active controlled clinical trials of topical rubefacient for musculoskeletal pain in adults, with at least 10 participants per treatment arm, and reporting outcomes at close to 7 (minimum 3, maximum 10) days for acute conditions and 14 (minimum 7) days or longer for chronic conditions. Data collection and analysis Two review authors independently assessed trials for inclusion and quality, and extracted data. Relative benefit or risk and number needed to treat to benefit or harm (NNT or NNH) were calculated with 95% confidence intervals (CI). Acute and chronic conditions were analysed separately. Main results Six placebo and one active controlled studies (560 and 137 participants) in acute pain, and seven placebo and two active controlled studies (489 and 90 participants) in chronic pain were included. All used topical salicylates. The evidence in acute conditions was not robust; using only better quality, valid studies, there was no difference between topical rubefacient and topical control, though overall, including lower quality studies, the NNT for clinical success compared with placebo was 3.2 (95% CI: 2.4 to 4.9). In chronic conditions the NNT was 6.2 (95% CI: 4.0 to 13) compared with topical placebo. Adverse events and withdrawals occurred more often with rubefacients than placebo

  20. Biology and treatment of adult acute lymphoblastic leukemia.

    PubMed Central

    Levitt, L; Lin, R

    1996-01-01

    The molecular analysis of acute lymphoblastic leukemia (ALL) has provided exciting insights into the pathogenesis of this disease. This disease is heterogenous and can be subtyped based on chromosomal, immunophenotypic, and structural criteria. The varying prognostic implications of different ALL subtypes markedly influence the treatment decisions in adults. Many patients with T-cell ALL can be cured with chemotherapy alone. In contrast, patients with early B-lineage ALL with certain chromosomal abnormalities, especially the Philadelphia chromosome, do not have durable responses to chemotherapy and should receive a bone marrow transplantation if an HLA-matched donor is available. Recent reports have shown improved results for adults with B-cell ALL (Burkitt's) after intensive alternating cycles of chemotherapy containing high doses of methotrexate and cyclophosphamide. Future clinical and laboratory investigation should lead to the development of novel and possibly more effective treatments specifically tailored for different subsets of ALL. PMID:8775728

  1. Single dose oral flurbiprofen for acute postoperative pain in adults

    PubMed Central

    Sultan, Asquad; McQuay, Henry J; Moore, R Andrew; Derry, Sheena

    2014-01-01

    Background Flurbiprofen is a non-selective non-steroidal anti-inflammatory drug (NSAID), related to ibuprofen and naproxen, used to treat acute and chronic painful conditions. There is no systematic review of its use in acute postoperative pain. Objectives To assess efficacy, duration of action, and associated adverse events of single dose oral flurbiprofen in acute postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to January 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered flurbiprofen in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk (RR) and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results Eleven studies compared flurbiprofen (699 participants) with placebo (362 participants) in studies lasting 6 to 12 hours. Studies were of adequate reporting quality, and most participants had pain following dental extractions. The dose of flurbiprofen used was 25 mg to 100 mg, with most information for 50 mg and 100 mg. The NNT for at least 50% pain relief over 4 to 6 hours for flurbiprofen 50 mg compared with placebo (692 participants) was 2.7 (2.3 to 3.3) and for 100 mg (416 participants) it was 2.5 (2.0 to 3.1). With flurbiprofen 50 mg and 100 mg 65% to 70% of participants experienced at least 50% pain relief, compared with 25% to 30% with placebo. Rescue medication was used by 25

  2. Positive and negative predictive values of HLA-DR and CD34 in the diagnosis of acute promyelocytic leukemia and other types of acute myeloid leukemia with recurrent chromosomal translocations.

    PubMed

    Promsuwicha, Orathai; Auewarakul, Chirayu U

    2009-12-01

    The predictive value of HLA-DR and CD34 in the diagnosis of four distinct genetic entities of acute myeloid leukemia (AML) is presently not established. We evaluated the positive and negative predictive values (PPV and NPV, respectively), sensitivity, specificity, and correlation coefficients of HLA-DR and CD34 in AML patients with t(15;17), t(8;21), inv(16), and abn(11q23). In AML with t(15;17) (n = 64), HLA-DR was expressed in 4.68% and CD34 was expressed in 15.62% and none of the cases expressed both HLA-DR and CD34. In AML with t(8;21) (n = 99), HLA-DR, CD34 or both antigens were expressed in the majority of cases (90.90%, 80.80%, and 79.79%, respectively). AML patients with inv(16) (n = 18) and abn(11q23) (n = 31) also highly expressed HLA-DR and CD34. Eight cases of t(8;21) and 1 case of abn(11q23) did not express either antigen. The highest correlation between CD34 and HLA-DR expression values was observed in cases with t(8;21) (r = 0.72) with the lowest correlation in inv(16) (r = 0.035). The PPV and NPV of HLA-DR-negativity plus CD34-negativity to predict t(15;17) was 85% and 100%, respectively, with 100% sensitivity and 92.74% specificity. The PPV and NPV of other myeloid markers such as CD117, MPO and CD11c to diagnose t(15;17) were much lower than those of HLA-DR and CD34. It was concluded that the absence of double negativity of HLA-DR and CD34 strongly predicts against t(15;17). Rare HLA-DR-positive/CD34-negative cases exist in patients with t(15;17) and 8% of t(8;21) cases expressed neither antigen. Further studies should determine whether HLA-DR-positive t(15;17) and HLA-DR-negative/CD34-negative t(8;21) represent a special entity associated with significant prognostic relevance.

  3. Acute coronary syndrome after levamisole-adultered cocaine abuse.

    PubMed

    Michaud, Katarzyna; Grabherr, Silke; Shiferaw, Kebede; Doenz, Franceso; Augsburger, Marc; Mangin, Patrice

    2014-01-01

    Cocaine is a well known trigger of acute coronary syndromes. Over the last 10 years levamisole, a veterinary anthelminthic drug has been increasingly used as an adulterant of cocaine. Levamisole was used to treat pediatric nephritic syndrome and rheumatoid arthritis before being withdrawn from the market due to its significant toxicity, i.e. hematological complications and vasculitis. The major complications of levamisole-adultered cocaine reported up to now are hematological and dermatological. The case reported here is of a 25 year old man with a history of cocaine abuse who died at home after complaining of retrosternal pain. Postmortem CT-angiography, autopsy, and chemical and toxicological analyses were performed. An eroded coronary artery plaque was found at the proximal segment of the left anterior descending coronary artery. Two myocardial infarct scars were present in the left ventricle. Microscopic examination of the coronary artery revealed infiltration of eosinophils into the adventitia and intima. Toxicological examination confirmed the presence of cocaine and its metabolites in the peripheral blood, and of levamisole in the urine and pericardial fluid. Eosinophilic inflammatory coronary artery pathologies have been clinically linked to coronary dissection, hypersensitivity coronary syndrome and vasospastic allergic angina. The coronary pathology in the presented case could be a complication of levamisole-adultered cocaine use, in which an allergic or immune-mediated mechanism might play a role. The rise in cocaine addiction worldwide and the increase of levamisole adulterated cocaine highlights the importance of updating our knowledge of the effects of adultered cocaine abuse. PMID:24365689

  4. Acute Lymphocytic Leukemia in Adults. Pathologic Features and Prognosis.

    PubMed

    Marinescu, Cristina; Vlădăreanu, Ana-Maria; Mihai, Felicia

    2015-01-01

    Acute lymphoblastic leukemia (ALL) is a malignant neoplasm of the lymphocyte precursor cells. Among adults it is a relatively rare neoplasm with a curability rate around 30% at 5 years. Currently, the diagnosis and classification of ALL is a multistep procedure that relies on the simultaneous application of multiple techniques that include: cytomorphology, immunophenotype and cytogenetic assays. Some of them have important clinical implications for both diagnosis and predicting response to specific treatment regimens, while the role of others is still to be defined. Over the years, several prognostic factors have been identified and today a risk stratification at diagnosis and during the follow-up is based on the characteristics of the leukemic cells.

  5. Mood alterations in older adults following acute exercise.

    PubMed

    Pierce, E F; Pate, D W

    1994-08-01

    Limited research indicates positive affective change following acute bouts of exercise, but whether this improved affect among younger subjects may be generalized to older individuals is not known. The present study, then, examined the effects of a single bout of physical activity among older participants. 16 trained women (Mage = 64.5 +/- 7.6 yr.) completed an abbreviated Profile of Mood States prior to and immediately following a 75-min. session of aerobic line dancing. A series of one-way analyses of variance with repeated measures were used to examine differences between pre- and posttest subscores on mood states. Significant decreases following exercise in scores on Tension, Depression, Fatigue, and Anger and a significant increase in scores on Vigor relative to preexercise (control) scores were found. Global mood was significantly improved after the exercise session. No significant difference was found between pre- and postexercise measures of Confusion. Previous findings of significant improvements in affect immediately after an acute bout of exercise may be generalized to older adults. Repetition with a nonexercised control group is desirable.

  6. [Recommendations for management of acute pharyngitis in adults].

    PubMed

    Cots, Josep M; Alós, Juan-Ignacio; Bárcena, Mario; Boleda, Xavier; Cañada, José L; Gómez, Niceto; Mendoza, Ana; Vilaseca, Isabel; Llor, Carles

    2015-10-01

    Acute pharyngitis in adults is one of the most common infectious diseases seen in general practitioners' consultations. Viral aetiology is the most common. Among bacterial causes, the main agent is Streptococcus pyogenes or group A β-haemolytic streptococcus (GABHS), which causes 5%-30% of the episodes. In the diagnostic process, clinical assessment scales can help clinicians to better predict suspected bacterial aetiology by selecting patients who should undergo a rapid antigen detection test. If these techniques are not performed, an overdiagnosis of streptococcal pharyngitis often occurs, resulting in unnecessary prescriptions of antibiotics, most of which are broad spectrum. Consequently, management algorithms that include the use of predictive clinical rules and rapid tests have been set up. The aim of the treatment is speeding up symptom resolution, reducing the contagious time span and preventing local suppurative and non-suppurative complications. Penicillin and amoxicillin are the antibiotics of choice for the treatment of pharyngitis. The association of amoxicillin and clavulanate is not indicated as the initial treatment of acute infection. Neither are macrolides indicated as first-line therapy; they should be reserved for patients allergic to penicillin. The appropriate diagnosis of bacterial pharyngitis and proper use of antibiotics based on the scientific evidence available are crucial. Using management algorithms can be helpful in identifying and screening the cases that do not require antibiotic therapy.

  7. Recommendations for management of acute pharyngitis in adults.

    PubMed

    Cots, Josep M; Alós, Juan-Ignacio; Bárcena, Mario; Boleda, Xavier; Cañada, José L; Gómez, Niceto; Mendoza, Ana; Vilaseca, Isabel; Llor, Carles

    2015-01-01

    Acute pharyngitis in adults is one of the most common infectious diseases seen in general practitioners' consultations. Viral aetiology is the most common. Among bacterial causes, the main agent is Streptococcus pyogenes or group A β-haemolytic streptococcus (GABHS), which causes 5%-30% of the episodes. In the diagnostic process, clinical assessment scales can help clinicians to better predict suspected bacterial aetiology by selecting patients who should undergo a rapid antigen detection test. If these techniques are not performed, an overdiagnosis of streptococcal pharyngitis often occurs, resulting in unnecessary prescriptions of antibiotics, most of which are broad spectrum. Consequently, management algorithms that include the use of predictive clinical rules and rapid tests have been set up. The aim of the treatment is speeding up symptom resolution, reducing the contagious time span and preventing local suppurative and non-suppurative complications. Penicillin and amoxicillin are the antibiotics of choice for the treatment of pharyngitis. The association of amoxicillin and clavulanate is not indicated as the initial treatment of acute infection. Neither are macrolides indicated as first-line therapy; they should be reserved for patients allergic to penicillin. The appropriate diagnosis of bacterial pharyngitis and proper use of antibiotics based on the scientific evidence available are crucial. Using management algorithms can be helpful in identifying and screening the cases that do not require antibiotic therapy.

  8. Management of adult Ph-positive acute lymphoblastic leukemia.

    PubMed

    Chiaretti, Sabina; Foà, Robin

    2015-01-01

    Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) has been regarded for decades as the ALL subgroup with the worse outcome. It represents the most frequent genetic subtype of adult ALL, and increases progressively with age. The introduction of tyrosine kinase inhibitors (TKIs) has enabled to obtain complete hematologic remissions (CHRs) in virtually all patients, including the elderly, to improve disease-free survival and overall survival, as well as to increase the percentage of patients who can undergo an allogeneic stem cell transplant (allo-SCT).The current management of adult Ph+ ALL patients relies on the use of a TKI with or without chemotherapy followed by an allo-SCT, which still remains the only curative option. Minimal residual disease screening is permitting not only a better stratification of patients, but has also allowed to reconsider the role of autologous stem cell transplant for a set of patients who do not have a donor or are not eligible for an allo-SCT. At present, clinical challenges are represented by the emergence of resistant mutations, particularly the gatekeeper T315I, for which alternative approaches, comprising novel TKIs or therapies based on the combination of TKI with immunotherapeutic strategies, are being considered in order to overcome resistance.

  9. Induction of differentiation and apoptosis- a possible strategy in the treatment of adult acute myelogenous leukemia.

    PubMed

    Bruserud, O; Gjertsen, B T; Huang, Ts

    2000-01-01

    A differentiation block with accumulation of immature myeloid cells characterizes acute myelogenous leukemia (AML). However, native AML cells often show some morphological signs of differentiation that allow a classification into different subsets, and further differentiation may be induced by exposure to various soluble mediators, e.g., all trans-retinoic acid (ATRA) and several cytokines. Combination therapy with ATRA and chemotherapy should now be regarded as the standard treatment for the acute promyelocytic leukemia variant of AML. Several agents can induce leukemic cell differentiation for other AML subtypes, although these effects differ between patients. Differentiation may then be associated with induction of apoptosis, and differentiation-inducing therapy may therefore become useful in combination with intensive chemotherapy to increase the susceptibility of AML blasts to drug-induced apoptosis. However, it should be emphasized that differentiation and apoptosis can occur as separate events with different regulation in AML cells, and future studies in AML should therefore focus on: A) the identification of new agents with more predictable effects on differentiation and apoptosis; B) the use of clinical and laboratory parameters to define new subsets of AML patients in which differentiation/apoptosis induction has a predictable and beneficial effect, and C) further characterization of how AML blast sensitivity to drug-induced apoptosis is modulated by differentiation induction.

  10. Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation.

    PubMed

    Gaillard, Coline; Tokuyasu, Taku A; Rosen, Galit; Sotzen, Jason; Vitaliano-Prunier, Adeline; Roy, Ritu; Passegué, Emmanuelle; de Thé, Hugues; Figueroa, Maria E; Kogan, Scott C

    2015-08-01

    Acute promyelocytic leukemia is an aggressive malignancy characterized by the accumulation of promyelocytes in the bone marrow. PML/RARA is the primary abnormality implicated in this pathology, but the mechanisms by which this chimeric fusion protein initiates disease are incompletely understood. Identifying PML/RARA targets in vivo is critical for comprehending the road to pathogenesis. Utilizing a novel sorting strategy, we isolated highly purified promyelocyte populations from normal and young preleukemic animals, carried out microarray and methylation profiling analyses, and compared the results from the two groups of animals. Surprisingly, in the absence of secondary lesions, PML/RARA had an overall limited impact on both the transcriptome and methylome. Of interest, we did identify down-regulation of secondary and tertiary granule genes as the first step engaging the myeloid maturation block. Although initially not sufficient to arrest terminal granulopoiesis in vivo, such alterations set the stage for the later, complete differentiation block seen in leukemia. Further, gene set enrichment analysis revealed that PML/RARA promyelocytes exhibit a subtle increase in expression of cell cycle genes, and we show that this leads to both increased proliferation of these cells and expansion of the promyelocyte compartment. Importantly, this proliferation signature was absent from the poorly leukemogenic p50/RARA fusion model, implying a critical role for PML in the altered cell-cycle kinetics and ability to initiate leukemia. Thus, our findings challenge the predominant model in the field and we propose that PML/RARA initiates leukemia by subtly shifting cell fate decisions within the promyelocyte compartment.

  11. Cerebrospinal fluid findings in adults with acute Lyme neuroborreliosis.

    PubMed

    Djukic, Marija; Schmidt-Samoa, Carsten; Lange, Peter; Spreer, Annette; Neubieser, Katja; Eiffert, Helmut; Nau, Roland; Schmidt, Holger

    2012-04-01

    Presence of BB-specific antibodies in the cerebrospinal fluid (CSF) with evidence of their intrathecal production in conjunction with the white cell count in the CSF and typical clinical symptoms is the traditional diagnostic gold standard of Lyme neuroborreliosis (LNB). Few data are available on the CSF lactate concentration in European adults with the diagnosis of acute LNB. The objective of the study was to investigate the CSF changes during acute LNB. Routine CSF parameters [leukocyte count, protein, lactate and albumin concentrations, CSF/serum quotients of albumin (Q(Alb)), IgG, IgA and IgM, and oligoclonal IgG bands] and the Borrelia burgdorferi (BB)-specific antibody index were retrospectively studied in relation to the clinical presentation in patients diagnosed with acute LNB. A total of 118 patients with LNB were categorized into the following groups according to their symptoms at presentation; group 1: polyradiculoneuritis (Bannwarth's syndrome), group 2: isolated facial palsy and group 3: predominantly meningitic course of the disease. In addition to the CSF of patients with acute LNB, CSF of 19 patients with viral meningitis (VM) and 3 with neurolues (NL) were analyzed. There were 97 patients classified with definite LNB, and 21 as probable LNB. Neck stiffness and fever were reported by 15.3% of patients. Most of these patients were younger than 50 years. Polyradiculoneuritis was frequently found in patients older than 50 years. Lymphopleocytosis was found in all patients. Only 5 patients had a CSF lactate ≥3.5 mmol/l, and the mean CSF lactate level was not elevated (2.1 ± 0.6 mmol/l). The patients with definite LNB had significantly higher lactate levels than patients with probable LNB. Elevated lactate levels were accompanied by fever and headache. In the Reiber nomograms, intrathecal immunoglobulin synthesis was found for IgM in 70.2% followed by IgG in 19.5%. Isoelectric focussing detected an intrathecal IgG synthesis in 83 patients (70

  12. Respiratory autoresuscitation following severe acute hypoxemia in anesthetized adult rats.

    PubMed

    Krause, A; Nowak, Z; Srbu, R; Bell, H J

    2016-10-01

    In the present study we investigated the pattern and efficacy of respiratory autoresuscitation in spontaneously breathing adult male rats across three separate anesthetic backgrounds. Each animal was administered one of three injectable anesthetics to achieve a surgical plane of anesthesia: ketamine-xylazine (KET, n=10), pentobarbital (PEN, n=10), or urethane (URE, n=10). Animals were tracheostomized and equipped with a femoral artery catheter to record airflow and arterial pressures. In response to a bout of breathing anoxic air, none of the 10 URE animals were able to mount a successful autoresuscitation response. In contrast, all KET and PEN animals survived all four consecutive anoxic exposures, restoring eupneic breathing in all cases. Moreover, only 4/10 URE animals expressed gasping breaths following the onset of respiratory arrest, and these were temporally delayed (p<0.001) and much smaller in volume (P≤0.012) compared to KET and PEN animals. URE animals showed no clear aberrations in their cardiovascular responses to anoxia, with the exception of lower arterial pulse pressures compared to either KET or PEN animals at specific points following RA. Ketamine-xylazine and pentobarbital anesthesia can be reliably and effectively used to create models for the study of autoresuscitation in adult rats. In contrast, urethane causes catastrophic failure of respiratory autoresuscitation, by delaying or outright preventing the elaboration of gasping breaths following anoxia-induced respiratory arrest. The neuronal and synaptic alterations accompanying urethane anesthesia may therefore provide a means of understanding potential pathological alterations in rhythm generation that can predispose the respiratory control system to failed autoresuscitation following an episode of acute severe hypoxemia. PMID:27378495

  13. Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia.

    PubMed

    Maury, Sébastien; Chevret, Sylvie; Thomas, Xavier; Heim, Dominik; Leguay, Thibaut; Huguet, Françoise; Chevallier, Patrice; Hunault, Mathilde; Boissel, Nicolas; Escoffre-Barbe, Martine; Hess, Urs; Vey, Norbert; Pignon, Jean-Michel; Braun, Thorsten; Marolleau, Jean-Pierre; Cahn, Jean-Yves; Chalandon, Yves; Lhéritier, Véronique; Beldjord, Kheira; Béné, Marie C; Ifrah, Norbert; Dombret, Hervé

    2016-09-15

    Background Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial. Methods We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. Results From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P=0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group. Conclusions Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678 .). PMID:27626518

  14. Acute Lymphoblastic Leukemia in a Young Adult Presenting as Hepatitis and Acute Kidney Injury

    PubMed Central

    Heincelman, Marc; Karakala, Nithin; Rockey, Don C.

    2016-01-01

    Acute lymphoblastic leukemia (ALL) in adults is a relatively rare malignancy. The typical presentation includes signs and symptoms associated with bone marrow failure, including fevers, infections, fatigue, and excessive bruising. In this article, we report an unusual systemic presentation of ALL in a previously healthy 18-year-old man. He initially presented with several-day history of nausea and vomiting, 10-pound weight loss, and right upper quadrant abdominal pain with evidence of acute hepatocellular liver injury (elevations in aspartate aminotransferase/alanine aminotransferase) and elevation in serum creatinine. Further history revealed that he just joined the Marine Corp; in preparation, he had been lifting weights and taking protein and creatine supplements. A complete serological evaluation for liver disease was negative and creatine phosphokinase was normal. His aspartate aminotransferase and alanine aminotransferase declined, and he was discharged with expected improvement. However, he returned one week later with continued symptoms and greater elevation of aminotransferases. Liver biopsy was nondiagnostic, revealing scattered portal and lobular inflammatory cells (primarily lymphocytes) felt to be consistent with drug-induced liver injury or viral hepatitis. Given his elevated creatinine, unresponsive to aggressive volume expansion, a kidney biopsy was performed, revealing normal histology. He subsequently developed an extensive left lower extremity deep venous thrombosis. Given his deep venous thrombosis, his peripheral blood was sent for flow cytometry, which revealed lymphoblasts. Bone marrow biopsy revealed 78% blasts with markers consistent with acute B-cell lymphoblastic leukemia. This report emphasizes that right upper quadrant abdominal pain with liver test abnormalities may be the initial presentation of a systemic illness such as ALL. PMID:27722178

  15. Acute behavioral toxicity of carbaryl and propoxur in adult rats.

    PubMed

    Ruppert, P H; Cook, L L; Dean, K F; Reiter, L W

    1983-04-01

    Motor activity and neuromotor function were examined in adult CD rats exposed to either carbaryl or propoxur, and behavioral effects were compared with the time course of cholinesterase inhibition. Rats received an IP injection of either 0, 2, 4, 6 or 8 mg/kg propoxur or 0, 4, 8, 16 or 28 mg/kg carbaryl in corn oil 20 min before testing. All doses of propoxur reduced 2 hr activity in a figure-eight maze, and crossovers and rears in an open field. For carbaryl, dosages of 8, 16 and 28 mg/kg decreased maze activity whereas 16 and 28 mg/kg reduced open field activity. In order to determine the time course of effects, rats received a single IP injection of either corn oil, 2 mg/kg propoxur or 16 mg/kg carbaryl, and were tested for 5 min in a figure-eight maze either 15, 30, 60, 120 or 240 min post-injection. Immediately after testing, animals were sacrificed and total cholinesterase was measured. Maximum effects of propoxur and carbaryl on blood and brain cholinesterase and motor activity were seen within 15 min. Maze activity had returned to control levels within 30 and 60 min whereas cholinesterase levels remained depressed for 120 and 240 min for propoxur and carbaryl, respectively. These results indicate that both carbamates decrease motor activity, but behavioral recovery occurs prior to that of cholinesterase following acute exposure.

  16. Acute Tryptophan Depletion and Sweet Food Consumption by Overweight Adults

    PubMed Central

    Pagoto, Sherry L.; Spring, Bonnie; McChargue, Dennis; Hitsman, Brian; Smith, Malaina; Appelhans, Bradley; Hedeker, Donald

    2009-01-01

    Serotonergic involvement has been implicated in preferential consumption of treat foods. We tested the effect of acute tryptophan depletion (ATD) on food consumption by overweight and lean adults with and without a history of recurrent major depressive disorder (MDD). ATD and taste-matched placebo challenges were administered double-blind in counter-balanced order. Participants were classified as lean (n = 36) or overweight (n=19) on the basis of body mass index (BMI). Total calorie, carbohydrate, protein, and sweet food consumption were assessed via a test meal 8-hours following ATD. Four food items of comparable palatability were offered as a part of the test: two sweet (one carbohydrate-rich, and one protein-rich) and two non-sweet (one carbohydrate-rich, and one protein-rich). As compared to the placebo challenge, ATD significantly increased sweet calorie intake among overweight participants and increased their propensity to consume sweet food first before any other type of food. Lean participants’ sweet calorie intake and food preference were unaffected by ATD. Findings suggest serotonergic involvement in the sweet food consumption by overweight individuals. PMID:19171315

  17. What's New in Adult Acute Myeloid Leukemia Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for acute myeloid leukemia What’s new in acute myeloid leukemia research and treatment? Researchers ... benefit from current treatments. Researchers are studying many new chemo drugs for use in AML, including: Sapacitabine, ...

  18. Acute rhinosinusitis in adults: an update on current management

    PubMed Central

    Masood, Ajmal; Moumoulidis, Ioannis; Panesar, Jaan

    2007-01-01

    Acute rhinosinusitis is a common disease with worldwide prevalence. It is a significant burden on the health services. It is most commonly caused by viruses and is self‐limiting in nature. The diagnosis of acute rhinosinusitis is clinical and sinus radiography is not indicated routinely. Most cases of acute rhinosinusitis are treated symptomatically. However, symptoms may persist beyond 10 days when secondary bacterial infection prevails. Antibiotics are reserved for moderate or severe cases or when there is development of complications of acute rhinosinusitis. This paper provides an update on the current management of acute rhinosinusitis. PMID:17551072

  19. [Acute rhinosinusitis in adults--EPOS 2012 Part II].

    PubMed

    Riechelmann, H; Giotakis, A; Kral, F

    2013-11-01

    Rhinosinusitis (RS) is an inflammatory disorder of the mucous membranes of the nose and paranasal sinuses, which are almost always affected concurrently. The EPOS2012 position paper initiated by the European Rhinologic Society and the European Academy of Allergy and Clinical Immunology is a recent comprehensive source on this common disease affecting approximately 20% of the population worldwide. Inflammation, not infection, is considered the cornerstone of RS, which is considered a temporal and pathophysiologic disease continuum with various subtypes. Acute rhinosinusitis is diagnosed, if typical symptoms last less than 12 weeks. It affects approximately 10% of the European population. Acute RS is further subdivided into acute viral, acute postviral and acute bacterial RS. Acute viral RS lasts less than 10 days with decreasing symptom intensity, while acute postviral RS is characterized by longer duration or a sudden increase of symptom severity around the 5th day ('double sickening'). Acute bacterial RS is assumed if 3 of the following 5 criteria are additionally met: Discoloured discharge (with unilateral predominance), severe local pain (with unilateral predominance), fever (>38ºC), elevated ESR/CRP, and 'double-sickening'. For the treatment of acute viral RS, nasal saline irrigations and OTC cold remedies are advised. In acute postviral RS, additional topical steroids are suggested. Advantages and disadvantages of antibiotic treatment in acute bacterial RS are detailed. Overall, the new EPOS position paper infers a reorientation in this area of high medical, pharmaceutical and economic relevance.

  20. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

    PubMed Central

    Ivey, Adam; Huntly, Brian J. P.

    2016-01-01

    Recent major advances in understanding the molecular basis of acute myeloid leukemia (AML) provide a double-edged sword. Although defining the topology and key features of the molecular landscape are fundamental to development of novel treatment approaches and provide opportunities for greater individualization of therapy, confirmation of the genetic complexity presents a huge challenge to successful translation into routine clinical practice. It is now clear that many genes are recurrently mutated in AML; moreover, individual leukemias harbor multiple mutations and are potentially composed of subclones with differing mutational composition, rendering each patient’s AML genetically unique. In order to make sense of the overwhelming mutational data and capitalize on this clinically, it is important to identify (1) critical AML-defining molecular abnormalities that distinguish biological disease entities; (2) mutations, typically arising in subclones, that may influence prognosis but are unlikely to be ideal therapeutic targets; (3) mutations associated with preleukemic clones; and (4) mutations that have been robustly shown to confer independent prognostic information or are therapeutically relevant. The reward of identifying AML-defining molecular lesions present in all leukemic populations (including subclones) has been exemplified by acute promyelocytic leukemia, where successful targeting of the underlying PML-RARα oncoprotein has eliminated the need for chemotherapy for disease cure. Despite the molecular heterogeneity and recognizing that treatment options for other forms of AML are limited, this review will consider the scope for using novel molecular information to improve diagnosis, identify subsets of patients eligible for targeted therapies, refine outcome prediction, and track treatment response. PMID:26660431

  1. Antiproliferative activity of various Uncaria tomentosa preparations on HL-60 promyelocytic leukemia cells.

    PubMed

    Pilarski, Radosław; Poczekaj-Kostrzewska, Magdalena; Ciesiołka, Danuta; Szyfter, Krzysztof; Gulewicz, Krzysztof

    2007-01-01

    The woody Amazonian vine Uncaria tomentosa (cat's claw) has been recently more and more popular all over the world as an immunomodulatory, antiinflammatory and anti-cancer remedy. This study investigates anti-proliferative potency of several cat's claw preparations with different quantitative and qualitative alkaloid contents on HL-60 acute promyelocytic human cells by applying trypan blue exclusion and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay (MTT). By standardization and statistical comparison of the obtained results pteropodine and isomitraphylline are indicated to be most suitable for standardization of medical cat's claw preparations.

  2. Hypocellular acute myeloid leukemia in adults: analysis of the clinical outcome of 123 patients

    PubMed Central

    Al-Kali, Aref; Konoplev, Sergej; Lin, Erpei; Kadia, Tapan; Faderl, Stefan; Ravandi, Farhad; Ayoubi, Mohamad; Brandt, Mark; Cortes, Jorge E.; Kantarjian, Hagop; Borthakur, Gautam

    2012-01-01

    Background The hypocellular variant of acute myeloid leukemia accounts for less than 10% of all cases of adult acute myeloid leukemia. It is defined by having less than 20 percent of cellular bone marrow in a biopsy at presentation. It is unclear in the literature whether the outcome of hypocellular acute myeloid leukemia differs from that of non-hypocellular acute myeloid leukemia. Design and Methods We retrospectively analyzed all the cases reported to be hypocellular acute myeloid leukemia between 2000 and 2009. A second pathology review was conducted and the diagnosis was confirmed in all cases. Results One hundred twenty-three (9%) patients were identified: patients with hypocellular acute myeloid leukemia were older than those with non-hypocellular acute myeloid leukemia (P=0.009) and more frequently presented with cytopenias (P<0.001). Forty-one patients with hypocellular acute myeloid leukemia had an antecedent hematologic disorder and 11 patients had received prior chemo-radiotherapy for non-hematopoietic neoplasms. On multivariate analysis, overall survival, remission duration and event-free survival were comparable to those of other patients with acute myeloid leukemia. Conclusions The outcome of hypocellular acute myeloid leukemia does not differ from that of non-hypocellular acute myeloid leukemia. PMID:22058194

  3. Bacillus cereus bacteremia in an adult with acute leukemia.

    PubMed

    Funada, H; Uotani, C; Machi, T; Matsuda, T; Nonomura, A

    1988-03-01

    Bacillus cereus, which used to be considered non-pathogenic, was isolated from the blood of a patient with acute leukemia who was receiving intensive chemotherapy. Fatal bacteremia developed with a clinical syndrome of acute gastroenteritis, followed by both meningoencephalitis with subarachnoid hemorrhage and multiple liver abscesses probably caused by infective vasculitis. Surveillance stool cultures revealed colonization with the organism prior to the onset of diarrhea, and repetitive blood cultures were found to be positive. Thus, this case suggested some new important clinicopathologic features of true B. cereus bacteremia complicating acute leukemia.

  4. Heterogeneous nuclear expression of the promyelocytic leukemia (PML) protein in normal and neoplastic human tissues.

    PubMed Central

    Gambacorta, M.; Flenghi, L.; Fagioli, M.; Pileri, S.; Leoncini, L.; Bigerna, B.; Pacini, R.; Tanci, L. N.; Pasqualucci, L.; Ascani, S.; Mencarelli, A.; Liso, A.; Pelicci, P. G.; Falini, B.

    1996-01-01

    The RING-finger promyelocytic leukemia (PML) protein is the product of the PML gene that fuses with the retinoic acid receptor-alpha gene in the t(15; 17) translocation of acute promyelocytic leukemia. Wild-type PML localizes in the nucleus with a typical speckled pattern that is a consequence of the concentration of the protein within discrete subnuclear domains known as nuclear bodies. Delocalization of PML from nuclear bodies has been documented in acute promyelocytic leukemia cells and suggested to contribute to leukemogenesis. In an attempt to get new insights into the function of the wild-type PML protein and to investigate whether it displays an altered expression pattern in neoplasms other than acute promyelocytic leukemia, we stained a large number of normal and neoplastic human tissues with a new murine monoclonal antibody (PG-M3) directed against the amino-terminal region of PML. As the PG-M3 epitope is partially resistant to fixatives, only cells that overexpress PML are detected by the antibody in microwave-heated paraffin sections. Among normal tissues, PML was characteristically up-regulated in activated epithelioid histiocytes and fibroblasts in a variety of pathological conditions, columnar epithelium in small active thyroid follicles, well differentiated foamy cells in the center of sebaceous glands, and hypersecretory endometria (Arias-Stella). Interferons, the PML of which is a primary target gene, and estrogens are likely to represent some of the cytokines and/or hormones that may be involved in the up-regulation of PML under these circumstances. In keeping with this concept, we found that PML is frequently overexpressed in Hodgkin and Reed-Sternberg cells of Hodgkin's disease, a tumor of cytokine-producing cells. Among solid tumors, overexpression of PML was frequently found in carcinomas of larynx and thyroid (papillary), epithelial thymomas, and Kaposi's sarcoma, whereas carcinomas of the lung, thyroid (follicular), breast, and colon were

  5. Outpatient diagnosis of acute chest pain in adults.

    PubMed

    McConaghy, John R; Oza, Rupal S

    2013-02-01

    Approximately 1 percent of primary care office visits are for chest pain, and 1.5 percent of these patients will have unstable angina or acute myocardial infarction. The initial goal in patients presenting with chest pain is to determine if the patient needs to be referred for further testing to rule in or out acute coronary syndrome and myocardial infarction. The physician should consider patient characteristics and risk factors to help determine initial risk. Twelve-lead electrocardiography is typically the test of choice when looking for ST segment changes, new-onset left bundle branch block, presence of Q waves, and new-onset T wave inversions. For persons in whom the suspicion for ischemia is lower, other diagnoses to consider include chest wall pain/costochondritis (localized pain reproducible by palpation), gastroesophageal reflux disease (burning retrosternal pain, acid regurgitation, and a sour or bitter taste in the mouth), and panic disorder/anxiety state. Other less common but important diagnostic considerations include pneumonia (fever, egophony, and dullness to percussion), heart failure, pulmonary embolism (consider using the Wells criteria), acute pericarditis, and acute thoracic aortic dissection (acute chest or back pain with a pulse differential in the upper extremities). Persons with a higher likelihood of acute coronary syndrome should be referred to the emergency department or hospital.

  6. Flavopiridol, Cytarabine, and Mitoxantrone in Treating Patients With Acute Leukemia

    ClinicalTrials.gov

    2013-10-07

    Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  7. What's New in Adult Acute Lymphocytic Leukemia (ALL) in Adults Research?

    MedlinePlus

    ... Topic Additional resources for acute lymphocytic leukemia What’s new in acute lymphocytic leukemia research and treatment? Researchers ... have the Philadelphia chromosome. Gene expression profiling This new lab technique is being studied to help identify ...

  8. Extracorporeal life support for adults with severe acute respiratory failure.

    PubMed

    Del Sorbo, Lorenzo; Cypel, Marcelo; Fan, Eddy

    2014-02-01

    Extracorporeal life support (ECLS) is an artificial means of maintaining adequate oxygenation and carbon dioxide elimination to enable injured lungs to recover from underlying disease. Technological advances have made ECLS devices smaller, less invasive, and easier to use. ECLS might, therefore, represent an important step towards improved management and outcomes of patients with acute respiratory distress syndrome. Nevertheless, rigorous evidence of the ability of ECLS to improve short-term and long-term outcomes is needed before it can be widely implemented. Moreover, how to select patients and the timing and indications for ECLS in severe acute respiratory distress syndrome remain unclear. We describe the physiological principles, the putative risks and benefits, and the clinical evidence supporting the use of ECLS in patients with acute respiratory distress syndrome. Additionally, we discuss controversies and future directions, such as novel technologies and indications, mechanical ventilation of the native lung during ECLS, and ethics considerations. PMID:24503270

  9. [Background factors in the detection of drug-resistant bacteria in adult patients with acute rhinosinusitis].

    PubMed

    Tomiyama, Michio

    2014-02-01

    In the treatment of adult patients with acute rhinosinusitis, it has been assumed that subjects over 65 years of age or living with children attending a day nursery, are at higher risk for infection with drug-resistant bacteria. However there are few reports which have discussed the relationship between those risk factors and adult patients with acute rhinosinusitis. I investigated the association between adult patients with acute rhinosinusitis living with children attending a day nursery and gender, ages, and frequency of detection of drug-resistant bacteria. From 2010 to 2012, a total of 598 adult patients with acute rhinosinusitis were enrolled. The majority of the study subjects were women, and the largest 10-year age group was 30-39 years. By sex, a greater proportion of the female subjects than the male subjects lived with children attending a day nursery. By age, the proportion of subjects who lived with children attending a day nursery was significantly higher in the 30-39-year age group than other age groups. Drug-resistant Streptococcus pneumoniae and ampicillin (ABPC)-resistant Haemophilus influenzae were detected at significantly higher rates in subjects with children attending a day nursery than in those without. There were no significant difference in drug-resistant bacteria detection between subjects over 65 years of age, and under 65 years. These findings suggested that living with children attending a day nursery is a risk factor and source of infection by drug-resistant organisms that may cause intra-familial infections of adult patients with acute rhinosinusitis. These results suggested we must ask adult patients with acute rhinosinusitis whether they are living with children attending a day nursery or not, when we plan their treatment strategy.

  10. Recognition of adult and pediatric acute lymphoblastic leukemia blasts by natural killer cells.

    PubMed

    Torelli, Giovanni F; Peragine, Nadia; Raponi, Sara; Pagliara, Daria; De Propris, Maria S; Vitale, Antonella; Bertaina, Alice; Barberi, Walter; Moretta, Lorenzo; Basso, Giuseppe; Santoni, Angela; Guarini, Anna; Locatelli, Franco; Foà, Robin

    2014-07-01

    In this study, we aimed to investigate the pathways of recognition of acute lymphoblastic leukemia blasts by natural killer cells and to verify whether differences in natural killer cell activating receptor ligand expression among groups defined by age of patients, or presence of cytogenetic/molecular aberrations correlate with the susceptibility to recognition and killing. We analyzed 103 newly diagnosed acute lymphoblastic leukemia patients: 46 adults and 57 children. Pediatric blasts showed a significantly higher expression of Nec-2 (P=0.03), ULBP-1 (P=0.01) and ULBP-3 (P=0.04) compared to adult cells. The differential expression of these ligands between adults and children was confined to B-lineage acute lymphoblastic leukemia with no known molecular alterations. Within molecularly defined subgroups of patients, a high surface expression of NKG2D and DNAM1 ligands was found on BCR-ABL(+) blasts, regardless of patient age. Accordingly, BCR-ABL(+) blasts proved to be significantly more susceptible to natural killer-dependent lysis than B-lineage blasts without molecular aberrations (P=0.03). Cytotoxic tests performed in the presence of neutralizing antibodies indicated a pathway of acute lymphoblastic leukemia cell recognition in the setting of the Nec-2/DNAM-1 interaction. These data provide a biological explanation of the different roles played by alloreactive natural killer cells in pediatric versus adult acute lymphoblastic leukemia and suggest that new natural killer-based strategies targeting specific subgroups of patients, particularly those BCR-ABL(+), are worth pursuing further.

  11. Impact of prenatal and acute methamphetamine exposure on behaviour of adult male rats.

    PubMed

    Schutová, B; Hrubá, L; Pometlová, M; Slamberová, R

    2009-01-01

    Psychostimulants have been shown to alter behaviour in both rats and humans. The aim of the present study was: (1) to assess the effect of prenatal and acute methamphetamine (MA) administration on behaviour in adult male rats and (2) to find out if the prenatal exposure to MA increases sensitivity to acute MA application in adulthood. Behaviour of adult male rats prenatally exposed to MA (5 mg/kg) or no drug was tested in Open field (OF) and Elevated plus maze (EPM). Half of the animals were injected with MA (1 mg/kg) subcutaneously 30 minutes prior to testing. Locomotion, exploration, comforting behaviour and anxiety were evaluated in the OF, while anxiety and exploratory behaviour were assessed in the EPM. Our results showed that prenatal MA did not have an effect on baseline behaviour in either of the tests. By contrast, acute MA increased overall psychomotor activity by increasing locomotion and exploratory behaviour and decreasing comforting behaviour. Moreover, adult rats prenatally exposed to MA were more sensitive to the effects of acute MA on exploration. In addition, acute MA application decreased anxiety in the OF as well as in the EPM. Our present study, thus, demonstrates that acute MA increases overall psychomotor activity and decreases anxiety to novel environment. To further support our hypothesis that prenatal MA exposure increases sensitivity to drugs in adulthood, studies investigating the levels of dopamine in the rat brain after prenatal MA exposure are planned.

  12. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups.

    PubMed

    Mandelli, F; Diverio, D; Avvisati, G; Luciano, A; Barbui, T; Bernasconi, C; Broccia, G; Cerri, R; Falda, M; Fioritoni, G; Leoni, F; Liso, V; Petti, M C; Rodeghiero, F; Saglio, G; Vegna, M L; Visani, G; Jehn, U; Willemze, R; Muus, P; Pelicci, P G; Biondi, A; Lo Coco, F

    1997-08-01

    Two hundred fifty-three patients with newly diagnosed acute promyelocytic leukemia (APL) were eligible to enter the multicentric GIMEMA-AIEOP "AIDA" trial during the period July 1993 to February 1996. As a mandatory prerequisite for eligibility, all patients had genetic evidence of the specific t(15;17) lesion in their leukemic cells confirmed by karyotyping or by reverse transcription-polymerase chain reaction (RT-PCR) of the PML/RAR alpha fusion gene (the latter available in 247 cases). Median age was 37.8 years (range, 2.2 to 73.9). Induction treatment consisted of oral all-trans retinoic acid (ATRA), 45 mg/m2/d until complete remission (CR), given with intravenous Idarubicin, 12 mg/m2/d on days 2, 4, 6, and 8. Three polychemotherapy cycles were given as consolidation. Hematologic and molecular response by RT-PCR was assessed after induction and after consolidation. At the time of analysis, 240 of the 253 eligible patients were evaluable for induction. Of these, 11 (5%) died of early complications and 229 (95%) achieved hematologic remission. No cases of resistant leukemia were observed. Of 139 cases studied by RT-PCR after induction, 84 (60.5%) were PCR-negative and 55 (39.5%) PCR-positive. One hundred sixty-two patients were evaluable by RT-PCR at the end of consolidation. Of these, 159 (98%) tested PCR-negative and 3 (2%), PCR-positive. After a median follow up of 12 months (range, 0 to 33), the estimated actuarial event-free survival for the whole series of 253 eligible patients was 83% +/- 2.6% and 79% +/- 3.2% at 1 and 2 years, respectively. This study indicates that the AIDA protocol is a well-tolerated regimen that induces molecular remission in almost all patients with PML/RAR alpha-positive APL. Preliminary survival data suggest that a remarkable cure rate can be obtained with this treatment.

  13. Neuropsychological and psychiatric profiles in acute encephalitis in adults.

    PubMed

    Pewter, Stephen M; Williams, W Huw; Haslam, Catherine; Kay, Janice M

    2007-01-01

    Acute encephalitis is an inflammation of brain tissue that can result from activity in the central nervous system (CNS) of a number of viruses. Although the neurological and psychiatric effects of encephalitis in the acute phase of the illness are well-known (Caroff, Mann, Gliatto, Sullivan, & Campbell, 2001), larger scale studies of the pattern of neuropsychological and psychiatric impairment following recovery from the acute inflammatory phase are less apparent. This paper reports the results of neuropsychological testing with a range of standardised cognitive measures in a case series of long-term post-acute participants. Psychiatric abnormality is examined using the SCL-90-R self-report scale of distress (Derogatis, 1983). We also examined the role of emerging insight in the aetiology of depression in this population. Two clusters of cognitive dysfunction were observed, one group of primarily herpes simplex cases showing a severe generalised deficit across a number of cognitive domains and a second cluster showing a variety of more isolated disorders of executive function. Abnormally high levels of distress were reported by participants, with depression, obsessive-compulsive symptoms, interpersonal sensitivity and phobic anxiety most significantly increased. Depression was found to be least severe in those with most accurate insight into their problems. Examining the correlations between cognitive and psychiatric test results demonstrates a relationship between depression and interpersonal anxiety and specific cognitive measures. Obsessive-compulsive behaviour and phobic anxiety, however, appear to exist independently of the assessed cognitive deficits.

  14. Neuropsychological and psychiatric profiles in acute encephalitis in adults.

    PubMed

    Pewter, Stephen M; Williams, W Huw; Haslam, Catherine; Kay, Janice M

    2007-01-01

    Acute encephalitis is an inflammation of brain tissue that can result from activity in the central nervous system (CNS) of a number of viruses. Although the neurological and psychiatric effects of encephalitis in the acute phase of the illness are well-known (Caroff, Mann, Gliatto, Sullivan, & Campbell, 2001), larger scale studies of the pattern of neuropsychological and psychiatric impairment following recovery from the acute inflammatory phase are less apparent. This paper reports the results of neuropsychological testing with a range of standardised cognitive measures in a case series of long-term post-acute participants. Psychiatric abnormality is examined using the SCL-90-R self-report scale of distress (Derogatis, 1983). We also examined the role of emerging insight in the aetiology of depression in this population. Two clusters of cognitive dysfunction were observed, one group of primarily herpes simplex cases showing a severe generalised deficit across a number of cognitive domains and a second cluster showing a variety of more isolated disorders of executive function. Abnormally high levels of distress were reported by participants, with depression, obsessive-compulsive symptoms, interpersonal sensitivity and phobic anxiety most significantly increased. Depression was found to be least severe in those with most accurate insight into their problems. Examining the correlations between cognitive and psychiatric test results demonstrates a relationship between depression and interpersonal anxiety and specific cognitive measures. Obsessive-compulsive behaviour and phobic anxiety, however, appear to exist independently of the assessed cognitive deficits. PMID:17676531

  15. Fatal measles presenting as acute respiratory distress syndrome in an immunocompetent adult

    PubMed Central

    Karanth, Suman S; Marupudi, Krishna Chaitanya; Gupta, Anurag; Rau, Nileshwar Radhakrishna

    2014-01-01

    Fatal measles is known to occur among immunocompromised adults. We report a rare case of an immunocompetent non-pregnant young lady who suffered from fatal acute respiratory distress syndrome due to measles. Physicians must be vigilant to this deadly presentation of measles even in immunocompetent individuals. We emphasise the inadequacies of vaccination programmes in India reflected not only by the existing high measles-related childhood mortalities, but also an emerging rise in deaths among adults. PMID:25139919

  16. Fatal measles presenting as acute respiratory distress syndrome in an immunocompetent adult.

    PubMed

    Karanth, Suman S; Marupudi, Krishna Chaitanya; Gupta, Anurag; Rau, Nileshwar Radhakrishna

    2014-08-19

    Fatal measles is known to occur among immunocompromised adults. We report a rare case of an immunocompetent non-pregnant young lady who suffered from fatal acute respiratory distress syndrome due to measles. Physicians must be vigilant to this deadly presentation of measles even in immunocompetent individuals. We emphasise the inadequacies of vaccination programmes in India reflected not only by the existing high measles-related childhood mortalities, but also an emerging rise in deaths among adults.

  17. Adolescent and adult male spontaneous hyperactive rats (SHR) respond differently to acute and chronic methylphenidate (Ritalin).

    PubMed

    Barron, Elyssa; Yang, Pamela B; Swann, Alan C; Dafny, Nachum

    2009-01-01

    Eight groups of male adolescent and adult spontaneous hyperactive rats (SHR) were used in a dose response (saline, 0.6, 2.5, and 10 mg/kg) experiment of methylphenidate (MPD). Four different locomotor indices were recorded for 2 hours postinjection using a computerized monitoring system. Acutely, the 0.6 mg/kg dose of MPD did not elicit an increase in locomotor activity in either the adolescent or in the adult male SHR. The 2.5 and the 10.0 mg/kg doses increased activity in the adolescent and the adult rats. Chronically, MPD treatment when comparing adolescent and adult gave the following results: the 0.6 mg/kg dose of MPD failed to cause sensitization in the adolescent group but caused sensitization in the adult group, while the 2.5 and 10 mg/kg both caused sensitization in the adolescent and adult groups.

  18. Prolonged weightlessness affects promyelocytic multidrug resistance.

    PubMed

    Piepmeier, E H; Kalns, J E; McIntyre, K M; Lewis, M L

    1997-12-15

    An immortalized promyelocytic cell line was studied to detect how doxorubicin uptake is affected by microgravity. The purpose of this experiment was to identify the effect that microgravity may have on multidrug resistance in leukocytes. HL60 cells and HL60 cells resistant to anthracycline (HL60/AR) were grown in RPMI and 10% FBS. Upon reaching orbit in the Space Shuttle Endeavour, the cells were robotically mixed with doxorubicin. Three days after mixing, cells were fixed with paraformaldehyde/glutaraldehyde. Ground control experiments were conducted concurrently using a robot identical to the one used on the Shuttle. Fixed cells were analyzed within 2 weeks of launch. Confocal micrographs identified changes in cell structure (transmittance), drug distribution (fluorescence), and microtubule polymerization (fluorescence). Flight cells showed a lack of cytoskeletal polymerization resulting in an overall amorphic globular shape. Doxorubicin distribution in ground cells included a large numbers of vesicles relative to flight cells. There was a greater amount of doxorubicin present in flight cells (85% +/- 9.7) than in ground control cells (43% +/- 26) as determined by image analysis. Differences in microtubule formation between flight cells and ground cells could be partially responsible for the differences in drug distribution. Cytoskeletal interactions are critical to the function of P-glycoprotein as a drug efflux pump responsible for multidrug resistance.

  19. Biology and treatment of acute lymphocytic leukemia in adolescents and young adults.

    PubMed

    Advani, Anjali S

    2013-01-01

    The treatment of young adults (16 to 39 years of age) with acute lymphocytic leukemia (ALL) has been a focus of clinical research over the past decade. This review will focus on the biology, optimal treatment, treatment-related toxicities, and psychosocial issues in this patient population.

  20. Clinical Application of the "Scribble Technique" with Adults in an Acute Inpatient Psychiatric Hospital.

    ERIC Educational Resources Information Center

    Hanes, Michael J.

    1995-01-01

    The "scribble technique," described by Florence Cane's book, "The Artist in Each of Us" (1983), has historically been employed by art therapists as a technique to reduce inhibitions and liberate spontaneous imagery from the unconscious. Reviews the technique and presents examples produced by adult patients in an acute inpatient psychiatric ward.…

  1. Acute low back problems in adults: assessment and treatment. Agency for Health Care Policy and Research.

    PubMed

    1994-12-01

    This Quick Reference Guide for Clinicians contains highlights from the Clinical Practice Guideline version of Acute Low Back Problems in Adults, which was developed by a private-sector panel of health care providers and consumers. The Quick Reference Guide is an example of how a clinician might implement the panel's findings and recommendations on the management of acute low back problems in working-age adults. Topics covered include the initial assessment of patients presenting with acute low back problems, identification of red flags that may indicate the presence of a serious underlying medical condition, initial management, special studies and diagnostic considerations, and further management considerations. Instructions for clinical testing for sciatic tension, recommendations for sitting and unassisted lifting, tests for identification of clinical pathology, and algorithms for patient management are included.

  2. Arterial cerebrovascular complications in 94 adults with acute bacterial meningitis

    PubMed Central

    2011-01-01

    Introduction Intracranial vascular complications are an important complication of acute bacterial meningitis. Ischemic stroke in meningitis is reported as a result of vasculitis, vasospasm, endocarditis or intraarterial thrombosis. The aim of the study was to identify the value of measuring cerebral blood flow velocity (CBFv) on transracranial doppler (TCD) in the identification of patients at risk for meningitis-associated stroke. Methods We retrospectively studied patients with acute bacterial meningitis who were treated in our university hospital from 2000 to 2009. Data were analyzed with the main focus on the incidence of an increase of CBFv on TCD, defined as peak systolic values above 150 cm/s, and the development of stroke. Results In total, 114 patients with acute bacterial meningitis were treated, 94 of them received routine TCD studies during their hospital stay. 41/94 patients had elevated CBFv values. This increase was associated with an increased risk of stroke (odds ratio (95% confidence intervall) = 9.15 (1.96-42.67); p < 0.001) and unfavorable outcome (Glasgow Outcome Score < 4; odds ratio (95% confidence intervall) = 2.93 (1.23-6.98); p = 0.018). 11/32 (34.4%) patients with an increase of CBFv who received nimodipine and 2/9 (22.2%) patients with an increase of CBFv who did not receive nimodipine developed stroke (p = 0.69). Conclusions In summary, TCD was found to be a valuable bedside test to detect arterial alterations in patients with bacterial meningitis. These patients have an increased risk of stroke. PMID:22112693

  3. Carbamazepine for acute and chronic pain in adults

    PubMed Central

    Wiffen, Philip J; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Carbamazepine is used to treat chronic neuropathic pain. Objectives Evaluation of analgesic efficacy and adverse effects of carbamazepine for acute and chronic pain management (except headaches). Search methods Randomised controlled trials (RCTs) of carbamazepine in acute, chronic or cancer pain were identified, searching MEDLINE, EMBASE, SIGLE and Cochrane CENTRAL to June 2010, reference lists of retrieved papers, and reviews. Selection criteria RCTs reporting the analgesic effects of carbamazepine. Data collection and analysis Two authors independently extracted results and scored for quality. Numbers needed to treat to benefit (NNT) or harm (NNH) with 95% confidence intervals (CI) were calculated from dichotomous data for effectiveness, adverse effects and adverse event withdrawal. Issues of study quality, size, duration, and outcomes were examined. Main results Fifteen included studies (12 cross-over design; three parallel-group) with 629 participants. Carbamazepine was less effective than prednisolone in preventing postherpetic neuralgia following acute herpes zoster (1 study, 40 participants). No studies examined acute postoperative pain. Fourteen studies investigated chronic neuropathic pain: two lasted eight weeks, others were four weeks or less (mean 3 weeks, median 2 weeks). Five had low reporting quality. Ten involved fewer than 50 participants; mean and median maximum treatment group sizes were 34 and 29. Outcome reporting was inconsistent. Most placebo controlled studies indicated that carbamazepine was better than placebo. Five studies with 298 participants provided dichotomous results; 70% improved with carbamazepine and 12% with placebo. Carbamazepine at any dose, using any definition of improvement was significantly better than placebo (70% versus 12% improved; 5 studies, 298 participants); relative benefit 6.1 (3.9 to 9.7), NNT 1.7 (1.5 to 2.0). Four studies (188 participants) reporting outcomes equivalent to 50% pain reduction or more

  4. Regulatory T cells are decreased in acute RHDV lethal infection of adult rabbits.

    PubMed

    Teixeira, Luzia; Marques, Raquel M; Aguas, Artur P; Ferreira, Paula G

    2012-08-15

    Rabbit hemorrhagic disease virus (RHDV) is the etiologic agent of rabbit hemorrhagic disease (RHD), an acute lethal infection that kills 90% of adult rabbits due to severe acute liver inflammation. Interestingly, young rabbits are naturally resistant to RHDV infection. Here, we have compared naturally occurring CD4(+)Foxp3(+) regulatory T cells (Tregs) between young and adult rabbits after infection by RHDV. The number and frequency of Tregs was decreased in the spleen of adult rabbits 24h after the RHDV infection; this was in contrast with the unchanged number and frequency of splenic Tregs found in young rabbits after the same infection. Also, serum levels of IL-10 and TGF-β were enhanced in the infected adult rabbits whereas no alteration was observed in infected young rabbits. However, this increase is accompanied by a burst of pro-inflammatory cytokines, but seems not able to prevent the death of the animals with severe acute liver inflammation in few days after infection. Since Tregs downregulate inflammation, we conclude that their decrease may contribute to the natural susceptibility of adult rabbits to RHDV infection.

  5. Incidence and outcomes for adults diagnosed with acute myeloid leukemia in the north of England: a real world study.

    PubMed

    McGregor, Andrew Kenneth; Moulton, Deborah; Bown, Nick; Cuthbert, Gavin; Bourn, David; Mathew, Susanna; Dang, Raymond; Mounter, Philip; Jones, Gail

    2016-07-01

    We conducted a retrospective population-based study of patients diagnosed with acute myeloid leukemia (AML) in northern England (population 3.1 million) in order to assess the impact of age and genetics on outcome. Four hundred and sixteen patients were diagnosed with AML, between 2007 and 2011. In those aged ≤60 years (n = 20) with acute promyelocytic leukemia (APL) overall survival (OS) was 100%. For non-APL patients aged ≤60 years, OS for those with favorable, intermediate and adverse cytogenetics was not reached, 17 and 9.8 months, respectively (p = 0.0001). Of particular note, intensively treated patients aged >60 years with intermediate cytogenetics and FLT3-/NPM1+ status had a five-year survival of 60% versus median OS of 11 months for other subsets (p = 0.04). Population-based studies reduce selection bias and have utility in studying rarer diseases, particularly in populations that recruit poorly to trials. The highly favorable outcome in our subgroup of intensively-treated FLT3-/NPM1+ older patients merits further study.

  6. Perceived social support among adults seeking care for acute respiratory tract infections in US EDs.

    PubMed

    Levin, Sara K; Metlay, Joshua P; Maselli, Judith H; Kersey, Ayanna S; Camargo, Carlos A; Gonzales, Ralph

    2009-06-01

    Emergency departments (EDs) provide a disproportionate amount of care to disenfranchised and vulnerable populations. We examined social support levels among a diverse population of adults seeking ED care for acute respiratory tract infections. A convenience sample of adults seeking care in 1 of 15 US EDs was telephone interviewed 1 to 6 weeks postvisit. The Multidimensional Scale of Perceived Social Support (7-point Likert) assessed social support across 3 domains: friends, family, and significant others. Higher scores indicate higher support. Of 1104 subjects enrolled, 704 (64%) completed the follow-up interview. Factor analysis yielded 3 factors. Mean social support score was 5.54 (SD 1.04). Female sex, greater household income, and better health status were independently associated with higher levels of social support. Social support levels among adults seeking care in the ED for acute respiratory tract infections are similar to general population cohorts, suggesting that social support is not a strong determinant of health care seeking in EDs.

  7. Central venous catheter infection in adults in acute hospital settings.

    PubMed

    Jones, Clare A

    As well as the human cost, central venous catheter (CVC)-related bloodstream infections significantly inflate hospital costs, mainly through increased length of stay in hospital, particularly in intensive care. This literature review appraises recent research on measures used to minimize CVC-related infection and compares it with current best practice. Randomized controlled trials and systematic reviews published on the subject between 2000 and 2005 were reviewed, concentrating on non-tunnelled, short-term CVCs in the acute hospital setting. The new evidence mainly backs up current best practice. However, skin disinfection could be improved by using alcoholic chlorhexidine followed by aqueous povidone-iodine before CVC insertion. Also, alcoholic chlorhexidine is the preferred solution for cleaning the hubs/connectors before accessing the CVC. Good hand hygiene and quality control and education programmes are vital to improve patient care. More research is needed to clarify the effectiveness of certain interventions and technologies, such as antimicrobial CVCs.

  8. Acute neuropsychiatric disorders in adolescents and young adults with Down syndrome: Japanese case reports

    PubMed Central

    Akahoshi, Keiko; Matsuda, Hiroshi; Funahashi, Masuko; Hanaoka, Tomoyuki; Suzuki, Yasuyuki

    2012-01-01

    Background: The aim of this study was to evaluate acute neuropsychiatric disorders in adolescents and young adults with Down syndrome. We report 13 Japanese adolescents or young adults with Down syndrome who developed acute neuropsychiatric disorders including withdrawal, depression, obsessive-compulsive behaviors, and occasional delusions or hallucinations. Methods: The following information was collected from each patient: age at onset of acute neuropsychiatric disorder, complications, signs and symptoms, personality traits before the onset of the acute neuropsychiatric disorder, prescribed medications with their respective doses and the response to treatment, and senile changes observed on magnetic resonance imaging or computed tomography. Results: The mean age at onset of these disorders was 21.2 years. Brain imaging showed almost senile changes; patients responded well to low-dose psychotropic therapy. Patients had an onset at a young age and presented with treatable conditions, although the average age of the onset of Alzheimer’s disease is generally over 40 years of age in patients with Down syndrome. Conclusion: These findings suggest that the pathology of acute neuropsychiatric disorder in patients with Down syndrome may be related to presenile changes; however, these disorders present features and a clinical course that is different from those presented in typical Alzheimer’s disease with Down syndrome. PMID:22888254

  9. Acute effects of exercise and active video games on adults' reaction time and perceived exertion.

    PubMed

    Guzmán, José F; López-García, Jesús

    2016-11-01

    The purpose of the present study was to examine the acute effects of resting, aerobic exercise practised alone, and aerobic exercise with active video games (AVG), on complex reaction time (CRT) and the post-exercise acute rate of perceived exertion (RPE) in young healthy adults. The experimental group was composed of 92 healthy young adults, 78 males and 13 females (age M = 21.9 ± 2.7 years) who completed two sessions, A and B. In session A, participants rode 30 min on an ergometer, while in session B they exercised for 30 min on an ergometer while playing an AVG on a Wii. The control group was composed of 30 young adults, 26 males and 4 females (age M = 21.4 ± 2.9 years) who rested for 30 min. In each session, a CRT task was performed before and after exercising or resting, and post-exercise global RPE was noted. Repeated measures general linear model (GLM) and Wilcoxon tests were performed. (1) Both aerobic exercise alone and aerobic exercise combined with AVG improved CRT, while resting did not; (2) aerobic exercise combined with AVG did not improve CRT more than aerobic exercise only; and (3) RPE was lower after aerobic exercise combined with AVG compared with aerobic exercise only. In young adults, exercise produces acute benefits on CRT, and practising exercise with AVG helps to decrease RPE.

  10. Acute effects of exercise and active video games on adults' reaction time and perceived exertion.

    PubMed

    Guzmán, José F; López-García, Jesús

    2016-11-01

    The purpose of the present study was to examine the acute effects of resting, aerobic exercise practised alone, and aerobic exercise with active video games (AVG), on complex reaction time (CRT) and the post-exercise acute rate of perceived exertion (RPE) in young healthy adults. The experimental group was composed of 92 healthy young adults, 78 males and 13 females (age M = 21.9 ± 2.7 years) who completed two sessions, A and B. In session A, participants rode 30 min on an ergometer, while in session B they exercised for 30 min on an ergometer while playing an AVG on a Wii. The control group was composed of 30 young adults, 26 males and 4 females (age M = 21.4 ± 2.9 years) who rested for 30 min. In each session, a CRT task was performed before and after exercising or resting, and post-exercise global RPE was noted. Repeated measures general linear model (GLM) and Wilcoxon tests were performed. (1) Both aerobic exercise alone and aerobic exercise combined with AVG improved CRT, while resting did not; (2) aerobic exercise combined with AVG did not improve CRT more than aerobic exercise only; and (3) RPE was lower after aerobic exercise combined with AVG compared with aerobic exercise only. In young adults, exercise produces acute benefits on CRT, and practising exercise with AVG helps to decrease RPE. PMID:27239681

  11. Management of acute promyelocytic leukemia in the elderly.

    PubMed

    Lo-Coco, Francesco; Latagliata, Roberto; Breccia, Massimo

    2013-01-01

    Unlike other forms of AML, APL is less frequently diagnosed in the elderly and has a relatively favourable outcome. Elderly patients with APL seem at least as responsive to therapy as do younger patients, but rates of response and survival are lower in this age setting owing to a higher incidence of early deaths and deaths in remission when conventional treatment with ATRA and chemotherapy is used. Elderly APL patients are more likely to present with low-risk features compared with younger patients, and this may explain the relative low risk of relapse reported in several clinical studies. Alternative approaches, such as arsenic trioxide and gentuzumab ozogamicin have been tested with success in this setting and could replace in the near future frontline conventional chemotherapy and ATRA.

  12. Late differentiation syndrome in acute promyelocytic leukemia: a challenging diagnosis.

    PubMed

    Cabral, Renata; Caballero, Juan Carlos; Alonso, Sara; Dávila, Julio; Cabrero, Monica; Caballero, Dolores; Vázquez, Lourdes; Sánchez-Guijo, Fermin; López, Lucia; Cañizo, Maria C; Mateos, Maria V; González, Marcos

    2014-11-19

    Detailed knowledge about differentiation syndrome (DS) has remained limited. There are 2 large studies conducted by the Spanish workgroup PETHEMA (Programa Español de Tratamientos en Hematología; Spanish Program on Hematology Treatments) and the European group trial (LPA 96-99 and APL 93) in which the incidence, characteristics, prognostic factors and outcome of patients developing DS are evaluated. Both have described the median time of DS development between 10 and 12 days. The severity of the DS has been evaluated in the study conducted by PETHEMA, and severe DS usually occurs at the beginning of the treatment (median of 6 days), as compared with moderate DS (median of 15 days). We report here in two cases of late severe DS, with late diagnosis due to both time and form of presentation. We discuss the physiopathology, clinical presentation, prophylaxis and treatment of DS.

  13. Studying nursing interventions in acutely ill, cognitively impaired older adults

    PubMed Central

    McCauley, Kathleen; Bradway, Christine; Hirschman, Karen B; Naylor, Mary D

    2015-01-01

    Background Between one and two of every five hospitalized older adults have cognitive deficits, often not accurately assessed or well managed. Cognitive impairment adds substantially to the complexity of these patients’ care, places them at high risk for poor outcomes and increases the cost of health care. Methods We describe three evidence-based interventions, each capitalizing on the unique contributions of nurses and designed to improve outcomes of hospitalized older adults who have cognitive deficits. Interventions of varying intensity were compared across three hospitals (Phase I) and subsequently within the same hospitals (Phase II). All enrolled patients were screened during their index hospitalizations and cognitive deficits were communicated to relevant health care team members (Augmented Standard Care-ASC, lowest intensity). At one hospital, ASC was the only intervention. Patients at a second hospital also had care influenced by specially prepared registered nurses (Resource Nurse Care-RNC, medium intensity). Finally, patients at third hospital also received advanced practice nurse coordinated care (Transitional Care Model-TCM, higher intensity). In Phase II, newly enrolled patients at these same hospitals all received the TCM. We summarize major themes from review of multiple data sources and researcher recollections related to facilitators and barriers to implementing a complex research study. Findings Effective implementation of the three intervention strategies depended on clinician engagement and communication; degree of participation by nurses in the educational program with subsequent practice improvement; and success of advanced practice nurses in implementing the TCM with both with patients, family caregivers and clinicians. Implications Based on lessons learned in implementing complex research studies within the “real world” of clinical practice settings, recommendations focus on strengthening facilitators, minimizing barriers and gaining

  14. Factors influencing prognosis in adults with acute myelogenous leukaemia.

    PubMed Central

    Crowther, D.; Beard, M. E.; Bateman, C. J.; Sewell, R. L.

    1975-01-01

    A study of the thymidine labelling index (TLI) of bone marrow blast cells in 58 untreated patients with acute myelogenous leukemia showed no correlation with remission rate but there was a strong correlation between labelling index and remission length in the 21 patients who achieved remission. The median remission length of the patients was 33 weeks. Of the 12 patients with initial labelling indices greater than 10%, only 2 had remissions longer than 33 weeks whereas 8 of the 9 patients with labelling indices less than 10% had remissions longer than 33 weeks. No correlation could be found between the degree of cytological differentiation and remission induction, remission length or survival. No correlation was found between the TLI and the degree of cytological differentiation. Age and initial platelet count were confirmed to be important factors influencing complete remission rate, but these factors did not correlate with remission length. Sixteen patients had their pretreatment sera assayed for mouse marrow colony stimulating activity and inhibitor levels but there was no correlation with subsequent response to treatment, although the number of patients examined was clearly too small for any definite conclusions to be drawn. PMID:1082343

  15. Epidemiology of severe acute respiratory syndrome (SARS): adults and children.

    PubMed

    Zhong, Nan-Shan; Wong, Gary W K

    2004-12-01

    Severe acute respiratory syndrome (SARS) is a newly described respiratory infection with pandemic potential. The causative agent is a new strain of coronavirus most likely originating from wild animals. This disease first emerged in November 2002 in Guangdong Province, China. Early in the outbreak the infection had been transmitted primarily via household contacts and healthcare settings. In late February 2003 the infection was transmitted to Hong Kong when an infected doctor from the mainland visited there. During his stay in Hong Kong at least 17 guests and visitors were infected at the hotel at which he stayed. By modern day air travel, the infection was rapidly spread to other countries including Vietnam, Singapore and Canada by these infected guests. With the implementation of effective control strategies including early isolation of suspected cases, strict infection control measures in the hospital setting, meticulous contact tracing and quarantine, the outbreak was finally brought under control by July 2003. In addition, there were another two events of SARS in China between the end of December 2003 and January 2004 and from March to May 2004; both were readily controlled without significant patient spread. PMID:15531250

  16. Defining and Treating Older Adults with Acute Myeloid Leukemia Who Are Ineligible for Intensive Therapies

    PubMed Central

    Pettit, Kristen; Odenike, Olatoyosi

    2015-01-01

    Although acute myeloid leukemia (AML) is primarily a disease of older adults (age ≥60 years), the optimal treatment for older adults remains largely undefined. Intensive chemotherapy is rarely beneficial for frail older adults or those with poor-risk disease, but criteria that define fitness and/or appropriateness for intensive chemotherapy remain to be standardized. Evaluation of disease-related and patient-specific factors in the context of clinical decision making has therefore been largely subjective. A uniform approach to identify those patients most likely to benefit from intensive therapies is needed. Here, we review currently available objective measures to define older adults with AML who are ineligible for intensive chemotherapy, and discuss promising investigational approaches. PMID:26697412

  17. Novel and Emerging Drugs for Acute Myeloid Leukemia

    PubMed Central

    Stein, E.M.; Tallman, M.S.

    2014-01-01

    Acute myeloid leukemia (AML) is a challenging disease to treat with the majority of patients dying from their illness. While overall survival has been markedly prolonged in acute promyelocytic leukemia (APL), survival in younger adults with other subtypes of AML has only modestly improved over the last twenty years. Physicians who treat AML eagerly await drugs like Imatinib for chronic myeloid leukemia, Cladribine for hairy cell leukemia, and Rituximab for non-Hodgkin Lymphoma which have had an important impact on improving outcome. Recent research efforts have focused on refining traditional chemotherapeutic agents to make them more active in AML, targeting specific genetic mutations in myeloid leukemia cells, and utilizing novel agents such as Lenalidomide that have shown activity in other hematologic malignancies. Here, we focus on reviewing the recent literature on agents that may assume a role in clinical practice for patients with AML over the next five years. PMID:22483153

  18. The effects of acute alcohol on motor impairments in adolescent, adult, and aged rats.

    PubMed

    Ornelas, Laura C; Novier, Adelle; Van Skike, Candice E; Diaz-Granados, Jaime L; Matthews, Douglas B

    2015-03-01

    Acute alcohol exposure has been shown to produce differential motor impairments between aged and adult rats and between adolescent and adult rats. However, the effects of acute alcohol exposure among adolescent, adult, and aged rats have yet to be systematically investigated within the same project using a dose-dependent analysis. We sought to determine the age- and dose-dependent effects of acute alcohol exposure on gross and coordinated motor performance across the rodent lifespan. Adolescent (PD 30), adult (PD 70), and aged (approximately 18 months) male Sprague-Dawley rats were tested on 3 separate motor tasks: aerial righting reflex (ARR), accelerating rotarod (RR), and loss of righting reflex (LORR). In a separate group of animals, blood ethanol concentrations (BEC) were determined at multiple time points following a 3.0 g/kg ethanol injection. Behavioral tests were conducted with a Latin square repeated-measures design in which all animals received the following doses: 1.0 g/kg or 2.0 g/kg alcohol or saline over 3 separate sessions via intraperitoneal (i.p.) injection. During testing, motor impairments were assessed on the RR 10 min post-injection and on ARR 20 min post-injection. Aged animals spent significantly less time on the RR when administered 1.0 g/kg alcohol compared to adult rats. In addition, motor performance impairments significantly increased with age after 2.0 g/kg alcohol administration. On the ARR test, aged rats were more sensitive to the effects of 1.0 g/kg and 2.0 g/kg alcohol compared to adolescents and adults. Seven days after the last testing session, animals were given 3.0 g/kg alcohol and LORR was examined. During LORR, aged animals slept longer compared to adult and adolescent rats. This effect cannot be explained solely by BEC levels in aged rats. The present study suggests that acute alcohol exposure produces greater motor impairments in older rats when compared to adolescent and adult rats and begins to establish a

  19. Efficacy of Retigabine on Acute Limbic Seizures in Adult Rats

    PubMed Central

    Friedman, LK; Slomko, AM; Wongvravit, JP; Naseer, Z; Hu, S; Wan, WY; Ali, SS

    2015-01-01

    Background and Purpose: The efficacy of retigabine (RGB), a positive allosteric modulator of K+ channels indicated for adjunct treatment of partial seizures, was studied in two adult models of kainic acid (KA)-induced status epilepticus to determine it’s toleratbility. Methods: Retigabine was administered systemiclly at high (5 mg/kg) and low (1–2 mg/kg) doses either 30 min prior to or 2 hr after KA-induced status epilepticus. High (1 µg/µL) and low (0.25 µg/µL) concentrations of RGB were also delivered by intrahippocampal microinjection in the presence of KA. Results: Dose-dependent effects of RGB were observed with both models. Lower doses increased seizure behavior latency and reduced the number of single spikes and synchronized burst events in the electroencephalogram (EEG). Higher doses worsened seizure behavior, produced severe ataxia, and increased spiking activity. Animals treated with RGB that were resistant to seizures did not exhibit significant injury or loss in GluR1 expression; however if stage 5–6 seizures were reached, typical hippocampal injury and depletion of GluR1 subunit protein in vulernable pyramidal fields occurred. Conclusions: RGB was neuroprotective only if seizures were significantly attenuated. GluR1 was simultaneously suppressed in the resistant granule cell layer in presence of RGB which may weaken excitatory transmission. Biphasic effects observed herein suggest that the human dosage must be carefully scrutinized to produce the optimal clinical response. PMID:26819936

  20. Review of Acute Traumatic Closed Mallet Finger Injuries in Adults.

    PubMed

    Salazar Botero, Santiago; Hidalgo Diaz, Juan Jose; Benaïda, Anissa; Collon, Sylvie; Facca, Sybille; Liverneaux, Philippe André

    2016-03-01

    In adults, mallet finger is a traumatic zone I lesion of the extensor tendon with either tendon rupture or bony avulsion at the base of the distal phalanx. High-energy mechanisms of injury generally occur in young men, whereas lower energy mechanisms are observed in elderly women. The mechanism of injury is an axial load applied to a straight digit tip, which is then followed by passive extreme distal interphalangeal joint (DIPJ) hyperextension or hyperflexion. Mallet finger is diagnosed clinically, but an X-ray should always be performed. Tubiana's classification takes into account the size of the bony articular fragment and DIPJ subluxation. We propose to stage subluxated fractures as stage III if the subluxation is reducible with a splint and as stage IV if not. Left untreated, mallet finger becomes chronic and leads to a swan-neck deformity and DIPJ osteoarthritis. The goal of treatment is to restore active DIPJ extension. The results of a six- to eight-week conservative course of treatment with a DIPJ splint in slight hyperextension for tendon lesions or straight for bony avulsions depends on patient compliance. Surgical treatments vary in terms of the approach, the reduction technique, and the means of fixation. The risks involved are stiffness, septic arthritis, and osteoarthritis. Given the lack of consensus regarding indications for treatment, we propose to treat all cases of mallet finger with a dorsal glued splint except for stage IV mallet finger, which we treat with extra-articular pinning. PMID:27019806

  1. Review of Acute Traumatic Closed Mallet Finger Injuries in Adults

    PubMed Central

    Salazar Botero, Santiago; Hidalgo Diaz, Juan Jose; Benaïda, Anissa; Collon, Sylvie; Facca, Sybille

    2016-01-01

    In adults, mallet finger is a traumatic zone I lesion of the extensor tendon with either tendon rupture or bony avulsion at the base of the distal phalanx. High-energy mechanisms of injury generally occur in young men, whereas lower energy mechanisms are observed in elderly women. The mechanism of injury is an axial load applied to a straight digit tip, which is then followed by passive extreme distal interphalangeal joint (DIPJ) hyperextension or hyperflexion. Mallet finger is diagnosed clinically, but an X-ray should always be performed. Tubiana's classification takes into account the size of the bony articular fragment and DIPJ subluxation. We propose to stage subluxated fractures as stage III if the subluxation is reducible with a splint and as stage IV if not. Left untreated, mallet finger becomes chronic and leads to a swan-neck deformity and DIPJ osteoarthritis. The goal of treatment is to restore active DIPJ extension. The results of a six- to eight-week conservative course of treatment with a DIPJ splint in slight hyperextension for tendon lesions or straight for bony avulsions depends on patient compliance. Surgical treatments vary in terms of the approach, the reduction technique, and the means of fixation. The risks involved are stiffness, septic arthritis, and osteoarthritis. Given the lack of consensus regarding indications for treatment, we propose to treat all cases of mallet finger with a dorsal glued splint except for stage IV mallet finger, which we treat with extra-articular pinning. PMID:27019806

  2. Decitabine, Cytarabine, and Daunorubicin Hydrochloride in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-07-20

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  3. MDCT of acute colitis in adults: an update in current imaging features.

    PubMed

    Barral, M; Boudiaf, M; Dohan, A; Hoeffel, C; Camus, M; Pautrat, K; Fishman, E K; Cohen, S; Soyer, P

    2015-02-01

    Acute colitis is often diagnosed on multidetector row computed tomography (MDCT) because patients with this condition present with abdominal pain and a variety of nonspecific symptoms. Acute colitis has multiple causes with varying degrees of severity. Analysis of the extent of colonic involvement, presence of specific MDCT imaging features and associated signs should help radiologist narrow the diagnosis. Integrating the results of clinical examination and biological tests is mandatory, and in case of ambiguous or nonspecific MDCT findings, endoscopy and colon biopsy should always be considered for a definite diagnosis. The purpose of this review is to discuss and illustrate MDCT features that are helpful for characterizing acute colitis in adults and to provide an update in current MDCT features. PMID:24835625

  4. MDCT of acute colitis in adults: an update in current imaging features.

    PubMed

    Barral, M; Boudiaf, M; Dohan, A; Hoeffel, C; Camus, M; Pautrat, K; Fishman, E K; Cohen, S; Soyer, P

    2015-02-01

    Acute colitis is often diagnosed on multidetector row computed tomography (MDCT) because patients with this condition present with abdominal pain and a variety of nonspecific symptoms. Acute colitis has multiple causes with varying degrees of severity. Analysis of the extent of colonic involvement, presence of specific MDCT imaging features and associated signs should help radiologist narrow the diagnosis. Integrating the results of clinical examination and biological tests is mandatory, and in case of ambiguous or nonspecific MDCT findings, endoscopy and colon biopsy should always be considered for a definite diagnosis. The purpose of this review is to discuss and illustrate MDCT features that are helpful for characterizing acute colitis in adults and to provide an update in current MDCT features.

  5. Acute Whole-Body Vibration does not Facilitate Peak Torque and Stretch Reflex in Healthy Adults

    PubMed Central

    Yeung, Ella W.; Lau, Cheuk C.; Kwong, Ada P.K.; Sze, Yan M.; Zhang, Wei Y.; Yeung, Simon S.

    2014-01-01

    The acute effect of whole-body vibration (WBV) training may enhance muscular performance via neural potentiation of the stretch reflex. The purpose of this study was to investigate if acute WBV exposure affects the stretch induced knee jerk reflex [onset latency and electromechanical delay (EMD)] and the isokinetic knee extensor peak torque performance. Twenty-two subjects were randomly assigned to the intervention or control group. The intervention group received WBV in a semi-squat position at 30° knee flexion with an amplitude of 0.69 mm, frequency of 45 Hz, and peak acceleration of 27.6 m/s2 for 3 minutes. The control group underwent the same semii-squatting position statically without exposure of WBV. Two-way mixed repeated measures analysis of variance revealed no significant group effects differences on reflex latency of rectus femoris (RF) and vastus lateralis (VL; p = 0.934 and 0.935, respectively) EMD of RF and VL (p = 0.474 and 0.551, respectively) and peak torque production (p = 0.483) measured before and after the WBV. The results of this study indicate that a single session of WBV exposure has no potentiation effect on the stretch induced reflex and peak torque performance in healthy young adults. Key Points There is no acute potentiation of stretch reflex right after whole body vibration. Acute whole body vibration does not improve mus-cle peak torque performance in healthy young adults. PMID:24570602

  6. Acute Alcohol Use and Injury Patterns in Young Adult Prehospital Patients.

    PubMed

    Barton, David J; Tift, Frank W; Cournoyer, Lauren E; Vieth, Julie T; Hudson, Korin B

    2016-01-01

    The objective was to determine if acute alcohol consumption is associated with differences in injury pattern among young adult patients with traumatic injuries presenting to emergency medical services (EMS). A cross-sectional, retrospective review of prehospital patient care reports (PCRs) was conducted evaluating injured patients who presented to a collegiate EMS agency from January 1, 2011 to December 31, 2012. Included patients were age 18-24 y and sustained an injury within the previous 24 h. PCRs were reviewed independently by two abstractors to determine if the patient was documented to have acutely consumed alcohol proximate to his/her injury. Primary and secondary sites of regional body injury were recorded. Injury severity was recorded using the Revised Trauma Score (RTS). The association between primary injury site and acute alcohol use was assessed using a chi-square test. Multiple logistic regression was used to control for sex in predicting injury type. Of 440 injured patients, 135 (30.6%) had documented alcohol use prior to injury. Acute alcohol consumption altered the overall pattern of regional injury (p < 0.001). Alcohol users were more likely to present with injury secondary to assault, fall/trip, and unknown mechanism of injury (p < 0.001, all comparisons). RTS scores were statistically lower in the alcohol group (p < 0.001), although the clinical significance of this is unclear. Controlling for sex, acute alcohol consumption predicted increased risk of head/neck injury 5.59-fold (p < 0.001). Acute alcohol use in collegiate EMS patients appears to alter injury patterns in young adults and increases risk of head/neck injury. EMS providers in similar agencies should consider these trends when assessing and treating injured college-aged patients. PMID:27002348

  7. Acute dietary nitrate supplementation enhances compensatory vasodilation during hypoxic exercise in older adults.

    PubMed

    Casey, Darren P; Treichler, David P; Ganger, Charles T; Schneider, Aaron C; Ueda, Kenichi

    2015-01-15

    We have previously demonstrated that aging reduces the compensatory vasodilator response during hypoxic exercise due to blunted nitric oxide (NO) signaling. Recent evidence suggests that NO bioavailability can be augmented by dietary nitrate through the nitrate-nitrite pathway. Thus we tested the hypothesis that acute dietary nitrate supplementation increases the compensatory vasodilator response to hypoxic exercise, particularly in older adults. Thirteen young (25 ± 1 yr) and 12 older (64 ± 2 yr) adults performed rhythmic forearm exercise at 20% of maximum voluntary contraction during normoxia and hypoxia (∼80% O2 saturation); both before (control) and 3 h after beetroot juice (BR) consumption. Forearm vascular conductance (FVC; ml·min(-1)·100 mmHg(-1)) was calculated from forearm blood flow (ml/min) and blood pressure (mmHg). Compensatory vasodilation was defined as the relative increase in FVC due to hypoxic exercise (i.e., % increase compared with respective normoxic exercise trial). Plasma nitrite was determined from venous blood samples obtained before the control trials and each of the exercise trials (normoxia and hypoxia) after BR. Consumption of BR increased plasma nitrite in both young and older adults (P < 0.001). During the control condition, the compensatory vasodilator response to hypoxic exercise was attenuated in older compared with young adults (3.8 ± 1.7% vs. 14.2 ± 1.2%, P < 0.001). Following BR consumption, compensatory vasodilation did not change in young (13.7 ± 3.3%, P = 0.81) adults but was substantially augmented in older adults (11.4 ± 2.1%, P < 0.01). Our data suggest that acute dietary nitrate supplementation increases the compensatory vasodilator response to hypoxic exercise in older but not young adults.

  8. [Acute intoxication in adults - what you should know].

    PubMed

    Zilker, Th

    2014-01-01

    Ingestion of household products and plants are the leading cause for calls to the poison control centres as far as children are involved. Severe intoxication in children has become infrequent due to childproofed package and blister packs for drugs. Chemical accidents in adults give rise to hospital admission in only 5 %. Suicidal selfpoisonings are still a challenge for paramedics, emergency and hospital doctors. Natural toxins as amatoxins, cholchicine and snakebites can lead to severe intoxication. Sedatives, antidepressants and analgesics are the drugs which are often used for suicidal intent due to their availability. Quetiapine and paracetamol are the drugs which are ingested for attempted suicide/ suicide mostly. The treatment of poisoning centers on the severity which can be judged by the poison severity score, the Reed classification or the GCS.Most intoxicated patients can be treated symptomatically or by intensive care measurements. Antidotal treatment however is needed for some specific poisonings.Exact sample drawing is essential for diagnostic and forensic purposes. There is no evidence based proof for the effectiveness of primary detoxification from the gastrointestinal tract like forced emesis, gastric lavage or the use of cathartics. Early after the ingestion of a harmful substance the administration of activated charcoal seems advisable. Hemodialysis can remove water soluble substances with a small volume of distribution. Multiple charcoal administration may exhibit some influence on secondary detoxification. Provision of evidence of the efficacy for newer antidotes like hydroxocobalamin in smoke inhalation, fomepizol for toxic alcohols and silibinin for amanita poisoning are emerging. Two recently recommended therapeutic principles have still to demonstrate their ability: Firstly the treatment of patients with calcium receptor antagonistic and beta-receptor antagonistic agents poisoning by high dose of insulin plus glucose, secondly the

  9. [Acute intoxication in adults - what you should know].

    PubMed

    Zilker, Th

    2014-01-01

    Ingestion of household products and plants are the leading cause for calls to the poison control centres as far as children are involved. Severe intoxication in children has become infrequent due to childproofed package and blister packs for drugs. Chemical accidents in adults give rise to hospital admission in only 5 %. Suicidal selfpoisonings are still a challenge for paramedics, emergency and hospital doctors. Natural toxins as amatoxins, cholchicine and snakebites can lead to severe intoxication. Sedatives, antidepressants and analgesics are the drugs which are often used for suicidal intent due to their availability. Quetiapine and paracetamol are the drugs which are ingested for attempted suicide/ suicide mostly. The treatment of poisoning centers on the severity which can be judged by the poison severity score, the Reed classification or the GCS.Most intoxicated patients can be treated symptomatically or by intensive care measurements. Antidotal treatment however is needed for some specific poisonings.Exact sample drawing is essential for diagnostic and forensic purposes. There is no evidence based proof for the effectiveness of primary detoxification from the gastrointestinal tract like forced emesis, gastric lavage or the use of cathartics. Early after the ingestion of a harmful substance the administration of activated charcoal seems advisable. Hemodialysis can remove water soluble substances with a small volume of distribution. Multiple charcoal administration may exhibit some influence on secondary detoxification. Provision of evidence of the efficacy for newer antidotes like hydroxocobalamin in smoke inhalation, fomepizol for toxic alcohols and silibinin for amanita poisoning are emerging. Two recently recommended therapeutic principles have still to demonstrate their ability: Firstly the treatment of patients with calcium receptor antagonistic and beta-receptor antagonistic agents poisoning by high dose of insulin plus glucose, secondly the

  10. Acute complications and outcomes of acute head injury in adult patients with haemophilia.

    PubMed

    Rivera-Núñez, Maria A; Borobia, Alberto M; García-Erce, Jose A; Martí de Gracia, Milagros; Pérez-Perilla, Patricia; Quintana-Díaz, Manuel

    2014-10-01

    The aim of the present study is to describe the clinical and epidemiological characteristics, complications and outcome of patients with haemophilia and acute head injury (AHI) at the emergency department (ED), and develop a protocol to prevent early and late complications. This is a retrospective cohort study including all patients with haemophilia and AHI admitted to the ED. We identified 26 patients with AHI. A computed tomography scan was carried out on all patients at admission, and again on two patients (with neurosurgical complications) 48 h later. The discharge diagnosis was as follows: 3.8% subdural haematoma, 3.8% cerebellar epidural haematoma and 92.3% uncomplicated AHI. We propose the following protocol: a computed tomography scan upon arrival and another within 48 h post-AHI, unless there is an absence of clinical symptoms. In addition, all patients must self-administer a clotting factor as soon as possible and be observed in the ED for at least 48 h.

  11. Staphylococcus aureus: is it a pathogen of acute bacterial sinusitis in children and adults?

    PubMed

    Wald, Ellen R

    2012-03-01

    Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the etiologic agents of acute bacterial sinusitis (ABS). Staphylococcus aureus has been an uncommon cause of ABS despite its frequent occupancy within the anterior nares. A quantitative culture of a maxillary sinus aspirate is the gold standard for determining etiology of ABS. Cultures of the middle meatus cannot be used as a surrogate for a maxillary sinus aspirate in children with ABS, although they may be used in adults if interpretation is confined to usual sinus pathogens. Recent studies highlighting S. aureus as a major pathogen in ABS should be interpreted cautiously. Most isolates in recent pediatric studies were derived from cultures of the middle meatus. The range of reported results for the incidence of S. aureus as a cause of ABS in adults is similar to the results reported for staphylococcal colonization of the middle meatus in healthy adults.

  12. Physiological and behavioral effects of acute ethanol hangover in juvenile, adolescent, and adult rats.

    PubMed

    Brasser, Susan M; Spear, Norman E

    2002-04-01

    This study examined differential responding of juvenile, adolescent, and adult rats after intoxication from an acute alcohol challenge. Experiment I generated blood ethanol curves for subjects 25, 35, or 110 days postnatal, after doses of 2.0 or 4.0 g/kg, assessing elimination rates and time of drug clearance. Experiment 2 compared ethanol's initial hypothermic and delayed hyperthermic effect across age by 48-hr temperature measurement with telemetry. At clearance or 24 hr after alcohol exposure, Experiment 3 tested subjects for changes in acoustic startle reactivity and ultrasonic vocalization (USV). Younger rats showed an absent or reduced tendency for residual hyperthermia, and adults showed alterations in USV observed as aftereffects of intoxication, despite greater initial blood alcohol levels and ethanol hypothermia in the former. The lesser ethanol hangover effects in weanlings and adolescents may be due in part to faster ethanol elimination at these ages compared with adults.

  13. A Systematic Review of Music Therapy Practice and Outcomes with Acute Adult Psychiatric In-Patients

    PubMed Central

    Carr, Catherine; Odell-Miller, Helen; Priebe, Stefan

    2013-01-01

    Background and Objectives There is an emerging evidence base for the use of music therapy in the treatment of severe mental illness. Whilst different models of music therapy have been developed in mental health care, none have specifically accounted for the features and context of acute in-patient settings. This review aimed to identify how music therapy is provided for acute adult psychiatric in-patients and what outcomes have been reported. Review Methods A systematic review using medical, psychological and music therapy databases. Papers describing music therapy with acute adult psychiatric in-patients were included. Analysis utilised narrative synthesis. Results 98 papers were identified, of which 35 reported research findings. Open group work and active music making for nonverbal expression alongside verbal reflection was emphasised. Aims were engagement, communication and interpersonal relationships focusing upon immediate areas of need rather than longer term insight. The short stay, patient diversity and institutional structure influenced delivery and resulted in a focus on single sessions, high session frequency, more therapist direction, flexible use of musical activities, predictable musical structures, and clear realistic goals. Outcome studies suggested effectiveness in addressing a range of symptoms, but were limited by methodological shortcomings and small sample sizes. Studies with significant positive effects all used active musical participation with a degree of structure and were delivered in four or more sessions. Conclusions No single clearly defined model exists for music therapy with adults in acute psychiatric in-patient settings, and described models are not conclusive. Greater frequency of therapy, active structured music making with verbal discussion, consistency of contact and boundaries, an emphasis on building a therapeutic relationship and building patient resources may be of particular importance. Further research is required to

  14. Differential Effects of Acute Alcohol on EEG and Sedative Responses in Adolescent and Adult Wistar Rats

    PubMed Central

    Pian, Jerry P.; Criado, Jose R.; Walker, Brendan M.; Ehlers, Cindy L.

    2008-01-01

    Age-related developmental differences in sensitivity to the acute effects of alcohol may play an important role in the development of alcoholism. The present study was designed to evaluate the acute effects of alcohol on cortical electroencephalogram (EEG) in adolescent (P36) and adult (P78) Wistar rats. Five minutes of EEG was recorded after administration of 0, 0.75 or 1.5 g/kg alcohol. The righting reflex was performed to measure the sedative effects of alcohol (3.5 g/kg) and total sleeping time for each rat. Our results showed that alcohol (1.5 g/kg) increased power in the 1–2 Hz band and decreased the power in the 32–50 Hz band in the parietal cortical region of adolescent rats. Alcohol (1.5 g/kg) also increased stability of the EEG power in the slow-wave frequency bands (2–4 Hz, 4–6 Hz, and 6–8 Hz) of adolescent rats. In the frontal cortex of adult rats, but not in adolescent rats, alcohol (1.5 or 0.75 g/kg) decreased the power in the 16–32 Hz frequency band. Alcohol (1.5 g/kg) differentially increased power in a multiple of slow-wave frequency bands (2–4 Hz and 4–6 Hz) in the parietal cortex of adult rats as compared to adolescent rats. Adolescent rats were shown significantly shorter sleeping time and higher blood alcohol levels after regaining reflex than adult rats. Our results provide additional evidence of age-related differences in the effects of acute alcohol on cortical EEG, sedation and tolerance. PMID:18191821

  15. Molecular analysis of the leukaemic B cell in adult and childhood acute lymphoblastic leukaemia.

    PubMed

    Coyle, L A; Papaioannou, M; Yaxley, J C; Chim, J S; Attard, M; Hoffbrand, A V; Foroni, L

    1996-09-01

    Immunoglobulin heavy chain gene (IgH gene) rearrangements are found in the majority of cases of B-lineage acute lymphoblastic leukaemia (ALL). We have examined bone marrow samples taken at presentation or relapse from 109 patients (79 adults and 30 children) and have performed sequence analysis of the complementarity determining region 3 (CDR3) on 65 alleles from 54 patients. We aimed to define immunoglobulin heavy chain (IgH) variable segment family use and investigate biological and structural features of the B cell in adult and childhood ALL. Using the FR1 fingerprinting method, a rearranged band was identified in 70 (89%) of 79 adult ALL and in 29 (97%) of 30 childhood ALL. This study found no preferential use or selection of IgH VH genes and no statistically significant structural differences between normal and leukaemic B cells in either adult and childhood ALL. An equal proportion of amplifiable cases of adult and childhood ALL uses more than one VH family gene (24/70, 34%, and 8/29, 27.5%, respectively). There were no significant differences in the structure or size of the CDR3 region and the variable (V) or joining (J) segment use in ALL patients compared to normal B cells. We observed that the N2 region was shorter than N1 in children whereas the opposite was observed in adults (not statistically significant). The J4 segment was a more common rearrangement in children than in adults, and in both groups J4 was more frequently associated with multiple D segment VDJ rearrangements. An increase in VH6 use in leukaemic alleles compared to normal B lymphocytes (2%) was observed but it was not statistically significant in our group of patients. Amongst children and adults, in-frame CDR3 junctions occurred in 78% and 64% of rearranged alleles, respectively, compared to 75% of in-frame sequences reported by others to occur among normal B cells.

  16. Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults.

    PubMed

    Lee, Kum Ja; Chow, Vivian; Weissman, Ashley; Tulpule, Sunil; Aldoss, Ibrahim; Akhtari, Mojtaba

    2016-01-01

    Adults with relapsed or refractory B-cell acute lymphoblastic leukemia have a dismal prognosis with a short median overall survival that can be measured in months. Because most patients will have chemotherapy-resistant disease, allogeneic hematopoietic stem cell transplantation remains the only potentially curative treatment. Despite advances in current management, patients continue to have poor outcomes and lack of durable responses. Thus, new therapies with alternative modes of actions are currently being investigated. Blinatumomab is a novel bispecific T-cell engager that simultaneously binds CD3-positive cytotoxic T-cells and CD19-positive B-cells, resulting in selective lysis of tumor cells. It has shown promising results in patients with relapsed or refractory acute lymphoblastic leukemia or those achieving hematologic response with persistent minimum residual disease. Future clinical trials will answer questions regarding its optimal place in the treatment paradigm. Dose-limiting toxicities include immunological toxicities and cytokine release syndrome. However, most patients tolerate the therapy relatively well. This review will focus on the pharmacology, clinical efficacy, and safety of blinatumomab in the treatment of adult B-cell acute lymphoblastic leukemia while highlighting its unique drug warnings and toxicity management. PMID:27601914

  17. Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults

    PubMed Central

    Lee, Kum Ja; Chow, Vivian; Weissman, Ashley; Tulpule, Sunil; Aldoss, Ibrahim; Akhtari, Mojtaba

    2016-01-01

    Adults with relapsed or refractory B-cell acute lymphoblastic leukemia have a dismal prognosis with a short median overall survival that can be measured in months. Because most patients will have chemotherapy-resistant disease, allogeneic hematopoietic stem cell transplantation remains the only potentially curative treatment. Despite advances in current management, patients continue to have poor outcomes and lack of durable responses. Thus, new therapies with alternative modes of actions are currently being investigated. Blinatumomab is a novel bispecific T-cell engager that simultaneously binds CD3-positive cytotoxic T-cells and CD19-positive B-cells, resulting in selective lysis of tumor cells. It has shown promising results in patients with relapsed or refractory acute lymphoblastic leukemia or those achieving hematologic response with persistent minimum residual disease. Future clinical trials will answer questions regarding its optimal place in the treatment paradigm. Dose-limiting toxicities include immunological toxicities and cytokine release syndrome. However, most patients tolerate the therapy relatively well. This review will focus on the pharmacology, clinical efficacy, and safety of blinatumomab in the treatment of adult B-cell acute lymphoblastic leukemia while highlighting its unique drug warnings and toxicity management.

  18. Clinical use of blinatumomab for B-cell acute lymphoblastic leukemia in adults

    PubMed Central

    Lee, Kum Ja; Chow, Vivian; Weissman, Ashley; Tulpule, Sunil; Aldoss, Ibrahim; Akhtari, Mojtaba

    2016-01-01

    Adults with relapsed or refractory B-cell acute lymphoblastic leukemia have a dismal prognosis with a short median overall survival that can be measured in months. Because most patients will have chemotherapy-resistant disease, allogeneic hematopoietic stem cell transplantation remains the only potentially curative treatment. Despite advances in current management, patients continue to have poor outcomes and lack of durable responses. Thus, new therapies with alternative modes of actions are currently being investigated. Blinatumomab is a novel bispecific T-cell engager that simultaneously binds CD3-positive cytotoxic T-cells and CD19-positive B-cells, resulting in selective lysis of tumor cells. It has shown promising results in patients with relapsed or refractory acute lymphoblastic leukemia or those achieving hematologic response with persistent minimum residual disease. Future clinical trials will answer questions regarding its optimal place in the treatment paradigm. Dose-limiting toxicities include immunological toxicities and cytokine release syndrome. However, most patients tolerate the therapy relatively well. This review will focus on the pharmacology, clinical efficacy, and safety of blinatumomab in the treatment of adult B-cell acute lymphoblastic leukemia while highlighting its unique drug warnings and toxicity management. PMID:27601914

  19. NUTRITIONAL THERAPY IN THE TREATMENT OF ACUTE CORROSIVE INTOXICATION IN ADULTS

    PubMed Central

    Chibishev, Andon; Markoski, Velo; Smokovski, Ivica; Shikole, Emilija; Stevcevska, Aleksandra

    2016-01-01

    Introduction: Acute intoxications with corrosive substances can cause severe chemical injuries of the upper gastrointestinal tract, most often located in the mouth, pharynx, esophagus, stomach and duodenum. If a patient survives the acute phase of intoxication, regenerative response may result in esophageal and/or gastric stenosis, and increased risk of esophageal and gastric cancer. Such intoxication may be fatal due to perforation or tracheal necrosis. Enteral nutrition is a nutritional method when nutritional substances are administered through specially designed tubing placed through the nose or percutaneously, directly into the GIT. Aim: The aim of this study is to describe the methods of artificial nutrition in patients with acute corrosive intoxications and the importance of nutritional support in the treatment of these intoxications. Discussion: Nutrition in the treatment of acute corrosive intoxications is one of the most important therapeutic processes that largely contribute to faster recovery of the post-corrosive injuries of upper GIT, stabilization of biologic, immunologic and metabolic parameters, and reduction of length of stay in hospital Aim of the treatment of acute corrosive intoxications is to prevent perforation and progressive fibrosis, and esophageal and gastric stenosis. There are different and often conflicting positions, on the conservative treatment of acute corrosive intoxications in adults. Such treatment mainly consists of anti-secretory treatment, antibiotics and intensive hyper-alimentation, aiming to prevent late post-corrosive intoxications. Conclusion: It is considered that nutritional support plays a major role in maintenance of metabolic processes and prevention of severe metabolic complications that could additionally aggravate the condition and impair the treatment. PMID:27047272

  20. [Expression and clinical significance of caudal type homeobox transcription factor-2 in adult acute lymphocytic leukemia].

    PubMed

    Lu, Hai-Yan; Xia, Hai-Long; Chen, Xiao-Wen; Zhu, Li-Xin; Wang, Qing-Yi; Cheng, Xin

    2011-04-01

    This study was aimed to investigate the expression and clinical significance of CDX1, CDX2 and CDX4 genes in acute lymphocytic leukemia (ALL). Expressions of CDX1, CDX2, and CDX4 in 51 adult acute lymphocytic leukemia patients and 14 healthy subjects were detected by reverse transcription polymerase chain reaction (RT-PCR). The results indicated that CDX1, CDX2 and CDX4 were not expressed in 14 healthy persons and 15 CR ALL patients, the positive expression rate of CDX2 gene in de novo ALL patients was 60.8%, while it obviously decreased in patients with complete remission (CR) (p < 0.05); the expression of CDX2 was increased again in relapsed patients (81.8%). When the expression of CDX2 was analyzed in different risk groups of ALL patients, the CDX2 expression rate in high risk (HR) patients was 91.7%, and that in the standard risk (SR) group was 45.7%. Furthermore, analyses of CDX1 and CDX4 expression in series of ALL samples did not show the expression of these genes. In patients with adult ALL at diagnosis and relapse, the CR rate of patients with CDX2 positive expression was lower than that of patients with CDX2 negative expression (p < 0.05). The median survival time in CDX2 positive expression patients was shorter than that in negative expression patient. It is concluded that expression of CDX2 may correlated with pathogenesis and relapse of adult ALL, but the expression of CDX1 and CDX4 don' t associated with pathogenesis and relapse of adult ALL; the CR rate and prognosis of patients with CDX2 positive expression is lower and poor. The expression of CDX2 may be used as a marker for occurrence, relapse and poor prognosis of adult ALL patients.

  1. Viral Infection in Adults with Severe Acute Respiratory Infection in Colombia

    PubMed Central

    Remolina, Yuly Andrea; Ulloa, María Mercedes; Vargas, Hernán; Díaz, Liliana; Gómez, Sandra Liliana; Saavedra, Alfredo; Sánchez, Edgar; Cortés, Jorge Alberto

    2015-01-01

    Objectives To identify the viral aetiology in adult patients with severe acute respiratory infection (SARI) admitted to sentinel surveillance institutions in Bogotá in 2012. Design A cross-sectional study was conducted in which microarray molecular techniques for viral identification were used on nasopharyngeal samples of adult patients submitted to the surveillance system, and further descriptions of clinical features and relevant clinical outcomes, such as mortality, need for critical care, use of mechanical ventilation and hospital stay, were obtained. Setting Respiratory infections requiring hospital admission in surveillance centres in Bogotá, Colombia. Participants Ninety-one adult patients with acute respiratory infection (55% were female). Measurements Viral identification, intensive care unit admission, hospital stay, and mortality. Results Viral identification was achieved for 63 patients (69.2%). Comorbidity was frequently identified and mainly involved chronic pulmonary disease or pregnancy. Influenza, Bocavirus and Adenovirus were identified in 30.8%, 28.6% and 18.7% of the cases, respectively. Admission to the intensive care unit occurred in 42.9% of the cases, while mechanical ventilation was required for 36.3%. The average hospital stay was 9.9 days, and mortality was 15.4%. Antibiotics were empirically used in 90.1% of patients. Conclusions The prevalence of viral aetiology of SARI in this study was high, with adverse clinical outcomes, intensive care requirements and high mortality. PMID:26576054

  2. Acute brain slice methods for adult and aging animals: application of targeted patch clampanalysis and optogenetics

    PubMed Central

    Daigle, Tanya L.; Chen, Qian; Feng, Guoping

    2014-01-01

    Summary The development of the living acute brain slice preparation for analyzing synaptic function roughly a half century ago was a pivotal achievement that greatly influenced the landscape of modern neuroscience. Indeed, many neuroscientists regard brain slices as the gold-standard model system for detailed cellular, molecular, and circuitry level analysis and perturbation of neuronal function. A critical limitation of this model system is the difficulty in preparing slices from adult and aging animals, and over the past several decades few substantial methodological improvements have emerged to facilitate patch clamp analysis in the mature adult stage. In this chapter we describe a robust and practical protocol for preparing brain slices from mature adult mice that are suitable for patch clamp analysis. This method reduces swelling and damage in superficial layers of the slices and improves the success rate for targeted patch clamp recordings, including recordings from fluorescently labeled populations in slices derived from transgenic mice. This adult brain slice method is suitable for diverse experimental applications, including both monitoring and manipulating neuronal activity with genetically encoded calcium indicators and optogenetic actuators, respectively. We describe the application of this adult brain slice platform and associated methods for screening kinetic properties of Channelrhodopsin (ChR) variants expressed in genetically-defined neuronal subtypes. PMID:25023312

  3. Survival improvements in adolescents and young adults after myeloablative allogeneic transplantation for acute lymphoblastic leukemia.

    PubMed

    Wood, William A; Lee, Stephanie J; Brazauskas, Ruta; Wang, Zhiwei; Aljurf, Mahmoud D; Ballen, Karen K; Buchbinder, David K; Dehn, Jason; Freytes, Cesar O; Lazarus, Hillard M; Lemaistre, Charles F; Mehta, Paulette; Szwajcer, David; Joffe, Steven; Majhail, Navneet S

    2014-06-01

    Adolescents and young adults (AYAs, ages 15 to 40 years) with cancer have not experienced survival improvements to the same extent as younger and older patients. We compared changes in survival after myeloablative allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL) among children (n = 981), AYAs (n = 1218), and older adults (n = 469) who underwent transplantation over 3 time periods: 1990 to 1995, 1996 to 2001, and 2002 to 2007. Five-year survival varied inversely with age group. Survival improved over time in AYAs and paralleled that seen in children; however, overall survival did not change over time for older adults. Survival improvements were primarily related to lower rates of early treatment-related mortality in the most recent era. For all cohorts, relapse rates did not change over time. A subset of 222 AYAs between the ages of 15 and 25 at 46 pediatric or 49 adult centers were also analyzed to describe differences by center type. In this subgroup, there were differences in transplantation practices among pediatric and adult centers, although HCT outcomes did not differ by center type. Survival for AYAs undergoing myeloablative allogeneic HCT for ALL improved at a similar rate as survival for children. PMID:24607554

  4. Hierarchy in Gene Expression is Predictive of Risk, Progression, and Outcome in Adult Acute Myeloid Leukemia

    PubMed Central

    Tripathi, Shubham; Deem, Michael W.

    2015-01-01

    Cancer progresses with a change in the structure of the gene network in normal cells. We define a measure of organizational hierarchy in gene networks of affected cells in adult acute myeloid leukemia (AML) patients. With a retrospective cohort analysis based on the gene expression profiles of 116 acute myeloid leukemia patients, we find that the likelihood of future cancer relapse and the level of clinical risk are directly correlated with the level of organization in the cancer related gene network. We also explore the variation of the level of organization in the gene network with cancer progression. We find that this variation is non-monotonic, which implies the fitness landscape in the evolution of AML cancer cells is nontrivial. We further find that the hierarchy in gene expression at the time of diagnosis may be a useful biomarker in AML prognosis. PMID:25685944

  5. Acute chest pain after bench press exercise in a healthy young adult

    PubMed Central

    Smereck, Janet A; Papafilippaki, Argyro; Sudarshan, Sawali

    2016-01-01

    Bench press exercise, which involves repetitive lifting of weights to full arm extension while lying supine on a narrow bench, has been associated with complications ranging in acuity from simple pectoral muscle strain, to aortic and coronary artery dissection. A 39-year-old man, physically fit and previously asymptomatic, presented with acute chest pain following bench press exercise. Diagnostic evaluation led to the discovery of critical multivessel coronary occlusive disease, and subsequently, highly elevated levels of lipoprotein (a). Judicious use of ancillary testing may identify the presence of “high-risk” conditions in a seemingly “low-risk” patient. Emergency department evaluation of the young adult with acute chest pain must take into consideration an extended spectrum of potential etiologies, so as to best guide appropriate management. PMID:27703399

  6. A Phase II Study Of The Farnesyltransferase Inhibitor ZANESTRA (R115777, NSC #702818, IND #58,359) In Complete Remission Following Induction And/Or Consolidation Chemotherapy In Adults With Poor-Risk Acute Myelogenous Leukemia (AML) And High-Risk Myelodysplasia (MDS)

    ClinicalTrials.gov

    2013-01-08

    Adult Acute Myeloid 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); de Novo Myelodysplastic Syndromes; Secondary Myelodysplastic Syndromes

  7. High-intensity telemedicine-enhanced acute care for older adults: an innovative healthcare delivery model.

    PubMed

    Shah, Manish N; Gillespie, Suzanne M; Wood, Nancy; Wasserman, Erin B; Nelson, Dallas L; Dozier, Ann; McConnochie, Kenneth M

    2013-11-01

    Accessing timely acute medical care is a challenge for older adults. This article describes an innovative healthcare model that uses high-intensity telemedicine services to provide rapid acute care for older adults without requiring them to leave their senior living community (SLC) residences. This program, based in a primary care geriatrics practice that cares for SLC residents, is designed to offer acute care through telemedicine for complaints that are felt to need attention before the next available outpatient visit but not to require emergency department (ED) resources. This option gives residents access to care in their residence. Measures used to evaluate the program include successful completion of telemedicine visits, satisfaction of residents and caregivers with telemedicine care, and site of care that would have been recommended had telemedicine been unavailable. During the first 2 years of the program's operation, 281 of 301 requested telemedicine visits were completed successfully. Twelve residents were sent to an ED for care after the telemedicine visit. Ninety-four percent of residents reported being satisfied or very satisfied with telemedicine care. Had telemedicine not been available, residents would have been sent to an ED (48.1%) or urgent care center (27.0%) or been scheduled for an outpatient visit (24.4%). The project demonstrated that high-intensity telemedicine services for acute illnesses are feasible and acceptable and can provide definitive care without requiring ED or urgent care use. Continuation of the program will require evaluation demonstrating equal or better resident-level outcomes and the development of sustainable business models.

  8. Effects of arsenic on modification of promyelocytic leukemia (PML): PML responds to low levels of arsenite

    SciTech Connect

    Hirano, Seishiro; Watanabe, Takayuki; Kobayashi, Yayoi

    2013-12-15

    Inorganic arsenite (iAs{sup 3+}) is a two-edged sword. iAs{sup 3+} is a well-known human carcinogen; nevertheless, it has been used as a therapeutic drug for acute promyelocytic leukemia (APL), which is caused by a fusion protein comprising retinoic acid receptor-α and promyelocytic leukemia (PML). PML, a nuclear transcription factor, has a RING finger domain with densely positioned cysteine residues. To examine PML-modulated cellular responses to iAs{sup 3+}, CHO-K1 and HEK293 cells were each used to establish cell lines that expressed ectopic human PML. Overexpression of PML increased susceptibility to iAs{sup 3+} in CHO-K1 cells, but not in HEK293 cells. Exposure of PML-transfected cells to iAs{sup 3+} caused PML to change from a soluble form to less soluble forms, and this modification of PML was observable even with just 0.1 μM iAs{sup 3+} (7.5 ppb). Western blot and immunofluorescent microscopic analyses revealed that the biochemical changes of PML were caused at least in part by conjugation with small ubiquitin-like modifier proteins (SUMOylation). A luciferase reporter gene was used to investigate whether modification of PML was caused by oxidative stress or activation of antioxidant response element (ARE) in CHO-K1 cells. Modification of PML protein occurred faster than activation of the ARE in response to iAs{sup 3+}, suggesting that PML was not modified as a consequence of oxidative stress-induced ARE activation. - Highlights: • PML was found in nuclear microspecles in response to arsenite. • Arsenite triggers SUMOylation of PML. • Arsenite modifies PML at as low as 0.1 μM. • Modification of PML is not caused by ARE activation.

  9. The Promyelocytic Leukemia Zinc Finger Protein: Two Decades of Molecular Oncology

    PubMed Central

    Suliman, Bandar Ali; Xu, Dakang; Williams, Bryan Raymond George

    2012-01-01

    The promyelocytic leukemia zinc finger (PLZF) protein, also known as Zbtb16 or Zfp145, was first identified in a patient with acute promyelocytic leukemia, where a reciprocal chromosomal translocation t(11;17)(q23;q21) resulted in a fusion with the RARA gene encoding retinoic acid receptor alpha. The wild-type Zbtb16 gene encodes a transcription factor that belongs to the POK (POZ and Krüppel) family of transcriptional repressors. In addition to nine Krüppel-type sequence-specific zinc fingers, which make it a member of the Krüppel-like zinc finger protein family, the PLZF protein contains an N-terminal BTB/POZ domain and RD2 domain. PLZF has been shown to be involved in major developmental and biological processes, such as spermatogenesis, hind limb formation, hematopoiesis, and immune regulation. PLZF is localized mainly in the nucleus where it exerts its transcriptional repression function, and many post-translational modifications affect this ability and also have an impact on its cytoplasmic/nuclear dissociation. PLZF achieves its transcriptional regulation by binding to many secondary molecules to form large multi-protein complexes that bind to the regulatory elements in the promoter region of the target genes. These complexes are also capable of physically interacting with its target proteins. Recently, PLZF has become implicated in carcinogenesis as a tumor suppressor gene, since it regulates the cell cycle and apoptosis in many cell types. This review will examine the major advances in our knowledge of PLZF biological activities that augment its value as a therapeutic target, particularly in cancer and immunological diseases. PMID:22822476

  10. Acute plastic bowing of the forearm in adults: a report of two cases.

    PubMed

    Tada, K; Ikeda, K; Tsubouchi, H; Tomita, K

    2008-08-01

    We report 2 adult cases where the diagnosis of acute plastic bowing of the forearm was either delayed or missed. In a 21-year-old man, ulnar bowing was missed and fixation was not performed because the patient had no limitation to his range of movement or pain. In a 24-year-old woman, the presentation of bowing in both the ulna and radius was delayed and corrective osteotomy was necessary for restoration of full range of movement. Prompt diagnosis enables manual reposition for easy restoration of full range of movement. PMID:18725680

  11. Self-management of acute asthma among low-income urban adults.

    PubMed

    George, Maureen; Campbell, Jacquelyn; Rand, Cynthia

    2009-08-01

    One approach to address asthma disparities has been to create evidence-based guidelines to standardize asthma care and education. However, the adoption of these recommendations has been suboptimal among many providers. As a result, low-income minority patients may not be receiving adequate instruction in asthma self-management. In addition, these patients may fail to follow guideline-based recommendations. We conducted 25 interviews to identify the extent to which urban low-income adults have received training in, and implement, self-management protocols for acute asthma. Twenty-five adults (92% female; 76% African American; mean age 39) were enrolled. Only one subject had received asthma self-management training and only 10 (40%) used short-acting beta-(2) agonist-based (SABA) self-management protocols for the early treatment of acute asthma. No subject used a peak flow meter or an asthma action plan. Most (52%) chose to initially treat acute asthma with complementary and alternative medicine (CAM) despite the availability of SABAs. Importantly, 21 (84%) preferred an integrated approach using both conventional and CAM treatments. Four themes associated with acute asthma self-management emerged from the qualitative analysis. The first theme safety reflected subjects' perception that CAM was safer than SABA. Severity addressed the calculation that subjects made in determining if SABA or CAM was indicated based on the degree of symptoms they were experiencing. The third theme speed and strength of the combination described subjects' belief in the superiority of integrating CAM and SABA for acute asthma self-management. The final themesense of identity spoke to the ability of CAM to provide a customized self-management strategy that subjects desired. It is unclear if subjects' greater use of CAM or delays in using SABA-based self-management protocols were functions of inadequate instruction or personal preference. Regardless, delays in, or under use of, conventional

  12. Self-Management of Acute Asthma among Low-Income Urban Adults

    PubMed Central

    George, Maureen; Campbell, Jacquelyn; Rand, Cynthia

    2009-01-01

    One approach to address asthma disparities has been to create evidence-based guidelines to standardize asthma care and education. However, the adoption of these recommendations has been suboptimal among many providers. As a result, low-income minority patients may not be receiving adequate instruction in asthma self-management. In addition, these patients may fail to follow guideline-based recommendations. We conducted 25 interviews to identify the extent to which urban low-income adults have received training in, and implement, self-management protocols for acute asthma. Twenty-five adults (92% female; 76% African American; mean age 39) were enrolled. Only one subject had received asthma self-management training and only 10 (40%) used short-acting beta-2 agonist-based (SABA) self-management protocols for the early treatment of acute asthma. No subject used a peak flow meter or an asthma action plan. Most (52%) chose to initially treat acute asthma with complementary and alternative medicine (CAM) despite the availability of SABAs. Importantly, 21 (84%) preferred an integrated approach using both conventional and CAM treatments. Four themes associated with acute asthma self-management emerged from the qualitative analysis. The first theme safety reflected subjects’ perception that CAM was safer than SABA. Severity addressed the calculation that subjects made in determining if SABA or CAM was indicated based on the degree of symptoms they were experiencing. The third theme speed and strength of the combination described subjects’ belief in the superiority of integrating CAM and SABA for acute asthma self-management. The final themesense of identity spoke to the ability of CAM to provide a customized self-management strategy that subjects desired. It is unclear if subjects’ greater use of CAM or delays in using SABA-based self-management protocols were functions of inadequate instruction or personal preference. Regardless, delays in, or under use of

  13. Examining the association between adult attachment style and cortisol responses to acute stress.

    PubMed

    Kidd, Tara; Hamer, Mark; Steptoe, Andrew

    2011-07-01

    The quality of social relationships may contribute to variations in biological stress responses, thereby affecting health risk. The association between an important indicator of social relationships, adult attachment style, and cortisol has been relatively unexplored. The present study examined adult romantic attachment style and cortisol responses to acute laboratory stress. Salivary cortisol was measured in response to two behavioural tasks, a colour/word interference task and mirror tracing task, in 498 healthy men and women from the Heart Scan study, a subsample of the Whitehall II cohort. Participants were classified as secure, fearful, preoccupied or dismissive on the basis of responses to the Relationship Questionnaire. Cortisol output was lowest in the fearful group, followed by the preoccupied group, with both secure and dismissive groups having higher levels. The results from this study tentatively support the proposition that attachment style is a factor in determining the manifestation of HPA dysregulation. PMID:21106296

  14. RBP2 Promotes Adult Acute Lymphoblastic Leukemia by Upregulating BCL2

    PubMed Central

    Wang, Xiaoming; Zhou, Minran; Fu, Yue; Sun, Ting; Chen, Jin; Qin, Xuemei; Yu, Yuan; Jia, Jihui; Chen, Chunyan

    2016-01-01

    Despite recent increases in the cure rate of acute lymphoblastic leukemia (ALL), adult ALL remains a high-risk disease that exhibits a high relapse rate. In this study, we found that the histone demethylase retinoblastoma binding protein-2 (RBP2) was overexpressed in both on-going and relapse cases of adult ALL, which revealed that RBP2 overexpression was not only involved in the pathogenesis of ALL but that its overexpression might also be related to relapse of the disease. RBP2 knockdown induced apoptosis and attenuated leukemic cell viability. Our results demonstrated that BCL2 is a novel target of RBP2 and supported the notion of RBP2 being a regulator of BCL2 expression via directly binding to its promoter. As the role of RBP2 in regulating apoptosis was confirmed, RBP2 overexpression and activation of BCL2 might play important roles in ALL development and progression. PMID:27008505

  15. Acute skin sun damage in children and its consequences in adults.

    PubMed

    Pustisek, Nives; Sikanić-Dugić, Nives; Hirsl-Hećej, Vlasta; Domljan, Mislav Luka

    2010-04-01

    Children spend more time outdoors than adults and there is compelling evidence that childhood is a particularly vulnerable time for the photocarcinogenic effects of the sun. The negative effects of solar radiation are accumulated during the entire lifetime; however 80% of total lifetime sun exposure is taking place before the age of 18 years. Child skin is more sensitive than adult skin because natural defense mechanisms are not fully developed. A short exposure to midday sun will result in sunburns. Epidemiologic studies show a higher incidence of malignant melanoma in persons with a history of sunburns during childhood and adolescence. Sun exposure among infants and pre-school children is largely dependent on the discretion of adult care providers. Sun protective habits of mothers may predict the level of sun exposure in children. It is very important to transfer the knowledge and positive habits of proper sun protection to children. The purpose of sun-safety behavior is not to avoid outdoor activities, but rather to protect the skin from detrimental sun effects. Proper sun protection of children includes protection from excessive sun exposure, sunburns and other forms of skin damage caused by sun, which may lead to the future development of skin cancers. This paper reviews acute skin reactivity to sun in childhood and adolescence that causes damage in skin structure and function and produces undesirable chronic changes in adults.

  16. Leukomogenic factors downregulate heparanase expression in acute myeloid leukemia cells

    SciTech Connect

    Eshel, Rinat; Ben-Zaken, Olga; Vainas, Oded; Nadir, Yona; Minucci, Saverio; Polliack, Aaron; Naparstek, Ella; Vlodavsky, Israel; Katz, Ben-Zion; E-mail: bkatz@tasmc.healt.gov.il

    2005-10-07

    Heparanase is a heparan sulfate-degrading endoglycosidase expressed by mature monocytes and myeloid cells, but not by immature hematopoietic progenitors. Heparanase gene expression is upregulated during differentiation of immature myeloid cells. PML-RAR{alpha} and PLZF-RAR{alpha} fusion gene products associated with acute promyelocytic leukemia abrogate myeloid differentiation and heparanase expression. AML-Eto, a translocation product associated with AML FAB M2, also downregulates heparanase gene expression. The common mechanism that underlines the activity of these three fusion gene products involves the recruitment of histone deacetylase complexes to specific locations within the DNA. We found that retinoic acid that dissociates PML-RAR{alpha} from the DNA, and which is used to treat acute promyelocytic leukemia patients, restores heparanase expression to normal levels in an acute promyelocytic leukemia cell line. The retinoic acid effects were also observed in primary acute promyelocytic leukemia cells and in a retinoic acid-treated acute promyelocytic leukemia patient. Histone deacetylase inhibitor reverses the downregulation of heparanase expression induced by the AML-Eto fusion gene product in M2 type AML. In summary, we have characterized a link between leukomogenic factors and the downregulation of heparanase in myeloid leukemic cells.

  17. Blueprint for Implementing New Processes in Acute Care: Rescuing Adult Patients With Intraosseous Access.

    PubMed

    Chreiman, Kristen M; Kim, Patrick K; Garbovsky, Lyudmila A; Schweickert, William D

    2015-01-01

    The intraosseous (IO) access initiative at an urban university adult level 1 trauma center began from the need for a more expeditious vascular access route to rescue patients in extremis. The goal of this project was a multidisciplinary approach to problem solving to increase access of IO catheters to rescue patients in all care areas. The initiative became a collaborative effort between nursing, physicians, and pharmacy to embark on an acute care endeavor to standardize IO access. This is a descriptive analysis of processes to effectively develop collaborative strategies to navigate hospital systems and successfully implement multilayered initiatives. Administration should empower nurse to advance their practice to include IO for patient rescue. Intraosseous access may expedite resuscitative efforts in patients in extremis who lack venous access or where additional venous access is required for life-saving therapies. Limiting IO dwell time may facilitate timely definitive venous access. Continued education and training by offering IO skill laboratory refreshers and annual e-learning didactic is optimal for maintaining proficiency and knowledge. More research opportunities exist to determine medication safety and efficacy in adult patients in the acute care setting. PMID:26352658

  18. Effective factors on linguistic disorder during acute phase following traumatic brain injury in adults.

    PubMed

    Chabok, Shahrokh Yousefzadeh; Kapourchali, Sara Ramezani; Leili, Ehsan Kazemnezhad; Saberi, Alia; Mohtasham-Amiri, Zahra

    2012-06-01

    Traumatic brain injury (TBI) has been known to be the leading cause of breakdown and long-term disability in people under 45 years of age. This study highlights the effective factors on post-traumatic (PT) linguistic disorder and relations between linguistic and cognitive function after trauma in adults with acute TBI. A cross-sectional design was employed to study 60 post-TBI hospitalized adults aged 18-65 years. Post-traumatic (PT) linguistic disorder and cognitive deficit after TBI were respectively diagnosed using the Persian Aphasia Test (PAT) and Persian version of Mini-Mental State Examination (MMSE) at discharge. Primary post-resuscitation consciousness level was determined using the Glasgow Coma Scale (GCS). Paracilinical data was obtained by CT scan technique. Multiple logistic regression analysis illustrated that brain injury severity was the first powerful significant predictor of PT linguistic disorder after TBI and frontotemporal lesion was the second. It was also revealed that cognitive function score was significantly correlated with score of each language skill except repetition. Subsequences of TBI are more commonly language dysfunctions that demand cognitive flexibility. Moderate, severe and fronto-temporal lesion can increase the risk of processing deficit in linguistic macrostructure production and comprehension. The dissociation risk of cortical and subcortical pathways related to cognitive-linguistic processing due to intracranial lesions can augment possibility of lexical-semantic processing deficit in acute phase which probably contributes to later cognitive-communication disorder.

  19. Unsuspected Dengue as a Cause of Acute Febrile Illness in Children and Adults in Western Nicaragua

    PubMed Central

    Reller, Megan E.; de Silva, Aravinda M.; Miles, Jeremy J.; Jadi, Ramesh S.; Broadwater, Anne; Walker, Katie; Woods, Christopher; Mayorga, Orlando; Matute, Armando

    2016-01-01

    Background Dengue is an emerging infectious disease of global significance. Suspected dengue, especially in children in Nicaragua’s heavily-urbanized capital of Managua, has been well documented, but unsuspected dengue among children and adults with undifferentitated fever has not. Methodology/Principal Findings To prospectively study dengue in semi-urban and rural western Nicaragua, we obtained epidemiologic and clinical data as well as acute and convalescent sera (2 to 4 weeks after onset of illness) from a convenience sample (enrollment Monday to Saturday daytime to early evening) of consecutively enrolled patients (n = 740) aged ≥ 1 years presenting with acute febrile illness. We tested paired sera for dengue IgG and IgM and serotyped dengue virus using reverse transcriptase-PCR. Among 740 febrile patients enrolled, 90% had paired sera. We found 470 (63.5%) were seropositive for dengue at enrollment. The dengue seroprevalance increased with age and reached >90% in people over the age of 20 years. We identified acute dengue (serotypes 1 and 2) in 38 (5.1%) patients. Only 8.1% (3/37) of confirmed cases were suspected clinically. Conclusions/Significance Dengue is an important and largely unrecognized cause of fever in rural western Nicaragua. Since Zika virus is transmitted by the same vector and has been associated with severe congenital infections, the population we studied is at particular risk for being devastated by the Zika epidemic that has now reached Central America. PMID:27792777

  20. Differential Effects of Acute Alcohol on Prepulse Inhibition and Event-Related Potentials in Adolescent and Adult Wistar Rats

    PubMed Central

    Pian, Jerry P.; Criado, Jose R.; Ehlers, Cindy L.

    2009-01-01

    Background Previous studies have demonstrated that adolescent and adult rats show differential sensitivity to many of the acute effects of alcohol. We recently reported evidence of developmental differences in the effects of acute alcohol on the cortical electroencephalogram (EEG). However, it is unclear whether developmental differences are also observed in other neurophysiological and neurobehavioral measurements known to be sensitive to alcohol exposure. The present study determined the age-related effects of acute alcohol on behavioral and event-related potential (ERP) responses to acoustic startle (AS) and prepulse inhibition (PPI). Methods Male adolescent and adult Wistar rats were implanted with cortical recording electrodes. The effects of acute alcohol (0.0, 0.75, and 1.5 g/kg) on behavioral and ERP responses to AS and PPI were assessed. Results Acute alcohol (0.75 and 1.5 g/kg) significantly reduced the behavioral and electrophysiological response to AS in adolescent and adult rats. Both 0.75 and 1.5 g/kg alcohol significantly enhanced the behavioral response to PPI in adolescent, but not in adult rats. During prepulse+pulse trials, 1.5 g/kg alcohol significantly increased the N10 pulse response in the adolescent frontal cortex. Acute alcohol (0.75 and 1.5 g/kg) also increased the N1 ERP pulse response to prepulse stimuli in frontal and parietal cortices in adult rats, but not in adolescent rats. Conclusions These data suggest that alcohol’s effect on behavioral and electrophysiological indices of AS do not differ between adults and adolescents whereas developmental stage does appear to significantly modify alcohol influenced response to PPI. PMID:18828807

  1. Acute Hypoglycemia Impairs Executive Cognitive Function in Adults With and Without Type 1 Diabetes

    PubMed Central

    Graveling, Alex J.; Deary, Ian J.; Frier, Brian M.

    2013-01-01

    OBJECTIVE Acute hypoglycemia impairs cognitive function in several domains. Executive cognitive function governs organization of thoughts, prioritization of tasks, and time management. This study examined the effect of acute hypoglycemia on executive function in adults with and without diabetes. RESEARCH DESIGN AND METHODS Thirty-two adults with and without type 1 diabetes with no vascular complications or impaired awareness of hypoglycemia were studied. Two hyperinsulinemic glucose clamps were performed at least 2 weeks apart in a single-blind, counterbalanced order, maintaining blood glucose at 4.5 mmol/L (euglycemia) or 2.5 mmol/L (hypoglycemia). Executive functions were assessed with a validated test suite (Delis-Kaplan Executive Function). A general linear model (repeated-measures ANOVA) was used. Glycemic condition (euglycemia or hypoglycemia) was the within-participant factor. Between-participant factors were order of session (euglycemia-hypoglycemia or hypoglycemia-euglycemia), test battery used, and diabetes status (with or without diabetes). RESULTS Compared with euglycemia, executive functions (with one exception) were significantly impaired during hypoglycemia; lower test scores were recorded with more time required for completion. Large Cohen d values (>0.8) suggest that hypoglycemia induces decrements in aspects of executive function with large effect sizes. In some tests, the performance of participants with diabetes was more impaired than those without diabetes. CONCLUSIONS Executive cognitive function, which is necessary to carry out many everyday activities, is impaired during hypoglycemia in adults with and without type 1 diabetes. This important aspect of cognition has not received previous systematic study with respect to hypoglycemia. The effect size is large in terms of both accuracy and speed. PMID:23780950

  2. Proton Beam Craniospinal Irradiation Reduces Acute Toxicity for Adults With Medulloblastoma

    SciTech Connect

    Brown, Aaron P.; Barney, Christian L.; Grosshans, David R.; McAleer, Mary Frances; Groot, John F. de; Puduvalli, Vinay K.; Tucker, Susan L.; Crawford, Cody N.; Khan, Meena; Khatua, Soumen; Gilbert, Mark R.; Brown, Paul D.; Mahajan, Anita

    2013-06-01

    Purpose: Efficacy and acute toxicity of proton craniospinal irradiation (p-CSI) were compared with conventional photon CSI (x-CSI) for adults with medulloblastoma. Methods and Materials: Forty adult medulloblastoma patients treated with x-CSI (n=21) or p-CSI (n=19) at the University of Texas MD Anderson Cancer Center from 2003 to 2011 were retrospectively reviewed. Median CSI and total doses were 30.6 and 54 Gy, respectively. The median follow-up was 57 months (range 4-103) for x-CSI patients and 26 months (range 11-63) for p-CSI. Results: p-CSI patients lost less weight than x-CSI patients (1.2% vs 5.8%; P=.004), and less p-CSI patients had >5% weight loss compared with x-CSI (16% vs 64%; P=.004). p-CSI patients experienced less grade 2 nausea and vomiting compared with x-CSI (26% vs 71%; P=.004). Patients treated with x-CSI were more likely to have medical management of esophagitis than p-CSI patients (57% vs 5%, P<.001). p-CSI patients had a smaller reduction in peripheral white blood cells, hemoglobin, and platelets compared with x-CSI (white blood cells 46% vs 55%, P=.04; hemoglobin 88% vs 97%, P=.009; platelets 48% vs 65%, P=.05). Mean vertebral doses were significantly associated with reductions in blood counts. Conclusions: This report is the first analysis of clinical outcomes for adult medulloblastoma patients treated with p-CSI. Patients treated with p-CSI experienced less treatment-related morbidity including fewer acute gastrointestinal and hematologic toxicities.

  3. Prognostic impact of persistent cytogenetic abnormalities at complete remission in adult patients with acute lymphoblastic leukemia.

    PubMed

    Short, Nicholas J; Kantarjian, Hagop M; Jabbour, Elias J; O'Brien, Susan M; Faderl, Stefan; Burger, Jan A; Garris, Rebecca; Qiao, Wei; Huang, Xuelin; Jain, Nitin; Konopleva, Marina; Kadia, Tapan M; Daver, Naval; Borthakur, Gautam; Cortes, Jorge E; Ravandi, Farhad

    2016-06-01

    In acute myelogenous leukemia, the persistent detection of abnormal cytogenetics at complete remission (ACCR) is associated with inferior outcomes. However, the prognostic significance of ACCR in adult patients with acute lymphoblastic leukemia (ALL) is unknown. We evaluated 272 adult patients with ALL and abnormal cytogenetics at baseline who were treated with frontline induction chemotherapy, achieved complete remission (CR) and had cytogenetic analysis performed at the time of CR. ACCR was observed in 26 patients (9.6%). Median relapse-free survival was 22 months (95% CI, 12 months to not reached) for patients with ACCR vs. 48 months (range, 30-125 months) in patients with normal cytogenetics at CR (NCCR; P = 0.31). Median overall survival also did not differ significantly between the ACCR (99 months [range, 17 months to not reached]) and NCCR groups (67 months [range, 47 months to not reached], P = 0.86). The specificity of ACCR for minimal residual disease (MRD) positivity by multi-parameter flow cytometry (MFC) was 43%, and there was overall poor correlation between these two methods for the detection of residual disease. When patients were stratified by MRD status, the presence or absence of persistent cytogenetic abnormalities at CR did not add additional prognostic information. This study suggests that there is poor association between MRD assessment by MFC and the presence or absence of cytogenetic abnormalities at CR in adult patients with ALL. ACCR was not associated with adverse outcomes in ALL and did not add additional prognostic information when MRD status by MFC was known. PMID:26800008

  4. Combined Detection of Serum IL-10, IL-17, and CXCL10 Predicts Acute Rejection Following Adult Liver Transplantation

    PubMed Central

    Kim, Nayoung; Yoon, Young-In; Yoo, Hyun Ju; Tak, Eunyoung; Ahn, Chul-Soo; Song, Gi-Won; Lee, Sung-Gyu; Hwang, Shin

    2016-01-01

    Discovery of non-invasive diagnostic and predictive biomarkers for acute rejection in liver transplant patients would help to ensure the preservation of liver function in the graft, eventually contributing to improved graft and patient survival. We evaluated selected cytokines and chemokines in the sera from liver transplant patients as potential biomarkers for acute rejection, and found that the combined detection of IL-10, IL-17, and CXCL10 at 1-2 weeks post-operation could predict acute rejection following adult liver transplantation with 97% specificity and 94% sensitivity. PMID:27498551

  5. Comparison of the responses of children and adults to acute ozone exposure

    SciTech Connect

    McDonnell, W.F.; Chapman, R.S.; Horstman, D.H.; Leigh, M.W.; Salaam, S.A.

    1986-07-01

    The purpose of the paper is to compare the results of two studies in which the respiratory responses of children and adults to acute ozone (O/sub 3/) exposure were measured. Forty-two 18-30 year old males were exposed for 2.5 hours in a controlled environmental chamber to either 0.0 or 0.12 ppm O3 while performing intermittent heavy exercise. Twenty-two 8-11 year old males were exposed in a similar manner to both air and 0.12 ppm O3. Measures of respiratory symptoms and function were made before and after exposure. Adults experienced an increase in the symptom cough and decrements in forced vital capacity and some measures of forced expiratory flow. Children experienced similar decrements in pulmonary function, but had no increase in symptoms. The authors concluded that as measured by pulmonary function children appear to be no more responsive to O3 exposure than are adults and may experience fewer symptoms.

  6. Regulatory T cells-derived IL-35 promotes the growth of adult acute myeloid leukemia blasts.

    PubMed

    Tao, Qianshan; Pan, Ying; Wang, Yiping; Wang, Huiping; Xiong, Shudao; Li, Qing; Wang, Jia; Tao, Lili; Wang, Zhitao; Wu, Fan; Zhang, Rui; Zhai, Zhimin

    2015-11-15

    Tumor immune escape mechanism mediated by CD4+CD25+regulatory T cells (Tregs) is a key factor in the pathogenesis of acute myeloid leukemia (AML). IL-35, as a novel inhibitory cytokine, is produced by Tregs specially and regulates functions of Tregs in murine. However, IL-35 expression of Tregs in human is still disputed, and its role in AML is yet to be elucidated. In this study, we found that IL-35 was expressed highly in peripheral blood plasma of adult patients with AML and significantly correlated with the clinical stages of malignancy. Tregs-derived from adult AML patients produced IL-35 in a stimulation-dependent manner. IL-35 promoted AML blasts immune escape by expanding Tregs and inhibiting CD4+CD25-effector T cells (Teffs). Furthermore, IL-35 directly promoted the proliferation of AML blasts and reduced the apoptosis of AML blasts. Together, our study demonstrates that IL-35-derived from Tregs promotes the growth of adult AML blasts, suggesting that IL-35 has an important role in the pathogenesis of AML.

  7. Impact of a dedicated infusion clinic for acute management of adults with sickle cell pain crisis.

    PubMed

    Lanzkron, Sophie; Carroll, C Patrick; Hill, Peter; David, Mandy; Paul, Nicklaine; Haywood, Carlton

    2015-05-01

    Most adults with sickle cell disease (SCD) receive care for their acute painful episodes in an emergency department (ED) setting. The purpose of this article is to describe the impact of opening a dedicated treatment center for adults with SCD [Sickle Cell Infusion Clinic (SCIC)] on patient outcomes and on hospital discharges for SCD. Descriptive data including demographics, time to first dose of narcotic, and pain scores were collected on patients presenting to the SCIC and ED. Maryland hospital discharge data were obtained from the Maryland Health Services Cost Review Commission. Analyses were conducted using T tests, χ(2) tests, and simple generalized estimating equation regression models accounting for the clustered nature of observations, as appropriate. There were 3,874 visits to the SCIC by 361 unique patients; 85% of those visits resulted in the patient being sent home. During the same time period, there were 3,408 visits to the ED by 558 unique patients with SCD. The overall admission rate from the ED for these patients was 35.9% but decreased significantly over the time period with a rate of 20% in December 2011. There was a significant decrease in readmissions over time for the entire Baltimore Metro area with the likelihood of readmission decreasing by 7% over time. The SCIC model provides adults with SCD access to high quality care that decreases the need for hospital admission. Further research needs to be done to evaluate the cost effectiveness of this model.

  8. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.

    PubMed

    Dhédin, Nathalie; Huynh, Anne; Maury, Sébastien; Tabrizi, Reza; Beldjord, Kheira; Asnafi, Vahid; Thomas, Xavier; Chevallier, Patrice; Nguyen, Stéphanie; Coiteux, Valérie; Bourhis, Jean-Henri; Hichri, Yosr; Escoffre-Barbe, Martine; Reman, Oumedaly; Graux, Carlos; Chalandon, Yves; Blaise, Didier; Schanz, Urs; Lhéritier, Véronique; Cahn, Jean-Yves; Dombret, Hervé; Ifrah, Norbert

    2015-04-16

    Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678. PMID:25587040

  9. Immunoglobulin G antibody response in children and adults with acute dengue 3 infection.

    PubMed

    Vazquez, Susana; Acosta, Nadia; Ruiz, Didye; Calzada, Naifi; Alvarez, Angel M; Guzman, Maria G

    2009-07-01

    Using a serological test, different criteria have been established for classifying a case as primary or secondary dengue virus infection. Considering the dengue epidemiological situation in Cuba, IgG antibody response to dengue virus infection in serum samples from children and adults with a dengue 3 infection, in Havana city during the 2001-2002 epidemic was evaluated. Samples were collected on days 5-7 of fever onset and tested by an ELISA inhibition. A total of 713 serum samples positive for IgM antibody, 93 from children and 620 from adult patients were studied. Serum samples collected from healthy blood donors and patients not infected with dengue were included as controls. An IgG primary infection pattern was observed in sera collected from children, with titers of < or =20 in the 89.3% of the patients, while both, a primary and secondary patterns were observed in sera collected from adult patients with titers of < or =20 (13.4%) and > or =1280 (83.9%), respectively. These results permitted the definition of a primary or secondary case of dengue virus infection in serum samples collected during the acute phase of dengue virus infection.

  10. Best Practices in Adolescent and Young Adult Patients with Acute Lymphoblastic Leukemia: A Focus on Asparaginase

    PubMed Central

    Boissel, Nicolas

    2015-01-01

    The inclusion of asparaginase in chemotherapy regimens to treat acute lymphoblastic leukemia (ALL) has had a positive impact on survival in pediatric patients. Historically, asparaginase has been excluded from most treatment protocols for adolescent and young adult (AYA) patients because of perceived toxicity in this population, and this is believed to have contributed to poorer outcomes in these patients. However, retrospective analyses over the past 12 years have shown that 2-, 5-, and 7-year overall survival of AYA patients is significantly improved with pediatric versus adult protocols. The addition of asparaginase to adult protocols yielded high rates of first remission and improved survival. However, long-term survival remains lower compared with what has been seen in pediatrics. The notion that asparaginase is poorly tolerated by AYA patients has been challenged in multiple studies. In some, but not all, studies, the incidences of hepatic and pancreatic toxicities were higher in AYA patients, whereas the rates of hypersensitivity reactions did not appear to differ with age. There is an increased risk of venous thromboembolic events, and management with anti-coagulation therapy is recommended. Overall, the risk of therapy-related mortality is low. Together, this suggests that high-intensity pediatric protocols offer an effective and tolerable approach to treating ALL in the AYA population. PMID:26421220

  11. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.

    PubMed

    Dhédin, Nathalie; Huynh, Anne; Maury, Sébastien; Tabrizi, Reza; Beldjord, Kheira; Asnafi, Vahid; Thomas, Xavier; Chevallier, Patrice; Nguyen, Stéphanie; Coiteux, Valérie; Bourhis, Jean-Henri; Hichri, Yosr; Escoffre-Barbe, Martine; Reman, Oumedaly; Graux, Carlos; Chalandon, Yves; Blaise, Didier; Schanz, Urs; Lhéritier, Véronique; Cahn, Jean-Yves; Dombret, Hervé; Ifrah, Norbert

    2015-04-16

    Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.

  12. [Clinical and epidemiologic characteristics of acute diarrhea in adults at a hospital from Cordoba city].

    PubMed

    Polo Friz, H; Toloza, S; Acosta, H; Toloza, C; Unsain, F; Marconetto, G; Massanet, P; Canova, S; Celli, J; Abdala, O; Gandini, B

    1997-01-01

    The purpose of this work was to assess the clinical and epidemiologic presentation features of adult acute diarrhea in a general hospital form Córdoba City. All the patients older than 14 years old who assisted to the Hospital Nacional de Clínicas Central Guard for acute diarrhea, during the periods: A (15-12-89 to 15-03-90), B (15-12-93 to 15-03-94) and C (15-12-94 to 15-03-95), were included. 594 patients were studied: 337 female (56.7%) and 257 male, 143 in the period A, 250 in B and 201 in C. The means +/- SD age was 34.6 +/- 13.3 and stool loose per day at admission 7.3 +/- 4.7. Eighty six percent of patients presented liquid consistent stool, 89.6% abdominal pain, 44.7% vomiting and 18.8% bloody stools. The rate of patients who consulted Central Guard referring acute diarrhea increased from period A (2.4%) to B (3.61%); p = 0.002 and decreased form B to C (2.85%); p = 0.01. The mean (+/- SD) days transcurred from the beginning of diarrhea episode till consultation was 3.5 +/- 2.7; 2.7 +/- 2.3 y 2.9 +/- 3.5 in the periods A, B and C respectively, statistically significant difference between A and B, p < 0.01. Thirty six percent, 21.1% and 23.1% of patients presented mucus with their stools in the periods A, B and C (p = 0.01), and high temperature 61.1%, 48.1% and 48.5% respectively (p = 0.04). Twenty seven percent of stools samples cultures became positive in the periods A, 17.6% in B and 11.5% in C, statistically significant difference between A and C; p = 0.008. The results show that in a general hospital from Córdoba City the adult acute diarrhea is a frequent cause of consult. In the last years there were modifications in its clinical an epidemiologic presentation features. PMID:10436614

  13. [Clinical and epidemiologic characteristics of acute diarrhea in adults at a hospital from Cordoba city].

    PubMed

    Polo Friz, H; Toloza, S; Acosta, H; Toloza, C; Unsain, F; Marconetto, G; Massanet, P; Canova, S; Celli, J; Abdala, O; Gandini, B

    1997-01-01

    The purpose of this work was to assess the clinical and epidemiologic presentation features of adult acute diarrhea in a general hospital form Córdoba City. All the patients older than 14 years old who assisted to the Hospital Nacional de Clínicas Central Guard for acute diarrhea, during the periods: A (15-12-89 to 15-03-90), B (15-12-93 to 15-03-94) and C (15-12-94 to 15-03-95), were included. 594 patients were studied: 337 female (56.7%) and 257 male, 143 in the period A, 250 in B and 201 in C. The means +/- SD age was 34.6 +/- 13.3 and stool loose per day at admission 7.3 +/- 4.7. Eighty six percent of patients presented liquid consistent stool, 89.6% abdominal pain, 44.7% vomiting and 18.8% bloody stools. The rate of patients who consulted Central Guard referring acute diarrhea increased from period A (2.4%) to B (3.61%); p = 0.002 and decreased form B to C (2.85%); p = 0.01. The mean (+/- SD) days transcurred from the beginning of diarrhea episode till consultation was 3.5 +/- 2.7; 2.7 +/- 2.3 y 2.9 +/- 3.5 in the periods A, B and C respectively, statistically significant difference between A and B, p < 0.01. Thirty six percent, 21.1% and 23.1% of patients presented mucus with their stools in the periods A, B and C (p = 0.01), and high temperature 61.1%, 48.1% and 48.5% respectively (p = 0.04). Twenty seven percent of stools samples cultures became positive in the periods A, 17.6% in B and 11.5% in C, statistically significant difference between A and C; p = 0.008. The results show that in a general hospital from Córdoba City the adult acute diarrhea is a frequent cause of consult. In the last years there were modifications in its clinical an epidemiologic presentation features.

  14. Clofarabine in Adult Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2014-02-04

    Solid Tumors; Leukemia, Lymphocytic, Acute, Pediatric; Leukemia, Lymphocytic, Acute, Adult; Leukemia, Myelocytic, Acute, Pediatric; Leukemia, Myelocytic, Acute, Adult; Myelodysplastic Syndromes, Adult

  15. The Effect of Statins Use on the Risk and Outcome of Acute Bacterial Infections in Adult Patients

    PubMed Central

    Ghorbani, Raheb; Afshar, Reza Kiaee

    2015-01-01

    Background Beyond their lipid-lowering abilities, statins have anti-inflammatory and immunomodulatory properties. In view of these effects, a growing interest has emerged in the possible role of statins, in preventing or decreasing morbidity and mortality from infection. Objectives The aim of this study was to determine whether previous statin use is associated with reduced risk of acute bacterial infections and better outcome of these infections. Materials and Methods In this historical cohort study, consecutive adult patients admitted with acute bacterial infection were enrolled. Control group were selected from adult outpatient and without history of acute bacterial infections. Acute bacterial infections included in this study were; pneumonia, acute pyelonephritis, cellulitis and sepsis with unknown origin. Data about baseline characteristics, co-morbidities and statins use of two groups was obtained. Results Finally 144 patients met inclusion criteria and were enrolled. Same numbers of controls were selected. Two groups were matched based on most baseline characteristics and co-morbidities. The patients’ categories were as follows: pneumonia 42.3%, acute pyelonephritis 23.6%, cellulitis 16% and sepsis 18%. From all participants 29.9% of patients and 45.8% controls were statin users. There was significant association between previous statin use and reduced risk of acute bacterial infections (Mantel Haenszel Weighted Odds Ratio=0.51, 95% CI: 0.30-0.85, p=0.009). Duration of hospitalization was significantly shorter in statin users (p=0.002). Hospital mortality rate was lower (14.6%) in statins users when compared with non-users (18.8%) with significant difference (p=0.028). Conclusion Prior therapy with statins is associated with considerably reduced onset of acute bacterial infections and better outcome in adult patients. PMID:26676277

  16. [Mutation and expression of LEF1 in adult acute lymphocytic leukemia and their clinical significance].

    PubMed

    Liu, Juan; Guo, Xing; Ge, Zheng; Zhang, Run; Xu, Jing-Yan; Li, Min; Wu, Yu-Jie; Qiao, Chun; Qiu, Hai-Rong; Zhang, Jian-Fu; Li, Jian-Yong

    2014-10-01

    Lymphoid enhancer factor 1 (LEF1) is a key transcription factor in Wingless-type (Wnt) pathway. The present study was aimed to explore the genetic mutation and expression of LEF1, and their clinical significance in adult patients with acute lymphocytic leukemia (ALL). Genomic DNA was amplified and sequenced to detect the mutation of LEF1 in 131 newly diagnosed adult patients with ALL. Quantitative PCR (qPCR) was performed to detect the expression of LEF1. Moreover, the correlations between mutations and expression of LEF1 with clinical characteristics were analyzed. The results showed that the frequency of LEF1 mutation in adult ALL was 3.1% (4/131) and all of them were point mutations located in exon 2 and 3; the median white blood cell count and median percentage of blasts at diagnosis were significantly higher in LEF1 high expression group than in low expression group (70.6 × 10⁹/L vs 26.2 × 10⁹/L)(P = 0.010); (81.0% vs 57.0%) (P = 0.014); in addition, the percentage of patients with Philadelphia chromosome positive and patients in high-risk group significantly increased in LEF1 high expression group compared with that in low expression group (66.7% vs 36.5%) (P = 0.038); (79.2% vs 56.2%) (P = 0.044). It is concluded that high expression of LEF1 may play an important role on development of adult ALL.

  17. An effective reinduction regimen for first relapse of adult acute lymphoblastic leukemia.

    PubMed

    Aldoss, Ibrahim; Pullarkat, Vinod; Patel, Ravindra; Watkins, Kristy; Mohrbacher, Ann; Levine, Alexandra M; Douer, Dan

    2013-12-01

    Current salvage regimens achieve complete remission (CR) in about a third of adults with relapsed/refractory acute lymphoblastic leukemia (ALL), and this represents a major barrier for performing allogeneic hematopoietic stem cell transplant (HSCT), the only potentially curative treatment. We conducted in adults with first relapse of ALL, a prospective clinical trial with intensive regimen derived from the pediatric Berlin-Frankfurt-Muenster-85 protocol, with addition of a continuous infusional multi-agent chemotherapy in phase II induction followed by consolidation with alternating monthly cycles. Objectives of this study included CR rate, leukemia-free survival (LFS) and toxicity of the regimen in adults. We report the outcome of 19 patients (19-51 years of age) treated prospectively on the study, as well as a subsequent cohort of 31 patients (18-53 years of age) treated off the study. Thirteen of 19 (68%) patients from the initial prospective study achieved CR, and the median overall survival (OS) of these 13 CR patients was 10.3 months. The median OS and LFS of all 19 patients were 5.6 and 4.3 months, respectively. The regimen was well tolerated, and no grade 4 non-hematological toxicity was observed. Of the 31 patients treated off the study and analyzed retrospectively, 16 (52%) achieved CR. After including all 50 patients, the CR rate was 58%. The regimen used in this trial appears to be feasible and effective salvage therapy option for adult patients younger than age 55 with relapsed ALL, produced a high CR rate and could facilitate subsequent allogeneic HSCT.

  18. Prevalence, diagnosis, and disease course of pertussis in adults with acute cough: a prospective, observational study in primary care

    PubMed Central

    Teepe, Jolien; Broekhuizen, Berna DL; Ieven, Margareta; Loens, Katherine; Huygen, Kris; Kretzschmar, Mirjam; de Melker, Hester; Butler, Chris C; Little, Paul; Stuart, Beth; Coenen, Samuel; Goossens, Herman; Verheij, Theo JM

    2015-01-01

    Background Most cases of adult pertussis probably remain undiagnosed. Aim To explore the prevalence, diagnosis, and disease course of acute pertussis infection in adult patients presenting with acute cough. Design and setting Prospective observational study between 2007 and 2010 in primary care in 12 European countries. Method Adults presenting with acute cough (duration of ≤28 days) were included. Bordetella pertussis infection was determined by polymerase chain reaction (from nasopharyngeal flocked swabs and sputa) and by measurement of immunoglobulin G antibodies to pertussis toxin (PT) in venous blood at day 28. An antibody titre to PT of ≥125 IU/ml or PCR positive result in a respiratory sample defined recent infection. Patients completed a symptom diary for 28 days. Results Serum and/or respiratory samples were obtained in 3074 patients. Three per cent (93/3074) had recent B. pertussis infection. Prior cough duration >2 weeks discriminated to some extent between those with and without pertussis (adjusted odds ratio 1.89, 95% confidence interval = 1.17 to 3.07; P = 0.010). Median cough duration after presentation was 17 and 12 days in patients with and without pertussis, respectively (P = 0.008). Patients with pertussis had longer duration of phlegm production (P = 0.010), shortness of breath (P = 0.037), disturbed sleep (P = 0.013) and interference with normal activities or work (P = 0.033) after presentation. Conclusion Pertussis infection plays a limited role among adults presenting with acute cough in primary care, but GPs should acknowledge the possibility of pertussis in uncomplicated lower respiratory tract infection. As in children, pertussis also causes prolonged symptoms in adults. However, pertussis is difficult to discern from other acute cough syndromes in adults at first presentation. PMID:26412843

  19. Hierarchy in gene expression is predictive of risk, progression, and outcome in adult acute myeloid leukemia

    NASA Astrophysics Data System (ADS)

    Tripathi, Shubham; Deem, Michael W.

    2015-02-01

    Cancer progresses with a change in the structure of the gene network in normal cells. We define a measure of organizational hierarchy in gene networks of affected cells in adult acute myeloid leukemia (AML) patients. With a retrospective cohort analysis based on the gene expression profiles of 116 AML patients, we find that the likelihood of future cancer relapse and the level of clinical risk are directly correlated with the level of organization in the cancer related gene network. We also explore the variation of the level of organization in the gene network with cancer progression. We find that this variation is non-monotonic, which implies the fitness landscape in the evolution of AML cancer cells is non-trivial. We further find that the hierarchy in gene expression at the time of diagnosis may be a useful biomarker in AML prognosis.

  20. Adult onset Still's disease accompanied by acute respiratory distress syndrome: A case report

    PubMed Central

    Xi, Xiao-Tu; Wang, Mao-Jie; Huang, Run-Yue; Ding, Bang-Han

    2016-01-01

    Adult onset Still's disease (AOSD) is a systemic inflammatory disorder characterized by rash, leukocytosis, fever and arthralgia/arthritis. The most common pulmonary manifestations associated with AOSD are pulmonary infiltrates and pleural effusion. The present study describes a 40-year-old male with AOSD who developed fever, sore throat and shortness of breath. Difficulty breathing promptly developed, and the patient was diagnosed with acute respiratory distress syndrome (ARDS). The patient did not respond to antibiotics, including imipenem, vancomycin, fluconazole, moxifloxacin, penicillin, doxycycline and meropenem, but was sensitive to glucocorticoid treatment, including methylprednisolone sodium succinate. ARDS accompanied by AOSD has been rarely reported in the literature. In conclusion, in a patient with ARDS who does not respond to antibiotic treatment, the involvement of AOSD should be considered. PMID:27588099

  1. Hierarchy in gene expression is predictive of risk, progression, and outcome in adult acute myeloid leukemia.

    PubMed

    Tripathi, Shubham; Deem, Michael W

    2015-02-01

    Cancer progresses with a change in the structure of the gene network in normal cells. We define a measure of organizational hierarchy in gene networks of affected cells in adult acute myeloid leukemia (AML) patients. With a retrospective cohort analysis based on the gene expression profiles of 116 AML patients, we find that the likelihood of future cancer relapse and the level of clinical risk are directly correlated with the level of organization in the cancer related gene network. We also explore the variation of the level of organization in the gene network with cancer progression. We find that this variation is non-monotonic, which implies the fitness landscape in the evolution of AML cancer cells is non-trivial. We further find that the hierarchy in gene expression at the time of diagnosis may be a useful biomarker in AML prognosis. PMID:25685944

  2. ROLE OF MINIMAL RESIDUAL DISEASE MONITORING IN ADULT AND PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA

    PubMed Central

    Campana, Dario

    2009-01-01

    SYNOPSIS Assays that measure minimal residual disease (MRD) can determine the response to treatment in patients with acute lymphoblastic leukemia (ALL) much more precisely than morphological screening of bone marrow smears. The clinical significance of MRD detected by flow cytometry or polymerase chain reaction-based methods in childhood ALL has been conclusively established. Hence, MRD is being used in several clinical trials to adjust treatment intensity. Similar findings have been gathered in adult patients with ALL, making MRD one of the most powerful and informative parameters to guide clinical management. This article discusses practical issues related to MRD methodologies and the evidence supporting the use of MRD for risk assignment in clinical trials. PMID:19825454

  3. Does aberrant membrane transport contribute to poor outcome in adult acute myeloid leukemia?

    PubMed Central

    Chigaev, Alexandre

    2015-01-01

    Acute myeloid leukemia in adults is a highly heterogeneous disease. Gene expression profiling performed using unsupervised algorithms can be used to distinguish specific groups of patients within a large patient cohort. The identified gene expression signatures can offer insights into underlying physiological mechanisms of disease pathogenesis. Here, the analysis of several related gene expression clusters associated with poor outcome, worst overall survival and highest rates of resistant disease and obtained from the patients at the time of diagnosis or from previously untreated individuals is presented. Surprisingly, these gene clusters appear to be enriched for genes corresponding to proteins involved in transport across membranes (transporters, carriers and channels). Several ideas describing the possible relationship of membrane transport activity and leukemic cell biology, including the “Warburg effect,” the specific role of chloride ion transport, direct “import” of metabolic energy through uptake of creatine phosphate, and modification of the bone marrow niche microenvironment are discussed. PMID:26191006

  4. Excess diuresis and natriuresis during acute sleep deprivation in healthy adults.

    PubMed

    Kamperis, Konstantinos; Hagstroem, Soren; Radvanska, Eva; Rittig, Soren; Djurhuus, Jens Christian

    2010-08-01

    The transition from wakefulness to sleep is associated with a pronounced decline in diuresis, a necessary physiological process that allows uninterrupted sleep. The aim of this study was to assess the effect of acute sleep deprivation (SD) on urine output and renal water, sodium, and solute handling in healthy young volunteers. Twenty young adults (10 male) were recruited for two 24-h studies under standardized dietary conditions. During one of the two admissions, subjects were deprived of sleep. Urine output, electrolyte excretions, and osmolar excretions were calculated. Activated renin, angiotensin II, aldosterone, arginine vasopressin, and atrial natriuretic peptide were measured in plasma, whereas prostaglandin E(2) and melatonin were measured in urine. SD markedly increased the diuresis and led to excess renal sodium excretion. The effect was more pronounced in men who shared significantly higher diuresis levels during SD compared with women. Renal water handling and arginine vasopressin levels remained unaltered during SD, but the circadian rhythm of the hormones of the renin-angiotensin-aldosterone system was significantly affected. Urinary melatonin and prostaglandin E(2) excretion levels were comparable between SD and baseline night. Hemodynamic changes were characterized by the attenuation of nocturnal blood pressure dipping and an increase in creatinine clearance. Acute deprivation of sleep induces natriuresis and osmotic diuresis, leading to excess nocturnal urine production, especially in men. Hemodynamic changes during SD may, through renal and hormonal processes, be responsible for these observations. Sleep architecture disturbances should be considered in clinical settings with nocturnal polyuria such as enuresis in children and nocturia in adults.

  5. Clinical and haemato-pathological characteristics of adult acute lymphoblastic leukaemia.

    PubMed

    Islam, N; Rahman, M M; Aziz, M A; Begum, M; Ferdous, J; Rahman, M J

    2014-04-01

    Acute lymphoblastic leukaemia (ALL) is a heterogeneous group of disorders. It varies with respect to the morphologic, cytogenetic, molecular and immunologic features of the neoplastic cells reflecting the variable clinical-pathologic presentations and outcome of the patients. The aim of the study was to observe the clinical and haemato-pathological characteristics in newly diagnosed adult ALL patients. A total number of 61 patients morphologically diagnosed as acute lymphoblastic leukaemia aged 15 and above assigned for this observational study. The study was carried out in the Department of Haematology, BSMMU from January 2007 to December 2008. Among 61 patients, aged 15 to 80 years with median age 25 years, 79% were male and 21% were female. Most of the patients presented with anaemia (67%), fever (66%), lymphadenopathy (64%) and splenomegaly (57%). Other common clinical findings were hepatomegaly (39%), bone tenderness (44%) and bleeding manifestations (34%). Among haemato-pathological findings 67% patients had Hb level ≤10gm/dl, 46% patients had WBC count ≥30×10⁹/L, 67% patients had platelet count ≤100×10⁹/L, 93% patients had blast in peripheral blood and 61% patients had ≥90 % blasts in the bone marrow at the time of diagnosis. In this study adult ALL patients were analyzed only for their clinical and haemato-pathological characteristics. But their biologic characteristics were not analyzed due to lack of availability of facility. A progressive understanding of the biologic and genetic characteristics of ALL will allow us to identify different prognostic subgroups with specific molecular and cellular features. All the necessary measures have to be developed in our country in order to identify prognostically distinct subgroups of patients.

  6. Acute leukemia of adults. Ultrastructural, cytochemical and histologic observations in 100 cases.

    PubMed

    Glick, A D; Paniker, K; Flexner, J M; Graber, S E; Collins, R D

    1980-04-01

    In order to establish guidelines for categorization of acute leukemia, marrow histology, special stains, and electron microscopy were performed in 100 adult leukemia cases. Differential counts for each stain were performed, and the results were combined with those obtained by electron microscopy for final classification. Myeloid (non-lymphoid) leukemia was most common (83 cases), and there were 13 lymphoid cases, two cases of erythroleukemia, and two undifferentiated leukemias. Histologic studies of marrow particles revealed significant admixtures of lymphocytes, plasma cells, and abnormal erythroid elements, particularly in acute myelomonocytic leukemia. Interpretations of cytochemical results were confirmed by ultrastructural studies in 90% of the cases. Clinically significant discrepancies between cytochemical and ultrastructural interpretations were rarely found. Only two myeloid and five lymphoid cases did not mark typically with any cytochemical stain. The single most reliable special stain was the periodic acid-Schiff stain, whereas the stain most difficult to interpret was the alpha-naphthyl acetate esterase stain. Sudan black stain was particularly helpful in demonstrating Auer rods. Five of six cases unclassified by cytochemistry were categorized by electron microscopy. Although patterns of cytochemical staining were delineated for each type of leukemia, significant intragroup variation in cytochemical reactions was recognized. This study indicates that ultrastructural examination should be routinely used for categorization of cases with equivocal cytochemical findings and for analysis of unclassified cases.

  7. Novel Cryptic Rearrangements in Adult B-Cell Precursor Acute Lymphoblastic Leukemia Involving the MLL Gene

    PubMed Central

    Othman, Moneeb A. K.; Grygalewicz, Beata; Pienkowska-Grela, Barbara; Rincic, Martina; Rittscher, Katharina; Melo, Joana B.; Carreira, Isabel M.; Meyer, Britta; Marzena, Watek

    2015-01-01

    MLL (mixed-lineage-leukemia) gene rearrangements are typical for acute leukemia and are associated with an aggressive course of disease, with a worse outcome than comparable case, and thus require intensified treatment. Here we describe a 69-year-old female with adult B cell precursor acute lymphoblastic leukemia (BCP-ALL) with hyperleukocytosis and immunophenotype CD10- and CD19+ with cryptic MLL rearrangements. G-banding at the time of diagnosis showed a normal karyotype: 46,XX. Molecular cytogenetics using multitude multicolor banding (mMCB) revealed a complex rearrangement of the two copies of chromosome 11. However, a locus-specific probe additionally identified that the MLL gene at 11q23.3 was disrupted, and that the 5′ region was inserted into the chromosomal sub-band 4q21; thus the aberration involved three chromosomes and five break events. Unfortunately, the patient died six months after the initial diagnosis from serious infections and severe complications. Overall, the present findings confirm that, by far not all MLL aberrations are seen by routine chromosome banding techniques and that fluorescence in situ hybridization (FISH) should be regarded as standard tool to access MLL rearrangements in patients with BCP-ALL. PMID:25699572

  8. Potential Reparative Role of Resident Adult Renal Stem/Progenitor Cells in Acute Kidney Injury

    PubMed Central

    Sallustio, Fabio; Serino, Grazia; Schena, Francesco Paolo

    2015-01-01

    Abstract Human kidney is particularly susceptible to ischemia and toxins with consequential tubular necrosis and activation of inflammatory processes. This process can lead to the acute renal injury, and even if the kidney has a great capacity for regeneration after tubular damage, in several circumstances, the normal renal repair program may not be sufficient to achieve a successful regeneration. Resident adult renal stem/progenitor cells could participate in this repair process and have the potentiality to enhance the renal regenerative mechanism. This could be achieved both directly, by means of their capacity to differentiate and integrate into the renal tissues, and by means of paracrine factors able to induce or improve the renal repair or regeneration. Recent genetic fate-tracing studies indicated that tubular damage is instead repaired by proliferative duplication of epithelial cells, acquiring a transient progenitor phenotype and by fate-restricted clonal cell progeny emerging from different nephron segments. In this review, we discuss about the properties and the reparative characteristics of high regenerative CD133+/CD24+ cells, with a view to a future application of these cells for the treatment of acute renal injury. PMID:26309808

  9. Successful cord blood transplantation in an adult acute lymphoblastic leukemia patient with congenital heart disease.

    PubMed

    Kowata, Shugo; Fujishima, Yukiteru; Suzuki, Yuzo; Tsukushi, Yasuhiko; Oyake, Tatsuo; Togawa, Ryou; Oyama, Kotaro; Ikai, Akio; Ito, Shigeki; Ishida, Yoji

    2016-08-01

    Recent advances in surgical corrections and supportive care for congenital heart disease have resulted in increasing numbers of adult survivors who may develop hematological malignancies. Treatments including chemotherapy for such patients may cause serious hemodynamic or cardiac complications, especially in those receiving stem cell transplantation. We present a 29-year-old woman with acute lymphoblastic leukemia and congenital heart disease. She had been diagnosed with pulmonary atresia with an intact ventricular septum at birth, and the anomaly was surgically corrected according to the Fontan technique at age 9 years. Her induction chemotherapy required modifications due to poor cardiac status with Fontan circulation. However, after surgical procedures including total cavopulmonary connection and aortic valve replacement at first complete remission, her cardiac status was significantly improved. Subsequently, she underwent cord blood stem cell transplantation at the third complete remission. She required intensive supportive care for circulatory failure as a pre-engraftment immune reaction and stage III acute graft versus host disease of the gut, but recovered from these complications. She was discharged on day 239, and remained in complete remission at 1-year post-transplantation. PMID:27599417

  10. A clinical pathologic study of four adult cases of acute mercury inhalation toxicity

    SciTech Connect

    Kanluen, S.; Gottlieb, C.A. )

    1991-01-01

    We report four cases of fatal mercury vapor inhalation, a rare occurrence. The mercury vapor was released at a private home, where one of the occupants was smelting silver from dental amalgam containing an unknown amount of mercury. Within 24 hours of the incident, all occupants began having shortness of breath necessitating hospital admission. The clinical courses are briefly detailed; however, all included rapid deterioration with respiratory failure. Chest roentgenograms in all four cases were consistent with adult respiratory distress syndrome. All patients were treated with dimercaprol, a mercury chelator, but all died, with survival varying from 9 to 23 days postexposure. Autopsies were performed on all four patients. The lungs in all cases were heavy, firm, and airless. Histologic examination revealed severe diffuse alveolar damage, with variable amounts of fibrosis, conforming with acute lung injury in various stages of organization. Additional postmortem findings included acute proximal renal tubular necrosis, vacuolar hepatoxicity, and a spectrum of central nervous system alterations including multifocal ischemic necrosis, gliosis, and vasculitis.

  11. Persistent Adult Zebrafish Behavioral Deficits Results from Acute Embryonic Exposure to Gold Nanoparticles

    PubMed Central

    Truong, Lisa; Saili, Katerine S.; Miller, John M.; Hutchison, James E.; Tanguay, Robert L.

    2011-01-01

    As the number of products containing nanomaterials increase, human exposure to nanoparticles (NPs) is unavoidable. Presently, few studies focus on the potential long-term consequences of developmental NP exposure. In this study, zebrafish embryos were acutely exposed to three gold NPs that possess functional groups with differing surface charge. Embryos were exposed to 50 μg/mL of 1.5 nm gold nanoparticles (AuNPs) possessing negatively charged 2-mercaptoethanesulfonic acid (MES) or neutral 2-(2-(2-mercaptoethoxy)ethoxy)ethanol (MEEE) ligands or 10 μg/mL of the AuNPs possessing positively charged trimethylammoniumethanethiol (TMAT). Both MES- and TMAT-AuNP exposed embryos exhibited hypo-locomotor activity, while those exposed to MEEE-AuNPs did not. A subset of embryos that were exposed to 1.5 nm MES- and TMAT-AuNPs during development from 6–120 hours post fertilization were raised to adulthood. Behavioral abnormalities and the number of survivors into adulthood were evaluated at 122 days post fertilization. We found that both treatments induced abnormal startle behavior following a tap stimulus. However, the MES-AuNPs exposed group also exhibited abnormal adult behavior in the light and had a lower survivorship into adulthood. This study demonstrates that acute, developmental exposure to 1.5 nm MES- and TMAT- AuNPs, two NPs differing only in the functional group, affects larval behavior, with behavioral effects persisting into adulthood. PMID:21946249

  12. Potential for a pluripotent adult stem cell treatment for acute radiation sickness

    PubMed Central

    Rodgerson, Denis O; Reidenberg, Bruce E; Harris, Alan G; Pecora, Andrew L

    2012-01-01

    Accidental radiation exposure and the threat of deliberate radiation exposure have been in the news and are a public health concern. Experience with acute radiation sickness has been gathered from atomic blast survivors of Hiroshima and Nagasaki and from civilian nuclear accidents as well as experience gained during the development of radiation therapy for cancer. This paper reviews the medical treatment reports relevant to acute radiation sickness among the survivors of atomic weapons at Hiroshima and Nagasaki, among the victims of Chernobyl, and the two cases described so far from the Fukushima Dai-Ichi disaster. The data supporting the use of hematopoietic stem cell transplantation and the new efforts to expand stem cell populations ex vivo for infusion to treat bone marrow failure are reviewed. Hematopoietic stem cells derived from bone marrow or blood have a broad ability to repair and replace radiation induced damaged blood and immune cell production and may promote blood vessel formation and tissue repair. Additionally, a constituent of bone marrow-derived, adult pluripotent stem cells, very small embryonic like stem cells, are highly resistant to ionizing radiation and appear capable of regenerating radiation damaged tissue including skin, gut and lung. PMID:24520532

  13. Novel Cryptic Rearrangements in Adult B-Cell Precursor Acute Lymphoblastic Leukemia Involving the MLL Gene.

    PubMed

    Othman, Moneeb A K; Grygalewicz, Beata; Pienkowska-Grela, Barbara; Rincic, Martina; Rittscher, Katharina; Melo, Joana B; Carreira, Isabel M; Meyer, Britta; Marzena, Watek; Liehr, Thomas

    2015-05-01

    MLL (mixed-lineage-leukemia) gene rearrangements are typical for acute leukemia and are associated with an aggressive course of disease, with a worse outcome than comparable case, and thus require intensified treatment. Here we describe a 69-year-old female with adult B cell precursor acute lymphoblastic leukemia (BCP-ALL) with hyperleukocytosis and immunophenotype CD10- and CD19+ with cryptic MLL rearrangements. G-banding at the time of diagnosis showed a normal karyotype: 46,XX. Molecular cytogenetics using multitude multicolor banding (mMCB) revealed a complex rearrangement of the two copies of chromosome 11. However, a locus-specific probe additionally identified that the MLL gene at 11q23.3 was disrupted, and that the 5' region was inserted into the chromosomal sub-band 4q21; thus the aberration involved three chromosomes and five break events. Unfortunately, the patient died six months after the initial diagnosis from serious infections and severe complications. Overall, the present findings confirm that, by far not all MLL aberrations are seen by routine chromosome banding techniques and that fluorescence in situ hybridization (FISH) should be regarded as standard tool to access MLL rearrangements in patients with BCP-ALL. PMID:25699572

  14. Potential for a pluripotent adult stem cell treatment for acute radiation sickness.

    PubMed

    Rodgerson, Denis O; Reidenberg, Bruce E; Harris, Alan G; Pecora, Andrew L

    2012-06-20

    Accidental radiation exposure and the threat of deliberate radiation exposure have been in the news and are a public health concern. Experience with acute radiation sickness has been gathered from atomic blast survivors of Hiroshima and Nagasaki and from civilian nuclear accidents as well as experience gained during the development of radiation therapy for cancer. This paper reviews the medical treatment reports relevant to acute radiation sickness among the survivors of atomic weapons at Hiroshima and Nagasaki, among the victims of Chernobyl, and the two cases described so far from the Fukushima Dai-Ichi disaster. The data supporting the use of hematopoietic stem cell transplantation and the new efforts to expand stem cell populations ex vivo for infusion to treat bone marrow failure are reviewed. Hematopoietic stem cells derived from bone marrow or blood have a broad ability to repair and replace radiation induced damaged blood and immune cell production and may promote blood vessel formation and tissue repair. Additionally, a constituent of bone marrow-derived, adult pluripotent stem cells, very small embryonic like stem cells, are highly resistant to ionizing radiation and appear capable of regenerating radiation damaged tissue including skin, gut and lung.

  15. Pharmacotherapy of Acute Bipolar Depression in Adults: An Evidence Based Approach.

    PubMed

    Muneer, Ather

    2016-05-01

    In the majority of cases of bipolar disorder, manic episodes are usually brief and typically responsive to currently available psychopharmacological agents. In contrast, depressive manifestations are more prevalent and persistent, and can present as major depressive/mixed episodes or residual interepisode symptoms. The depressive phase is often associated with other neuropsychiatric conditions, such as anxiety spectrum disorders, substance use disorders, stressor-related disorders, and eating disorders. It is viewed as a systemic disease with associated ailments such as metabolic syndrome, diabetes mellitus, and cardiovascular disease. There is an increased rate of mortality not only from suicide, but also from concomitant physical illness. This scenario is made worse by the fact that depressive symptoms, which represent the main disease burden, are often refractory to existing psychotropic drugs. As such, there is a pressing need for novel agents that are efficacious in acute depressive exacerbations, and also have applicable value in preventing recurrent episodes. The rationale of the present review is to delineate the pharmacotherapy of the depressive phase of bipolar disorder with medications for which there is evidence in the form of observational, open-label, or double-blind randomized controlled studies. In the treatment of acute bipolar depression in adults, a comprehensive appraisal of the extant literature reveals that among mood stabilizers, the most robust proof of efficacy exists for divalproex sodium; while atypical antipsychotics, which include olanzapine, quetiapine, lurasidone, and cariprazine, are also effective, as demonstrated in controlled trials. PMID:27274384

  16. Blinatumomab: Bridging the Gap in Adult Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia.

    PubMed

    Folan, Stephanie A; Rexwinkle, Amber; Autry, Jane; Bryan, Jeffrey C

    2016-08-01

    Adult patients with acute lymphoblastic leukemia who relapse after frontline therapy have extremely poor outcomes despite advances in chemotherapy and hematopoietic stem cell transplantation. Blinatumomab is a first-in-class bispecific T-cell engager that links T cells to tumor cells leading to T-cell activation and tumor cell lysis. In December 2014, the Food and Drug Administration approved blinatumomab for treatment of relapsed or refractory Philadelphia chromosome-negative precursor B-cell acute lymphoblastic leukemia. In a phase II trial, blinatumomab produced response rates of 43%, and 40% of patients achieving a complete remission proceeded to hematopoietic stem cell transplantation. Early use of blinatumomab was complicated with adverse effects, including cytokine release syndrome and neurotoxicity. Management strategies, including dexamethasone premedication and 2-step dose escalation during the first cycle of blinatumomab, have decreased the incidence and severity of these adverse effects. Blinatumomab currently is being studied for other B-cell malignancies and has the potential to benefit many patients with CD19+ malignancies in the future. PMID:27521320

  17. Pharmacotherapy of Acute Bipolar Depression in Adults: An Evidence Based Approach

    PubMed Central

    2016-01-01

    In the majority of cases of bipolar disorder, manic episodes are usually brief and typically responsive to currently available psychopharmacological agents. In contrast, depressive manifestations are more prevalent and persistent, and can present as major depressive/mixed episodes or residual interepisode symptoms. The depressive phase is often associated with other neuropsychiatric conditions, such as anxiety spectrum disorders, substance use disorders, stressor-related disorders, and eating disorders. It is viewed as a systemic disease with associated ailments such as metabolic syndrome, diabetes mellitus, and cardiovascular disease. There is an increased rate of mortality not only from suicide, but also from concomitant physical illness. This scenario is made worse by the fact that depressive symptoms, which represent the main disease burden, are often refractory to existing psychotropic drugs. As such, there is a pressing need for novel agents that are efficacious in acute depressive exacerbations, and also have applicable value in preventing recurrent episodes. The rationale of the present review is to delineate the pharmacotherapy of the depressive phase of bipolar disorder with medications for which there is evidence in the form of observational, open-label, or double-blind randomized controlled studies. In the treatment of acute bipolar depression in adults, a comprehensive appraisal of the extant literature reveals that among mood stabilizers, the most robust proof of efficacy exists for divalproex sodium; while atypical antipsychotics, which include olanzapine, quetiapine, lurasidone, and cariprazine, are also effective, as demonstrated in controlled trials. PMID:27274384

  18. Two distinctly regulated events, priming and triggering, during retinoid-induced maturation and resistance of NB4 promyelocytic leukemia cell line.

    PubMed Central

    Ruchaud, S; Duprez, E; Gendron, M C; Houge, G; Genieser, H G; Jastorff, B; Doskeland, S O; Lanotte, M

    1994-01-01

    In t(15;17) acute promyelocytic leukemia, all-trans retinoic acid (RA) induces leukemic cell maturation in vitro and remission in acute promyelocytic leukemia patients, but in vivo treatments invariably lead to relapse with resistance to RA. NB4, a maturation-inducible cell line, and NB4-RAr sublines (R1 and R2) displaying no maturation in the presence of RA have been isolated from a patient in relapse. We show that resistance to maturation is not a mere unresponsiveness to RA: rather, R1 "resistant" cells do respond to RA (1 microM) by sustained growth, become competent to undergo terminal maturation, and up-regulate CD11c/CD18 integrins. Interestingly, maturation of "resistant" cells, rendered competent by RA, can be achieved by cAMP-elevating agents (prostaglandin E, isoproterenol, cholera toxin, or phosphodiesterase inhibitor) or stable agonistic cAMP analogs such as (SP)-8-chloroadenosine cyclic 3',5'-phosphorothioate. This shows that activation of cAMP-dependent protein kinase (cA kinase) can override the RA resistance and suggests interdependent RA and cAMP signaling pathways in acute promyelocytic leukemia maturation. No such cooperation was observed in the R2 resistant cells, though their cA-kinase was functional. (RP)-8-Chloroadenosine cyclic 3',5'-phosphorothioate, which by displacing endogenous cAMP inhibits the basal cA-kinase activity, decreased the response of sensitive cells to RA. This raises the possibility that cA-kinase plays a key role in the maturation also of RA-sensitive cells. Our results define two discrete steps in the maturation process: an RA-dependent priming step that maintains proliferation while cells become competent to undergo maturation in response to retinoids and a cAMP-dependent step that triggers RA-primed cells to undergo terminal maturation. Uncoupling RA and cAMP action might cause the so-called "resistance." Images PMID:7915840

  19. Novel dynamin 2 mutations in adult T-cell acute lymphoblastic leukemia

    PubMed Central

    Ge, Zheng; Li, Min; Zhao, Gang; Xiao, Lichan; Gu, Yan; Zhou, Xilian; Yu, Michael D.; Li, Jianyong; Dovat, Sinisa; Song, Chunhua

    2016-01-01

    Genetic mutations on signaling pathways are found in patients with T-cell acute lymphoblastic leukemia (T-ALL) and act as markers of high-risk leukemia. Mutations in dynamin 2 (DNM2) have been reported in T-ALL, particularly in early T-cell precursor-ALL. In the present study, DNM2 mutations were screened by sequencing DNM2 exons obtained by polymerase chain reaction amplification and gel purification in adult T-ALL patients. A total of 4 novel DNM2 mutations were identified in adult T-ALL patients, with a mutation rate of 9.5%, and the DNM2 mutations were found to co-exist with NOTCH1 and PHD finger protein 6, and were also associated with high-risk leukemia. A high rate of silent mutation was also found in the patients, but no significant association was found between the silent mutations and patients' clinical features. The present findings suggested the DNM2 mutations may be involved in the oncogenesis of T-ALL.

  20. Central Nervous System Involvement in Adult Acute Lymphoblastic Leukemia: Diagnostic Tools, Prophylaxis, and Therapy

    PubMed Central

    Del Principe, Maria Ilaria; Maurillo, Luca; Buccisano, Francesco; Sconocchia, Giuseppe; Cefalo, Mariagiovanna; De Santis, Giovanna; Di Veroli, Ambra; Ditto, Concetta; Nasso, Daniela; Postorino, Massimiliano; Refrigeri, Marco; Attrotto, Cristina; Del Poeta, Giovanni; Lo-Coco, Francesco; Amadori, Sergio; Venditti, Adriano

    2014-01-01

    In adult patients with acute lymphoblastic leukemia (ALL), Central Nervous System (CNS) involvement is associated with a very poor prognosis. The diagnostic assessment of this condition relies on the use of neuroradiology, conventional cytology (CC) and flow cytometry (FCM). Among these approaches, which is the gold standard it is still a matter of debate. Neuroradiology and CC have a limited sensitivity with a higher rate of false negative results. FCM demonstrated a superior sensitivity over CC, particularly when low levels of CNS infiltrating cells are present. Although prospective studies of a large series of patients are still awaited, a positive finding by FCM appears to anticipate an adverse outcome even if CC shows no infiltration. Current strategies for adult ALL CNS-directed prophylaxis or therapy involve systemic and intrathecal chemotherapy and radiation therapy. An early and frequent intrathecal injection of cytostatic combined with systemic chemotherapy is the most effective strategy to reduce the frequency of CNS involvement. In patients with CNS overt ALL, at diagnosis or upon relapse, allogeneic hematopoietic stem cell transplantation might be considered. This review discusses risk factors, diagnostic techniques for identification of CNS infiltration and modalities of prophylaxis and therapy to manage it. PMID:25408861

  1. Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR.

    PubMed

    Mizutani, M; Hara, M; Fujita, H; Aoki, J; Kanamori, H; Ohashi, K; Usuki, K; Fukuda, T; Chou, T; Tanaka, J; Atsuta, Y; Takami, A

    2016-05-01

    Although allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor (MSD) is a potentially curative post-remission treatment for adults with acute myeloid leukemia (AML) in their first CR, transplant-related morbidity and mortality remains a major drawback. We retrospectively compared the outcomes of patients who underwent autologous peripheral blood stem cell transplantation (auto-PBSCT; n=375) with those who underwent allogeneic bone marrow transplantation (allo-BMT; n=521) and allo-PBSCT (n=380) from MSDs for adults with AML/CR1, in which propensity score models were used to adjust selection biases among patients, primary physicians and institutions to overcome ambiguity in the patients' background information. Both the multivariate analysis and propensity score models indicated that the leukemia-free survival rate of auto-PBSCT was not significantly different from that of allo-BMT (hazard ratio (HR), 1.23; 95% confidence interval (CI), 0.92 to 1.66; P=0.16) and allo-PBSCT (HR, 1.13; 95% CI, 0.85-1.51; P=0.40). The current results suggest that auto-PBSCT remains a promising alternative treatment for patients with AML/CR1 in the absence of an available MSD. PMID:26808566

  2. How I treat acute lymphoblastic leukemia in older adolescents and young adults

    PubMed Central

    Curran, Emily

    2015-01-01

    At the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. Although the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease-free survival rates of 60% to 70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and the availability of disease-specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients. PMID:25805810

  3. Whole adult organism transcriptional profiling of acute metal exposures in male Zebrafish

    PubMed Central

    2014-01-01

    Background A convergence of technological breakthroughs in the past decade has facilitated the development of rapid screening tools for biomarkers of toxicant exposure and effect. Platforms using the whole adult organism to evaluate the genome-wide response to toxicants are especially attractive. Recent work demonstrates the feasibility of this approach in vertebrates using the experimentally robust zebrafish model. In the present study, we evaluated gene expression changes in whole adult male zebrafish following an acute 24 hr high dose exposure to three metals with known human health risks. Male adult zebrafish were exposed to nickel chloride, cobalt chloride or sodium dichromate concentrations corresponding to their respective 96 hr LC20, LC40 and LC60. Histopathology was performed on a subset of metal-exposed zebrafish to phenotypically anchor transcriptional changes associated with each metal. Results Comparative analysis identified subsets of differentially expressed transcripts both overlapping and unique to each metal. Application of gene ontology (GO) and transcription factor (TF) enrichment algorithms revealed a number of key biological processes perturbed by metal poisonings and the master transcriptional regulators mediating gene expression changes. Metal poisoning differentially activated biological processes associated with ribosome biogenesis, proteosomal degradation, and p53 signaling cascades, while repressing oxygen-generating pathways associated with amino acid and lipid metabolism. Despite appreciable effects on gene regulation, nickel poisoning did not induce any morphological alterations in male zebrafish organs and tissues. Histopathological effects of cobalt remained confined to the olfactory system, while chromium targeted the gills, pharynx, and intestinal mucosa. A number of enriched transcription factors mediated the observed gene response to metal poisoning, including known targets such as p53, HIF1α, and the myc oncogene, and novel

  4. Sensorineural hearing loss: a complication of acute otitis media in adults.

    PubMed

    Park, Joo Hyun; Park, Sung Joon; Kim, Young Ho; Park, Min-Hyun

    2014-07-01

    We aim to evaluate the incidence and clinical manifestations of sensorineural hearing loss (SNHL) in adult patients with acute otitis media (AOM). Seventy-five patients (age > 18 years; 83 ears) diagnosed with AOM between January 2008 and March 2011 at our clinic were enroled and retrospectively reviewed. We detected audiometrically confirmed SNHL during the course of AOM in eight patients. The clinical course, treatment, and audiometric final outcome of each case were reviewed. SNHL was associated with AOM in 8 out of 83 ears (9.3%). The mean age of patients was 57.5 years, and the mean follow-up period was 21.1 months (range 0.6-46.3 months). The most common symptom was tinnitus. Mean bone conduction hearing threshold was 39.5 dB in pure tone audiometry. All patients showed high-frequency HL, and three showed pan-frequency HL. All patients were treated with oral antibiotics at the initial visit. Seven ears were treated with a combination of oral steroids. Myringotomy was also performed. Seven of eight patients showed improvement; however, 8 kHz thresholds were not improved. This suggested that the inflammation spread through the round window. The mean duration of recovery was 18.6 days. SNHL associated with AOM in adult patients occurs during the early phases of the disease course. High-frequency hearing was commonly affected and was well treated with oral antibiotics, myringotomy, and steroid therapy. Audiometry can be helpful for treating adult patients with AOM. Active treatment, including myringotomy, should be performed during the early phase, if SNHL is suspected. PMID:23990061

  5. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.

    PubMed

    Beldjord, Kheira; Chevret, Sylvie; Asnafi, Vahid; Huguet, Françoise; Boulland, Marie-Laure; Leguay, Thibaut; Thomas, Xavier; Cayuela, Jean-Michel; Grardel, Nathalie; Chalandon, Yves; Boissel, Nicolas; Schaefer, Beat; Delabesse, Eric; Cavé, Hélène; Chevallier, Patrice; Buzyn, Agnès; Fest, Thierry; Reman, Oumedaly; Vernant, Jean-Paul; Lhéritier, Véronique; Béné, Marie C; Lafage, Marina; Macintyre, Elizabeth; Ifrah, Norbert; Dombret, Hervé

    2014-06-12

    With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively. PMID:24740809

  6. Antioxidant vitamins reduce acute meal-induced memory deficits in adults with type 2 diabetes.

    PubMed

    Chui, Michael Herman; Greenwood, Carol E

    2008-07-01

    Memory impairment is observed in adults with type 2 diabetes mellitus (T2DM), with further acute deficits after meal ingestion. This study explored whether postprandial oxidative stress was a contributor to these meal-induced memory deficits. Sixteen adults with T2DM (mean age, 63.5 +/- 2.1 years) who were not regularly taking high-dose antioxidant supplements were fed a high-fat meal, the same test meal with vitamins C (1000 mg) and E (800 IU) tablets, or water on 3 separate occasions. After meal ingestion, a battery of cognitive tests were administered, which included measures of delayed verbal memory, assessed at 60 and 105 minutes after meal ingestion. Relative to water consumption, the high-fat meal resulted in poorer performance at 105 minutes postingestion on measures of delayed verbal recall (word list and paragraph recall) and working memory (Digit-Span Forward). Coconsumption of antioxidant vitamins and high-fat meal prevented this meal-induced deficit such that performance on these tasks was indistinguishable from that after water intake. At the same time point, a small but significant improvement on the word-naming and color-naming components of Stroop was observed after meal ingestion, relative to water, irrespective of whether antioxidants were consumed, demonstrating the specificity of meal-induced impairments to memory function. Executive function, assessed by Trails Parts A and B, was not influenced by meal or antioxidant ingestion. In adults with T2DM, coconsumption of antioxidant vitamins minimizes meal-induced memory impairment, implicating oxidative stress as a potential contributor to these decrements. PMID:19083441

  7. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.

    PubMed

    Beldjord, Kheira; Chevret, Sylvie; Asnafi, Vahid; Huguet, Françoise; Boulland, Marie-Laure; Leguay, Thibaut; Thomas, Xavier; Cayuela, Jean-Michel; Grardel, Nathalie; Chalandon, Yves; Boissel, Nicolas; Schaefer, Beat; Delabesse, Eric; Cavé, Hélène; Chevallier, Patrice; Buzyn, Agnès; Fest, Thierry; Reman, Oumedaly; Vernant, Jean-Paul; Lhéritier, Véronique; Béné, Marie C; Lafage, Marina; Macintyre, Elizabeth; Ifrah, Norbert; Dombret, Hervé

    2014-06-12

    With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.

  8. The quality of patient experience of short-stay acute medical admissions: findings of the Adult Inpatient Survey in England.

    PubMed

    Sullivan, Paul; Harris, Mary L; Bell, Derek

    2013-12-01

    Introduction of the specialty of acute medicine and of acute medical units (AMUs) in the UK have been associated with improvements in mortality, length of stay and flow, but there is no literature on the patient experience during the early phase of acute medical admissions. We analysed the Adult Inpatient Survey (AIPS) findings for short-stay unscheduled medical admissions who did not move from their first admission ward (n=3325) and therefore are likely to have been managed entirely in the AMU. We compared these with short-stay emergencies in other specialties (n=3420) and short-stay scheduled admissions (n=10,347). Scheduled admissions reported a better experience for all survey items. Scores for unscheduled admissions were worse in medical patients compared with other specialties for pain control, privacy, involvement, information, and for a number of questions relating to information on discharge. The specialty of acute medicine should work to improve future patient experience.

  9. Effects of acute and chronic administration of fenproporex on DNA damage parameters in young and adult rats.

    PubMed

    Gonçalves, Cinara L; Rezin, Gislaine T; Ferreira, Gabriela K; Jeremias, Isabela C; Cardoso, Mariane R; Valvassori, Samira S; Munhoz, Bruna J P; Borges, Gabriela D; Bristot, Bruno N; Leffa, Daniela D; Andrade, Vanessa M; Quevedo, João; Streck, Emilio L

    2013-08-01

    Obesity is a chronic and multifactorial disease, whose prevalence is increasing in many countries. Pharmaceutical strategies for the treatment of obesity include drugs that regulate food intake, thermogenesis, fat absorption, and fat metabolism. Fenproporex is the second most commonly consumed amphetamine-based anorectic worldwide; this drug is rapidly converted in vivo into amphetamine, which is associated with neurotoxicity. In this context, the present study evaluated DNA damage parameters in the peripheral blood of young and adult rats submitted to an acute administration and chronic administration of fenproporex. In the acute administration, both young and adult rats received a single injection of fenproporex (6.25, 12.5 or 25 mg/kg i.p.) or vehicle. In the chronic administration, both young and adult rats received one daily injection of fenproporex (6.25, 12.5, or 25 mg/kg i.p.) or Tween for 14 days. 2 h after the last injection, the rats were killed by decapitation and their peripheral blood removed for evaluation of DNA damage parameters by alkaline comet assay. Our study showed that acute administration of fenproporex in young and adult rats presented higher levels of damage index and frequency in the DNA. However, chronic administration of fenproporex in young and adult rats did not alter the levels of DNA damage in both parameters of comet assay. The present findings showed that acute administration of fenproporex promoted damage in DNA, in both young and adult rats. Our results are consistent with other reports which showed that other amphetamine-derived drugs also caused DNA damage. We suggest that the activation of an efficient DNA repair mechanism may occur after chronic exposition to fenproporex. Our results are consistent with other reports that showed some amphetamine-derived drugs also caused DNA damage. PMID:23636618

  10. Prevalence and genetic diversity of noroviruses in adults with acute gastroenteritis in Huzhou, China, 2013-2014.

    PubMed

    Wu, Xiaofang; Han, Jiankang; Chen, Liping; Xu, Deshun; Shen, Yuehua; Zha, Yunfeng; Zhu, Xiaojuan; Ji, Lei

    2015-07-01

    Norovirus (NoV) infection is the most common cause of nonbacterial acute gastroenteritis, which affects both adults and children. However, the molecular epidemiology of NoV in adults with acute gastroenteritis in China has not been investigated extensively. In this study, we investigated the occurrence of NoV infections and analyzed the genetic diversity of NoV in adults with acute gastroenteritis in Huzhou, China. A total of 796 fecal samples were collected from outpatients (≥16 years of age) between March 2013 and February 2014. Real-time RT-PCR was performed to detect NoV genogroups I (GI) and II (GII). For genotyping, the capsid and RNA-dependent RNA polymerase (RdRp) genes were partially amplified and sequenced for phylogenetic analysis. NoVs were detected in 26.51% (211/796) of the specimens, with GII being predominant, representing 96.20% of the NoV infections. At least nine genotypes were identified among GI and GII specimens, including GI.P2/GI.2, GI.P3/GI.3, GI.P4/GI.4, GII.Pe/GII.4 Sydney_2012, GII.P12/GII.3, GII.P7/GII.6, GII.P16/GII.13, GII.Pe, and GII.Pg (RdRp only). This is the first report of a GII.P16/GII.13 recombinant virus in adults in China. GII.Pe/GII.4 Sydney_2012 was the most prevalent genotype and the only GII.4 variant identified during the study period. Our findings suggested that NoV was a common causative agent of acute gastroenteritis in adults in Huzhou, China. During the study period, the NoVs circulating in adults in Huzhou were predominantly GII.4 Sydney_2012 variants and GII NoV recombinants.

  11. Acute and Chronic Effects of Dietary Lactose in Adult Rats Are not Explained by Residual Intestinal Lactase Activity.

    PubMed

    van de Heijning, Bert J M; Kegler, Diane; Schipper, Lidewij; Voogd, Eline; Oosting, Annemarie; van der Beek, Eline M

    2015-07-08

    Neonatal rats have a high intestinal lactase activity, which declines around weaning. Yet, the effects of lactose-containing products are often studied in adult animals. This report is on the residual, post-weaning lactase activity and on the short- and long-term effects of lactose exposure in adult rats. Acutely, the postprandial plasma response to increasing doses of lactose was studied, and chronically, the effects of a 30% lactose diet fed from postnatal (PN) Day 15 onwards were evaluated. Intestinal lactase activity, as assessed both in vivo and in vitro, was compared between both test methods and diet groups (lactose vs. control). A 50%-75% decreased digestive capability towards lactose was observed from weaning into adulthood. Instillation of lactose in adult rats showed disproportionally low increases in plasma glucose levels and did not elicit an insulin response. However, gavages comprising maltodextrin gave rise to significant plasma glucose and insulin responses, indicative of a bias of the adult GI tract to digest glucose polymers. Despite the residual intestinal lactase activity shown, a 30% lactose diet was poorly digested by adult rats: the lactose diet rendered the animals less heavy and virtually devoid of body fat, whereas their cecum tripled in size, suggesting an increased bacterial fermentation. The observed acute and chronic effects of lactose exposure in adult rats cannot be explained by the residual intestinal lactase activity assessed.

  12. The impact of recurrent acute chest syndrome on the lung function of young adults with sickle cell disease.

    PubMed

    Knight-Madden, Jennifer M; Forrester, Terrence S; Lewis, Norma A; Greenough, Anne

    2010-12-01

    The aim of this study was to assess the impact of recurrent acute chest syndrome (ACS) episodes on the lung function of young adults with sickle cell disease (SCD). Our prospective study included 80 SCD adults [26 with recurrent acute chest syndrome (ACS)] and 80 ethnically matched controls aged between 18 and 28 years. Lung function (spirometry and lung volumes) was measured and the results were expressed as the percentage predicted for height. Bronchial hyperresponsiveness (BHR) was assessed by the response to either a bronchodilator or an exercise challenge. The adults with recurrent ACS (two or more ACS episodes) had lower median forced vital capacity (74 vs. 83%, p = 0.03), forced expiratory volume in 1 s (79 vs. 90%, p < 0.03), and total lung capacity (69 vs. 81%, p = 0.04) than SCD adults who had one or no ACS episodes. The greater the number of ACS episodes, the greater the reduction in lung function (p = 0.001). The adults with SCD had lower median forced vital capacity (81 vs. 106%), forced expiratory volume in 1 s (85 vs. 107%), and total lung capacity (80 vs. 87%) than the controls (p < 0.001). Similar numbers in each group had BHR (p = 0.2). The prevalence of restrictive ventilatory defect in the patients with SCD was almost double that of the controls (p = 0.004). Young adults with SCD have worse lung function than ethnically matched controls, particularly if they have suffered recurrent ACS episodes.

  13. Acute and Chronic Effects of Dietary Lactose in Adult Rats Are not Explained by Residual Intestinal Lactase Activity

    PubMed Central

    van de Heijning, Bert J. M.; Kegler, Diane; Schipper, Lidewij; Voogd, Eline; Oosting, Annemarie; van der Beek, Eline M.

    2015-01-01

    Neonatal rats have a high intestinal lactase activity, which declines around weaning. Yet, the effects of lactose-containing products are often studied in adult animals. This report is on the residual, post-weaning lactase activity and on the short- and long-term effects of lactose exposure in adult rats. Acutely, the postprandial plasma response to increasing doses of lactose was studied, and chronically, the effects of a 30% lactose diet fed from postnatal (PN) Day 15 onwards were evaluated. Intestinal lactase activity, as assessed both in vivo and in vitro, was compared between both test methods and diet groups (lactose vs. control). A 50%–75% decreased digestive capability towards lactose was observed from weaning into adulthood. Instillation of lactose in adult rats showed disproportionally low increases in plasma glucose levels and did not elicit an insulin response. However, gavages comprising maltodextrin gave rise to significant plasma glucose and insulin responses, indicative of a bias of the adult GI tract to digest glucose polymers. Despite the residual intestinal lactase activity shown, a 30% lactose diet was poorly digested by adult rats: the lactose diet rendered the animals less heavy and virtually devoid of body fat, whereas their cecum tripled in size, suggesting an increased bacterial fermentation. The observed acute and chronic effects of lactose exposure in adult rats cannot be explained by the residual intestinal lactase activity assessed. PMID:26184291

  14. Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-09-09

    Adult Acute Lymphoblastic Leukemia in Remission; Adult B Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1; Adult L1 Acute Lymphoblastic Leukemia; Adult L2 Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  15. Gene networks and toxicity pathways induced by acute cadmium exposure in adult largemouth bass (Micropterus salmoides).

    PubMed

    Mehinto, Alvine C; Prucha, Melinda S; Colli-Dula, Reyna C; Kroll, Kevin J; Lavelle, Candice M; Barber, David S; Vulpe, Christopher D; Denslow, Nancy D

    2014-07-01

    Cadmium is a heavy metal that can accumulate to toxic levels in the environment leading to detrimental effects in animals and humans including kidney, liver and lung injuries. Using a transcriptomics approach, genes and cellular pathways affected by a low dose of cadmium were investigated. Adult largemouth bass were intraperitoneally injected with 20μg/kg of cadmium chloride (mean exposure level - 2.6μg of cadmium per fish) and microarray analyses were conducted in the liver and testis 48h after injection. Transcriptomic profiles identified in response to cadmium exposure were tissue-specific with the most differential expression changes found in the liver tissues, which also contained much higher levels of cadmium than the testis. Acute exposure to a low dose of cadmium induced oxidative stress response and oxidative damage pathways in the liver. The mRNA levels of antioxidants such as catalase increased and numerous transcripts related to DNA damage and DNA repair were significantly altered. Hepatic mRNA levels of metallothionein, a molecular marker of metal exposure, did not increase significantly after 48h exposure. Carbohydrate metabolic pathways were also disrupted with hepatic transcripts such as UDP-glucose, pyrophosphorylase 2, and sorbitol dehydrogenase highly induced. Both tissues exhibited a disruption of steroid signaling pathways. In the testis, estrogen receptor beta and transcripts linked to cholesterol metabolism were suppressed. On the contrary, genes involved in cholesterol metabolism were highly increased in the liver including genes encoding for the rate limiting steroidogenic acute regulatory protein and the catalytic enzyme 7-dehydrocholesterol reductase. Integration of the transcriptomic data using functional enrichment analyses revealed a number of enriched gene networks associated with previously reported adverse outcomes of cadmium exposure such as liver toxicity and impaired reproduction. PMID:24794047

  16. Gene networks and toxicity pathways induced by acute cadmium exposure in adult largemouth bass (Micropterus salmoides).

    PubMed

    Mehinto, Alvine C; Prucha, Melinda S; Colli-Dula, Reyna C; Kroll, Kevin J; Lavelle, Candice M; Barber, David S; Vulpe, Christopher D; Denslow, Nancy D

    2014-07-01

    Cadmium is a heavy metal that can accumulate to toxic levels in the environment leading to detrimental effects in animals and humans including kidney, liver and lung injuries. Using a transcriptomics approach, genes and cellular pathways affected by a low dose of cadmium were investigated. Adult largemouth bass were intraperitoneally injected with 20μg/kg of cadmium chloride (mean exposure level - 2.6μg of cadmium per fish) and microarray analyses were conducted in the liver and testis 48h after injection. Transcriptomic profiles identified in response to cadmium exposure were tissue-specific with the most differential expression changes found in the liver tissues, which also contained much higher levels of cadmium than the testis. Acute exposure to a low dose of cadmium induced oxidative stress response and oxidative damage pathways in the liver. The mRNA levels of antioxidants such as catalase increased and numerous transcripts related to DNA damage and DNA repair were significantly altered. Hepatic mRNA levels of metallothionein, a molecular marker of metal exposure, did not increase significantly after 48h exposure. Carbohydrate metabolic pathways were also disrupted with hepatic transcripts such as UDP-glucose, pyrophosphorylase 2, and sorbitol dehydrogenase highly induced. Both tissues exhibited a disruption of steroid signaling pathways. In the testis, estrogen receptor beta and transcripts linked to cholesterol metabolism were suppressed. On the contrary, genes involved in cholesterol metabolism were highly increased in the liver including genes encoding for the rate limiting steroidogenic acute regulatory protein and the catalytic enzyme 7-dehydrocholesterol reductase. Integration of the transcriptomic data using functional enrichment analyses revealed a number of enriched gene networks associated with previously reported adverse outcomes of cadmium exposure such as liver toxicity and impaired reproduction.

  17. Acute coronary syndrome in young adults from a Malaysian tertiary care centre

    PubMed Central

    Hoo, Fan Kee; Foo, Yoke Loong; Lim, Sazlyna Mohd Sazlly; Ching, Siew Mooi; Boo, Yang Liang

    2016-01-01

    Background and Objective: Acute coronary syndrome (ACS) is one of the leading cause of morbidity and mortality worldwide. It is relatively uncommon in young adults as compared to the older population. Our objective was to assess the prevalence, demographic distribution, and risk factors for acute coronary syndrome (ACS) in patients less than 45 years of age admitted to a Malaysian tertiary care centre. Methods: This is a cross-sectional, retrospective, and single centre study with random sampling of the patients admitted for ACS to hospital from January 2005 to December 2013. Data were collected and analyzed. Patients less than 45 years of age were compared with patients more than 45 years of age. Result: A total of 628 patients were included in the study and with the prevalence of young ACS was 6.1% and mean age of 39±6 years. All the young ACS patients were diagnosed with unstable angina and non-ST elevation myocardial infarction (NSTEMI). Tobacco smoking and family history of coronary artery disease (CAD) were more frequent in young ACS. 59.5% of the young ACS patients were smokers, while 37.8% and 51.4% of them were found to suffer from diabetes mellitus and hypertension respectively. Tobacco smoking, diabetes mellitus, and hypertension had shown significant association with the onset of young ACS (p ≤ 0.05). Conclusion: Three leading risk factors (tobacco smoking, diabetes mellitus, and hypertension) had been shown to be significantly associated with the onset of young ACS. Thus, it is important to identify this cohort and implement aggressive measures in tackling the risk factors in order to prevent or halt the development of coronary artery disease.

  18. Acute and chronic caffeine administration increases physical activity in sedentary adults.

    PubMed

    Schrader, Patrick; Panek, Leah M; Temple, Jennifer L

    2013-06-01

    Caffeine is a commonly used stimulant thought to have ergogenic properties. Most studies on the ergogenic effects of caffeine have been conducted in athletes. The purpose of this study was to test the hypothesis that caffeine reduces ratings of perceived exertion and increases liking of physical activity in sedentary adults. Participants completed treadmill walking at 60% to 70% of their maximal heart rate at baseline and for 6 subsequent visits, during which half of the participants were given caffeine (3 mg/kg) and half given placebo in a sports drink vehicle. To investigate the potential synergistic effects of acute and chronic caffeine on self-determined exercise duration, participants were rerandomized to either the same or different condition for the last visit, creating 4 chronic/acute treatment groups (placebo/placebo, placebo/caffeine, caffeine/placebo, caffeine/caffeine). Participants rated how much they liked the activity and perceived exertion at each visit. There was a main effect of time on liking of physical activity, with liking increasing over time and an interaction of sex and caffeine treatment on liking, with liking of activity increasing in female participants treated with caffeine, but not with placebo. There was no effect of caffeine on ratings of perceived exertion. Individuals who received caffeine on the final test day exercised for significantly longer than those who received placebo. These data suggest that repeated exposure to physical activity significantly increases liking of exercise and reduces ratings of perceived exertion and that caffeine does little to further modify these effects.

  19. Acute coronary syndrome in young adults from a Malaysian tertiary care centre

    PubMed Central

    Hoo, Fan Kee; Foo, Yoke Loong; Lim, Sazlyna Mohd Sazlly; Ching, Siew Mooi; Boo, Yang Liang

    2016-01-01

    Background and Objective: Acute coronary syndrome (ACS) is one of the leading cause of morbidity and mortality worldwide. It is relatively uncommon in young adults as compared to the older population. Our objective was to assess the prevalence, demographic distribution, and risk factors for acute coronary syndrome (ACS) in patients less than 45 years of age admitted to a Malaysian tertiary care centre. Methods: This is a cross-sectional, retrospective, and single centre study with random sampling of the patients admitted for ACS to hospital from January 2005 to December 2013. Data were collected and analyzed. Patients less than 45 years of age were compared with patients more than 45 years of age. Result: A total of 628 patients were included in the study and with the prevalence of young ACS was 6.1% and mean age of 39±6 years. All the young ACS patients were diagnosed with unstable angina and non-ST elevation myocardial infarction (NSTEMI). Tobacco smoking and family history of coronary artery disease (CAD) were more frequent in young ACS. 59.5% of the young ACS patients were smokers, while 37.8% and 51.4% of them were found to suffer from diabetes mellitus and hypertension respectively. Tobacco smoking, diabetes mellitus, and hypertension had shown significant association with the onset of young ACS (p ≤ 0.05). Conclusion: Three leading risk factors (tobacco smoking, diabetes mellitus, and hypertension) had been shown to be significantly associated with the onset of young ACS. Thus, it is important to identify this cohort and implement aggressive measures in tackling the risk factors in order to prevent or halt the development of coronary artery disease. PMID:27648025

  20. Thoracic Society of Australia and New Zealand oxygen guidelines for acute oxygen use in adults: 'Swimming between the flags'.

    PubMed

    Beasley, Richard; Chien, Jimmy; Douglas, James; Eastlake, Leonie; Farah, Claude; King, Gregory; Moore, Rosemary; Pilcher, Janine; Richards, Michael; Smith, Sheree; Walters, Haydn

    2015-11-01

    The purpose of the Thoracic Society of Australia and New Zealand guidelines is to provide simple, practical evidence-based recommendations for the acute use of oxygen in adults in clinical practice. The intended users are all health professionals responsible for the administration and/or monitoring of oxygen therapy in the management of acute medical patients in the community and hospital settings (excluding perioperative and intensive care patients), those responsible for the training of such health professionals, and both public and private health care organizations that deliver oxygen therapy.

  1. Mechanism for the acute effects of organophosphate pesticides on the adult 5-HT system

    PubMed Central

    Judge, Sarah J.; Savy, Claire Y.; Campbell, Matthew; Dodds, Rebecca; Gomes, Larissa Kruger; Laws, Grace; Watson, Anna; Blain, Peter G.; Morris, Christopher M.; Gartside, Sarah E.

    2016-01-01

    The neurotransmitter serotonin (5-HT) is involved in mood disorder aetiology and it has been reported that (organophosphate) OP exposure affects 5-HT turnover. The aim of this study was to elucidate the mechanism underlying OP effects on the adult 5-HT system. First, acute in vivo administration of the OP diazinon (0, 1.3, 13 or 39 mg/kg i.p.) to male Hooded Lister rats inhibited the activity of the cholinergic enzyme acetylcholinesterase in blood and in the hippocampus, dorsal raphe nucleus (DRN), striatum and prefrontal cortex. Diazinon-induced cholinesterase inhibition was greatest in the DRN, the brain's major source of 5-HT neurones. Second, acute in vivo diazinon exposure (0 or 39 mg/kg i.p.) increased the basal firing rate of DRN neurones measured ex vivo in brain slices. The excitatory responses of DRN neurones to α1-adrenoceptor or AMPA/kainate receptor activation were not affected by in vivo diazinon exposure but the inhibitory response to 5-HT was attenuated, indicating 5-HT1A autoreceptor down-regulation. Finally, direct application of the diazinon metabolite diazinon oxon to naive rat brain slices increased the firing rate of DRN 5-HT neurones, as did chlorpyrifos-oxon, indicating the effect was not unique to diazinon. The oxon-induced augmentation of firing was blocked by the nicotinic acetylcholine receptor antagonist mecamylamine and the AMPA/kainate glutamate receptor antagonist DNQX. Together these data indicate that 1) acute OP exposure inhibits DRN cholinesterase, leading to acetylcholine accumulation, 2) the acetylcholine activates nicotinic receptors on 5-HT neurones and also on glutamatergic neurones, thus releasing glutamate and activating 5-HT neuronal AMPA/kainate receptors 3) the increase in 5-HT neuronal activity, and resulting 5-HT release, may lead to 5-HT1A autoreceptor down-regulation. This mechanism may be involved in the reported increase in risk of developing anxiety and depression following occupational OP exposure. PMID

  2. Induction of promyelocytic leukemia (PML) oncogenic domains (PODs) by papillomavirus

    SciTech Connect

    Nakahara, Tomomi; Lambert, Paul F.

    2007-09-30

    Promyelocytic leukemia oncogenic domains (PODs), also called nuclear domain 10 (ND10), are subnuclear structures that have been implicated in a variety of cellular processes as well as the life cycle of DNA viruses including papillomaviruses. In order to investigate the interplay between papillomaviruses and PODs, we analyzed the status of PODs in organotypic raft cultures of human keratinocytes harboring HPV genome that support the differentiation-dependent HPV life cycle. The number of PODs per nucleus was increased in the presence of HPV genomes selectively within the poorly differentiated layers but was absent in the terminally differentiated layers of the stratified epithelium. This increase in PODs was correlated with an increase in abundance of post-translationally modified PML protein. Neither the E2-dependent transcription nor viral DNA replication was reliant upon the presence of PML. Implications of these findings in terms of HPV's interaction with its host are discussed.

  3. Clinical Profiles and Short-Term Outcomes of Acute Disseminated Encephalomyelitis in Adult Chinese Patients

    PubMed Central

    Yang, Hong-Qi; Zhao, Wen-Cong; Yang, Wei-Min; Li, Yong-Li; Sun, Zhi-Kun; Chen, Shuai

    2016-01-01

    Background and Purpose Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder that predominantly affects children. Previous studies have mostly involved children in Western developed countries. Methods This study retrospectively reviewed the clinical profiles of ADEM in adult Chinese patients. Results ADEM occurred during summer and autumn in about two-thirds of the 42 included patients. Prior infection was found in five patients and no preimmunization was recorded. The most frequent clinical presentations were alterations in consciousness (79%) and behavior changes (69%), followed by motor deficits (64%) and fever (50%). About one-quarter (26%) of the patients showed positive results for oligoclonal bands, and about half of them exhibited increases in the IgG index and 24-hour IgG synthesis rate. Magnetic resonance imaging showed white- and gray-matter lesions in 83% and 23% of the patients, respectively. Steroids were the main treatment, and full recovery occurred in 62% of the patients, with residual focal neurological deficits recorded in a few patients. After a mean follow-up period of 3.4 years, two patients exhibited recurrence and one patient exhibited a multiphasic course. One patient was diagnosed with multiple sclerosis (MS). Conclusions With the exception of the seasonal distribution pattern and prior vaccine rate, the clinical profiles of ADEM in adult Chinese patients are similar to those in pediatric populations. No specific markers are available for distinguishing ADEM from MS at the initial presentation. Careful clinical evaluations, cerebrospinal fluid measurements, and neuroradiological examinations with long-term follow-up will aid the correct diagnosis of ADEM. PMID:27449911

  4. Impaired cardiovascular structure and function in adult survivors of severe acute malnutrition.

    PubMed

    Tennant, Ingrid A; Barnett, Alan T; Thompson, Debbie S; Kips, Jan; Boyne, Michael S; Chung, Edward E; Chung, Andrene P; Osmond, Clive; Hanson, Mark A; Gluckman, Peter D; Segers, Patrick; Cruickshank, J Kennedy; Forrester, Terrence E

    2014-09-01

    Malnutrition below 5 years remains a global health issue. Severe acute malnutrition (SAM) presents in childhood as oedematous (kwashiorkor) or nonoedematous (marasmic) forms, with unknown long-term cardiovascular consequences. We hypothesized that cardiovascular structure and function would be poorer in SAM survivors than unexposed controls. We studied 116 adult SAM survivors, 54 after marasmus, 62 kwashiorkor, and 45 age/sex/body mass index-matched community controls who had standardized anthropometry, blood pressure, echocardiography, and arterial tonometry performed. Left ventricular indices and outflow tract diameter, carotid parameters, and pulse wave velocity were measured, with systemic vascular resistance calculated. All were expressed as SD scores. Mean (SD) age was 28.8±7.8 years (55% men). Adjusting for age, sex, height, and weight, SAM survivors had mean (SE) reductions for left ventricular outflow tract diameter of 0.67 (0.16; P<0.001), stroke volume 0.44 (0.17; P=0.009), cardiac output 0.5 (0.16; P=0.001), and pulse wave velocity 0.32 (0.15; P=0.03) compared with controls but higher diastolic blood pressures (by 4.3; 1.2-7.3 mm Hg; P=0.007). Systemic vascular resistance was higher in marasmus and kwashiorkor survivors (30.2 [1.2] and 30.8 [1.1], respectively) than controls 25.3 (0.8), overall difference 5.5 (95% confidence interval, 2.8-8.4 mm Hg min/L; P<0.0001). No evidence of large vessel or cardiac remodeling was found, except closer relationships between these indices in former marasmic survivors. Other parameters did not differ between SAM survivor groups. We conclude that adult SAM survivors had smaller outflow tracts and cardiac output when compared with controls, yet markedly elevated peripheral resistance. Malnutrition survivors are thus likely to develop excess hypertension in later life, especially when exposed to obesity.

  5. Genetically Modified T-cell Immunotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-08-10

    Adult Acute Myeloid Leukemia in Remission; Donor; Early Relapse of Acute Myeloid Leukemia; Late Relapse of Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

  6. Tipifarnib in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia

    ClinicalTrials.gov

    2013-03-22

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Erythroid Leukemia (M6); Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monoblastic Leukemia and Acute Monocytic Leukemia (M5); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); 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(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Cellular Diagnosis, Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  7. Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia

    PubMed Central

    Gökbuget, N; Kelsh, M; Chia, V; Advani, A; Bassan, R; Dombret, H; Doubek, M; Fielding, A K; Giebel, S; Haddad, V; Hoelzer, D; Holland, C; Ifrah, N; Katz, A; Maniar, T; Martinelli, G; Morgades, M; O'Brien, S; Ribera, J-M; Rowe, J M; Stein, A; Topp, M; Wadleigh, M; Kantarjian, H

    2016-01-01

    We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data. PMID:27662202

  8. Retroviral induction of acute lymphoproliferative disease and profound immunosuppression in adult C57BL/6 mice

    PubMed Central

    1985-01-01

    We have shown that a mixture of murine leukemia viruses (MuLV) causes the acute onset of lymphoproliferation and immunosuppression when injected into adult C57BL/6 mice. The ecotropic/MCF (mink cell focus- inducing) mixture of MuLV stimulates polyclonal B lymphocyte proliferation and differentiation to antibody-secreting cells. Serum Ig levels are elevated for all isotypes except IgA. The viral infection leads to a rapid decline in T lymphocyte responses to mitogens and alloantigens, as well as a decrease in helper cell activity. Specific antibody responses to both T-dependent and T-independent antigens are impaired, and the response of B lymphocytes to mitogens is abolished. The profound immunosuppression seems to be due to the MuLV-induced polyclonal activation of lymphocytes. No active suppression of normal lymphocyte responses by cells from virus-infected mice was observed. The disease induced by the LP-BM5 MuLV isolate thus seems a promising model for the study of lymphocyte activation and the mechanisms of retrovirus-induced immunosuppression. PMID:2984305

  9. Mitoxantrone and cytosine arabinoside in previously untreated adult patients with acute non-lymphocytic leukemia.

    PubMed

    Osman, I; Akin, U; Ismet, A; Meral, B; Hamdi, A; Haluk, K

    1996-01-01

    Twenty-five adult patients with previously untreated acute non-lymphocytic leukemia (ANLL) were treated with mitoxantrone (Mto) 12 mg/m2 daily by 30 minutes intravenous (IV) infusion for 3 days and cytosine arabinoside (Ara-C) 200 mg/m2 daily by continuous infusion for 7 days, as an induction therapy. After complete remission (CR) was observed, they were given two more courses of consolidation therapy which was as Mto 12 mg/m2 daily by 30 minutes IV infusion for one day, and Ara-C 200 mg/m2 daily by 30 minutes IV infusion for 5 days. CR was obtained in 18 of 25 patients (72%). Median remission duration was 294 days and length of survival was 366 days. 11 patients (44%) are still in remission. Myelosupression developed in all patients following induction therapy, but it was not observed after consolidation therapies. Non-hematological side-effects consisted of nausea, vomiting, alopecia, stomatitis, and transient elevation in liver enzymes. Our therapeutic responses are similar to those obtained by others. PMID:14651226

  10. The Effects of Acute Physical Exercise on Memory, Peripheral BDNF, and Cortisol in Young Adults

    PubMed Central

    Röder, Brigitte; Schmidt-Kassow, Maren

    2016-01-01

    In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans. PMID:27437149

  11. [Access to medicines prescribed for acute health conditions in adults in South and Northeast Brazil].

    PubMed

    Paniz, Vera Maria Vieira; Cechin, Isabel Carolina Coelho Flores; Fassa, Anaclaudia Gastal; Piccini, Roberto Xavier; Tomasi, Elaine; Thumé, Elaine; Silveira, Denise Silva da; Facchini, Luiz Augusto

    2016-01-01

    This was a cross-sectional study within Brazil's Project for the Expansion and Consolidation of Family Health, 2005, with the objective of universal and free access to the medication prescribed in the last medical appointment for acute health problems and to estimate the degree to which access may have improved with inclusion of the medicines in prevailing policies and programs. The sample included 4,060 adults living in the area of primary health care units in 41 municipalities in South and Northeast Brazil. Access was greater in the South (83.2%) than in the Northeast (71%), and free access was similar (37%), with a greater share by the Family Health Program (FHP) when compared to the traditional model, especially in the Northeast. Some 60% of prescribed medicines and 50% of those on the National List of Essential Medicines (RENAME) were paid for. No variation was observed in the proportion of medicines present on the prevailing RENAME list and access. However, 40% of the medicines that were paid for can currently be obtained through the Popular Pharmacy Program. The latter program appears to emerge as a new way to guarantee access to medicines prescribed in the health system.

  12. The Effects of Acute Physical Exercise on Memory, Peripheral BDNF, and Cortisol in Young Adults.

    PubMed

    Hötting, Kirsten; Schickert, Nadine; Kaiser, Jochen; Röder, Brigitte; Schmidt-Kassow, Maren

    2016-01-01

    In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans. PMID:27437149

  13. Acute Liver Failure in Adults: An Evidence-Based Management Protocol for Clinicians

    PubMed Central

    Misel, Michael; Gish, Robert G.

    2012-01-01

    With the goal of providing guidance on the provision of optimal intensive care to adult patients with acute liver failure (ALF), this paper defines ALF and describes a protocol for appropriately diagnosing this relatively rare clinical entity and ascertaining its etiology, where possible. This paper also identifies the few known therapies that may be effective for specific causes of ALF and provides a comprehensive approach for anticipating, identifying, and managing complications. Finally, one of the more important aspects of care for patients with ALF is the determination of prognosis and, specifically, the need for liver transplantation. Prognostic tools are provided to help guide the clinician in this critical decision process. Management of patients with ALF is complex and challenging, even in centers where staff members have high levels of expertise and substantial experience. This evidence-based protocol may, therefore, assist in the delivery of optimal care to this critically ill patient population and may substantially increase the likelihood of positive outcomes. PMID:22675278

  14. Role of Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Acute Lymphoblastic Leukemia

    PubMed Central

    Lussana, Federico; Rambaldi, Alessandro

    2014-01-01

    Adult acute lymphoblastic leukemia (ALL) is a heterogeneous disease, due to the expression of different biological and clinical risk factors, for which allogeneic stem cell transplantation (alloHSCT) is an effective consolidation therapy. The non-relapse mortality of alloHSCT remains significantly higher compared with that of conventional chemotherapy. Therefore, one of the main challenges in the care of ALL is to establish a more precise prognostic definition to select patients who could take advantage from an alloHSCT. Currently, the use of minimal residual disease following induction and early consolidation therapy has improved the prognostic accuracy in defining ALL risk class. In Philadelphia-positive ALL, the introduction of tyrosine kinase inhibitors pre and post alloHSCT appears to improve outcomes significantly and, in the absence of specially designed clinical trials, alloHSCT remains the most effective post-remission therapy. Nowadays, alloHSCT can be performed according to various modalities encompassing the use of different conditioning regimens, as well as distinct donors and stem cell source, with a significant accessibility to transplant. PMID:25408851

  15. The Effects of Acute Physical Exercise on Memory, Peripheral BDNF, and Cortisol in Young Adults.

    PubMed

    Hötting, Kirsten; Schickert, Nadine; Kaiser, Jochen; Röder, Brigitte; Schmidt-Kassow, Maren

    2016-01-01

    In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans.

  16. Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults.

    PubMed

    Yasuda, Takahiko; Tsuzuki, Shinobu; Kawazu, Masahito; Hayakawa, Fumihiko; Kojima, Shinya; Ueno, Toshihide; Imoto, Naoto; Kohsaka, Shinji; Kunita, Akiko; Doi, Koichiro; Sakura, Toru; Yujiri, Toshiaki; Kondo, Eisei; Fujimaki, Katsumichi; Ueda, Yasunori; Aoyama, Yasutaka; Ohtake, Shigeki; Takita, Junko; Sai, Eirin; Taniwaki, Masafumi; Kurokawa, Mineo; Morishita, Shinichi; Fukayama, Masashi; Kiyoi, Hitoshi; Miyazaki, Yasushi; Naoe, Tomoki; Mano, Hiroyuki

    2016-05-01

    The oncogenic mechanisms underlying acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA; 15-39 years old) remain largely elusive. Here we have searched for new oncogenes in AYA-ALL by performing RNA-seq analysis of Philadelphia chromosome (Ph)-negative AYA-ALL specimens (n = 73) with the use of a next-generation sequencer. Interestingly, insertion of D4Z4 repeats containing the DUX4 gene into the IGH locus was frequently identified in B cell AYA-ALL, leading to a high level of expression of DUX4 protein with an aberrant C terminus. A transplantation assay in mice demonstrated that expression of DUX4-IGH in pro-B cells was capable of generating B cell leukemia in vivo. DUX4 fusions were preferentially detected in the AYA generation. Our data thus show that DUX4 can become an oncogenic driver as a result of somatic chromosomal rearrangements and that AYA-ALL may be a clinical entity distinct from ALL at other ages. PMID:27019113

  17. Capacity of a natural strain of woodchuck hepatitis virus, WHVNY, to induce acute infection in naive adult woodchucks.

    PubMed

    Freitas, Natalia; Lukash, Tetyana; Dudek, Megan; Litwin, Sam; Menne, Stephan; Gudima, Severin O

    2015-07-01

    Woodchuck hepatitis virus (WHV) is often used as surrogate to study mechanism of HBV infection. Currently, most infections are conducted using strains WHV7 or WHV8 that have very high sequence identity. This study focused on natural strain WHVNY that is more genetically distant from WHV7. Three naive adult woodchucks inoculated with WHVNY developed productive acute infection with long lasting viremia. However, only one of two woodchucks infected with WHV7 at the same multiplicity demonstrated productive liver infection. Quantification of intracellular WHV RNA and DNA replication intermediates; percentages of core antigen-positive hepatocytes; and serum relaxed circular DNA showed that strains WHVNY and WHV7 displayed comparable replication levels and capacities to induce acute infection in naive adult woodchucks. Strain WHVNY was therefore validated as valuable reagent to analyze the mechanism of hepadnavirus infection, especially in co- and super-infection settings, which required discrimination between two related virus genomes replicating in the same liver. PMID:25979221

  18. Acute rhinosinusitis (ARS). Diagnosis and treatment of adults in general practice.

    PubMed

    Hansen, Jens Georg

    2014-02-01

    The idea behind this thesis is to present how ARS and especially acute maxillary sinusitis in adults is diagnosed and treated in general practice. The study extends over many years, beginning with the first survey in 1991. Based on doctors' answers, we then investigated the diagnostic values ​​of the symptoms, signs and examinations which the doctors reported using. All patients over 18 years suspected of acute maxillary sinusitis were included consecutively and only once and, after a clinical examination with the GP, they were offered the opportunity to enter into the prospective study referred to acute CT scan and by changes in the CT, immediately referred to sinus puncture. Both examinations were conducted at Aalborg Hospital. The disease was found most frequently in younger and 2/3 were women. The reason for this gender difference is unknown. We have assessed the diagnostic values of the symptoms, objective findings and investigations ​​using 3 different reference standards: sinus puncture, microbiological diagnosis and CT scan described in three articles. In all examinations, it appeared that the usual signs and symptoms of acute maxillary sinusitis occur almost equally often and with a few exceptions in patients, with and without pus in the sinus cavities. Pain in the sinus cavities occurring in 95% of patients, and only elevated levels of CRP and ESR are significantly and independently associated with pus in the sinus cavities. This finding is surprising, because they are two nonspecific markers. CRP tested by near-patient testing has, within the investigations period, been introduced in general practice, and from 1999 the doctors also get reimbursed for performing the test. We have on this background originally defined a clinical criterion with pain over the sinuses accompanied by elevated values ​​of CRP and/or ESR giving a sensitivity of 0.82, specificity 0.57, ppv 0.68 and npv 0.74. But looking at the ROC curve we suggest that a more clinical

  19. Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2.

    PubMed

    Kirby, Elizabeth D; Muroy, Sandra E; Sun, Wayne G; Covarrubias, David; Leong, Megan J; Barchas, Laurel A; Kaufer, Daniela

    2013-04-16

    Stress is a potent modulator of the mammalian brain. The highly conserved stress hormone response influences many brain regions, particularly the hippocampus, a region important for memory function. The effect of acute stress on the unique population of adult neural stem/progenitor cells (NPCs) that resides in the adult hippocampus is unclear. We found that acute stress increased hippocampal cell proliferation and astrocytic fibroblast growth factor 2 (FGF2) expression. The effect of acute stress occurred independent of basolateral amygdala neural input and was mimicked by treating isolated NPCs with conditioned media from corticosterone-treated primary astrocytes. Neutralization of FGF2 revealed that astrocyte-secreted FGF2 mediated stress-hormone-induced NPC proliferation. 2 weeks, but not 2 days, after acute stress, rats also showed enhanced fear extinction memory coincident with enhanced activation of newborn neurons. Our findings suggest a beneficial role for brief stress on the hippocampus and improve understanding of the adaptive capacity of the brain. DOI:http://dx.doi.org/10.7554/eLife.00362.001.

  20. Systematic review of randomised controlled trials of over the counter cough medicines for acute cough in adults

    PubMed Central

    Schroeder, Knut; Fahey, Tom

    2002-01-01

    Objectives To determine whether over the counter cough medicines are effective for acute cough in adults. Design Systematic review of randomised controlled trials. Data sources Search of the Cochrane Acute Respiratory Infections Group specialised register, Cochrane Controlled Trials Register, Medline, Embase, and the UK Department of Health National Research Register in all languages. Included studies All randomised controlled trials that compared oral over the counter cough preparations with placebo in adults with acute cough due to upper respiratory tract infection in ambulatory settings and that had cough symptoms as an outcome. Results 15 trials involving 2166 participants met all the inclusion criteria. Antihistamines seemed to be no better than placebo. There was conflicting evidence on the effectiveness of antitussives, expectorants, antihistamine-decongestant combinations, and other drug combinations compared with placebo. Conclusion Over the counter cough medicines for acute cough cannot be recommended because there is no good evidence for their effectiveness. Even when trials had significant results, the effect sizes were small and of doubtful clinical relevance. Because of the small number of trials in each category, the results have to be interpreted cautiously. What is already know on this topicThe NHS encourages self treatment of acute self limiting illnessesOver the counter cough medicines are commonly used as first line treatment for acute coughWhat this study addsThere is little evidence for or against the effectiveness of over the counter cough medicinesAlthough cough medicines are generally well tolerated, they may be an unnecessary expenseRecommendation of over the counter cough medicines to patients is not justified by current evidence PMID:11834560

  1. An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

    PubMed Central

    Bond, Jonathan; Marchand, Tony; Touzart, Aurore; Cieslak, Agata; Trinquand, Amélie; Sutton, Laurent; Radford-Weiss, Isabelle; Lhermitte, Ludovic; Spicuglia, Salvatore; Dombret, Hervé; Macintyre, Elizabeth; Ifrah, Norbert; Hamel, Jean-François; Asnafi, Vahid

    2016-01-01

    Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA. Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently

  2. Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults

    PubMed Central

    Derry, Christopher J; Derry, Sheena; Moore, R Andrew

    2014-01-01

    Background Migraine is a highly disabling condition for the individual and also has wide-reaching implications for society, healthcare services, and the economy. Sumatriptan is an abortive medication for migraine attacks, belonging to the triptan family. Subcutaneous administration may be preferable to oral for individuals experiencing nausea and/or vomiting Objectives To determine the efficacy and tolerability of subcutaneous sumatriptan compared to placebo and other active interventions in the treatment of acute migraine attacks in adults. Search methods We searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, online databases, and reference lists for studies through 13 October 2011. Selection criteria We included randomised, double-blind, placebo- and/or active-controlled studies using subcutaneous sumatriptan to treat a migraine headache episode, with at least 10 participants per treatment arm. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or ‘risk ratio’) and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment. Main results Thirty-five studies (9365 participants) compared subcutaneous sumatriptan with placebo or an active comparator. Most of the data were for the 6 mg dose. Sumatriptan surpassed placebo for all efficacy outcomes. For sumatriptan 6 mg versus placebo the NNTs were 2.9, 2.3, 2.2, and 2.1 for pain-free at one and two hours, and headache relief at one and two hours, respectively, and 6.1 for sustained pain-free at 24 hours. Results for the 4 mg and 8 mg doses were similar to the 6 mg dose, with 6 mg significantly better than 4 mg only for pain-free at one hour, and 8 mg significantly better than 6 mg only for headache relief at one hour. There was no evidence of increased migraine relief if a second dose of sumatriptan 6

  3. [A comparative cytogenetic analysis in large scale between adult and childhood patients with acute lymphoblastic leukemia].

    PubMed

    Liu, Xu-Ping; Zhu, Xiao-Fan; Wang, Jian-Xiang; Mi, Ying-Chang; Zou, Yao; Chen, Yu-Mei; Li, Cheng-Wen; Dai, Yun; Qin, Shuang; Xiao, Ji-Gang; Xu, Fang-Yun; Gong, Jin-Ying; Wang, Si-Ping; Yu, Cheng-Long; Fan, Jing

    2009-12-01

    This study was purposed to comparatively analyze the cytogenetic characteristics between 566 cases of adult acute lymphoblastic leukemia (aALL) and 586 cases of childhood acute lymphoblastic leukemia (cALL). The cytogenetic analysis of all the patients was performed, and the FISH detection for partial patients was carried out. The result showed that the difference of chromosome abnormality between cALL and aALL was statistically significant. The percentage of abnormal karyotypes in aALL was 62.0%, including mainly t(9;22)(q34;q11), hypodiploidy, hyperdiploidy (47 - 50), abn(6q), abn(9p) and -7, most of which conferring an unfavorable prognosis. The percentage of abnormal karyotypes in cALL was 39.2%, composed mainly of high hyperdiploidy, hypodiploidy, TEL/AML1(+), +8, hyperdiploidy (47 - 50) and +21, etc, most of which conferring a favorable prognosis. The incidences of abnormal karyotypes, total hypodiploidy, total hyperdiploidy (47 - 50), t(9;22)(q34;q11), -7, abn(7q), abn(14q32) and +Ph in aALL were significantly higher than those of cALL (p < 0.05), whereas the incidences of normal karyotype (N), high hyperdiploidy, +8, +21*2 and TEL/AML1(+) in cALL were significantly higher than those of aALL (p < 0.05). 20.5% of aALL were Ph+ aALL, with 63.8% of which being with additional abnormalities, composed mainly of +Ph, -7, i (9q+), 9p-, +8, +21, +X, 6q-, abn(14q32) and +14. In contrast, only 4.4% of cALL were Ph+ aALL, with 42.3% of which being with additional abnormalities, including mainly abn(9p), abn(7p), -7, 17p- and +21. It is concluded that almost every chromosome is involved in the numerical and structural abnormalities and complex karyotypes are common. The significant difference of chromosome abnormality exists between aALL and cALL.

  4. Aspirin with or without an antiemetic for acute migraine headaches in adults

    PubMed Central

    Kirthi, Varo; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting commonly associated with migraine headaches. Objectives To determine the efficacy and tolerability of aspirin, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 10 March 2010. Selection criteria We included randomised, double-blind, placebo- or active-controlled studies using aspirin to treat a discrete migraine headache episode, with at least 10 participants per treatment arm. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. Main results Thirteen studies (4222 participants) compared aspirin 900 mg or 1000 mg, alone or in combination with metoclopramide 10 mg, with placebo or other active comparators, mainly sumatriptan 50 mg or 100 mg. For all efficacy outcomes, all active treatments were superior to placebo, with NNTs of 8.1, 4.9 and 6.6 for 2-hour pain-free, 2-hour headache relief, and 24-hour headache relief with aspirin alone versus placebo, and 8.8, 3.3 and 6.2 with aspirin plus metoclopramide versus placebo. Sumatriptan 50 mg did not differ from aspirin alone for 2-hour pain-free and headache relief, while sumatriptan 100 mg was better than the combination of aspirin plus metoclopramide for 2-hour pain-free, but not headache relief; there were no data for 24-hour headache relief. Associated symptoms of nausea, vomiting

  5. Single dose oral mefenamic acid for acute postoperative pain in adults

    PubMed Central

    Moll, Rachel; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID). It is most often used for treating pain of dysmenorrhoea in the short term (seven days or less), as well as mild to moderate pain including headache, dental pain, postoperative and postpartum pain. It is widely available in many countries worldwide. Objectives To assess the efficacy of single dose oral mefenamic acid in acute postoperative pain, and any associated adverse events. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to December 2010. Selection criteria Single oral dose, randomised, double-blind, placebo-controlled trials of mefenamic acid for relief of established moderate to severe postoperative pain in adults. Data collection and analysis Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief (TOTPAR) or pain intensity difference (SPID) over 4 to 6 hours was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 4 to 6 hours. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Four studies with 842 participants met the inclusion criteria; 126 participants were treated with mefenamic acid 500 mg, 67 with mefenamic acid 250 mg, 197 with placebo, and 452 with lignocaine, aspirin, zomepirac or nimesulide. Participants had pain following third molar extraction, episiotomy and orthopaedic surgery. The NNT for at least 50% pain relief over 6 hours with a single dose of mefenamic acid 500 mg compared to placebo was 4.0 (2

  6. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia.

    PubMed

    Wang, Lan; Zhou, Guang-Biao; Liu, Ping; Song, Jun-Hong; Liang, Yang; Yan, Xiao-Jing; Xu, Fang; Wang, Bing-Shun; Mao, Jian-Hua; Shen, Zhi-Xiang; Chen, Sai-Juan; Chen, Zhu

    2008-03-25

    To enhance therapeutic efficacy and reduce adverse effects, practitioners of traditional Chinese medicine (TCM) prescribe a combination of plant species/minerals, called formulae, based on clinical experience. Nearly 100,000 formulae have been recorded, but the working mechanisms of most remain unknown. In trying to address the possible beneficial effects of formulae with current biomedical approaches, we use Realgar-Indigo naturalis formula (RIF), which has been proven to be very effective in treating human acute promyelocytic leukemia (APL) as a model. The main components of RIF are realgar, Indigo naturalis, and Salvia miltiorrhiza, with tetraarsenic tetrasulfide (A), indirubin (I), and tanshinone IIA (T) as major active ingredients, respectively. Here, we report that the ATI combination yields synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro. ATI causes intensified ubiquitination/degradation of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARalpha) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G(1)/G(0) arrest in APL cells through hitting multiple targets compared with the effects of mono- or biagents. Furthermore, ATI intensifies the expression of Aquaglyceroporin 9 and facilitates the transportation of A into APL cells, which in turn enhances A-mediated PML-RARalpha degradation and therapeutic efficacy. Our data also indicate A as the principal component of the formula, whereas T and I serve as adjuvant ingredients. We therefore suggest that dissecting the mode of action of clinically effective formulae at the molecular, cellular, and organism levels may be a good strategy in exploring the value of traditional medicine.

  7. Cancer procoagulant in the human promyelocytic cell line NB4 and its modulation by all-trans-retinoic acid.

    PubMed

    Falanga, A; Consonni, R; Marchetti, M; Mielicki, W P; Rambaldi, A; Lanotte, M; Gordon, S G; Barbui, T

    1994-01-01

    Acute promyelocytic leukemia (APL) cells express different types of procoagulant activity (PCA), including tissue factor (TF), and cancer procoagulant (CP). The aim of this study was to investigate whether the NB4 cell line, the first ever isolated human APL line, with the typical t(15;17) chromosomal balance translocation, possess CP as well as the cells freshly isolated from APL patients. Secondly, since the NB4 line is maturation inducible by all-trans-retinoic acid (ATRA), we wanted to verify whether CP, if present, was affected by ATRA treatment. The NB4 cells were able to shorten the recalcification assay of normal human plasma (total PCA). To distinguish CP in the assay for clotting activity, two criteria were used, the independence from factor VII to trigger blood coagulation and the sensitivity to cysteine proteinase inhibitors. Forty-seven per cent of total PCA of cell extracts was found to be FVII-independent PCA. A similar proportion of FVII-independent activity (42%) was detected in the cell serum-free supernatants. The activity was significantly decreased by cysteine proteinase inhibitors, including HgCl2, lodoacetic acid and Z-Ala-AlaCHN2. Additionally CP was directly identified and quantified by an immunocapture enzyme assay. The mean +/- SD concentration of CP detected by this assay in the NB4 cells, before any treatment, was 1.89 +/- 0.5 microgram/mg protein. Treatment of NB4 cells with 10(-6) M ATRA for 5 days significantly decreased the expression of CP, which became virtually undetectable by the clotting assay, and was 64% less than the untreated control by the immunocapture enzyme assay. This study provides the first evidence that the human promyelocytic cell line NB4 possess CP. The expression of this procoagulant is modulated by ATRA.

  8. Acute high-intensity exercise-induced cognitive enhancement and brain-derived neurotrophic factor in young, healthy adults.

    PubMed

    Hwang, Jungyun; Brothers, R Matthew; Castelli, Darla M; Glowacki, Elizabeth M; Chen, Yen T; Salinas, Mandy M; Kim, Jihoon; Jung, Yeonhak; Calvert, Hannah G

    2016-09-01

    Acute exercise can positively impact cognition. The present study examined the effect of acute high-intensity aerobic exercise on prefrontal-dependent cognitive performance and brain-derived neurotrophic factor (BDNF). Fifty-eight young adults were randomly assigned to one of two experimental groups: (a) an acute bout of high-intensity exercise (n=29) or (b) a non-exercise control (n=29). Participants in the exercise group improved performance on inhibitory control in Stroop interference and on cognitive flexibility in Trail Making Test (TMT) Part-B compared with participants in the control group and increased BDNF immediately after exercise. There was a significant relationship between BDNF and TMT Part-B on the pre-post change following exercise. These findings provide support for the association between improved prefrontal-dependent cognitive performance and increased BDNF in response to acute exercise. We conclude that the changes in BDNF concentration may be partially responsible for prefrontal-dependent cognitive functioning following an acute bout of exercise. PMID:27450438

  9. Acute high-intensity exercise-induced cognitive enhancement and brain-derived neurotrophic factor in young, healthy adults.

    PubMed

    Hwang, Jungyun; Brothers, R Matthew; Castelli, Darla M; Glowacki, Elizabeth M; Chen, Yen T; Salinas, Mandy M; Kim, Jihoon; Jung, Yeonhak; Calvert, Hannah G

    2016-09-01

    Acute exercise can positively impact cognition. The present study examined the effect of acute high-intensity aerobic exercise on prefrontal-dependent cognitive performance and brain-derived neurotrophic factor (BDNF). Fifty-eight young adults were randomly assigned to one of two experimental groups: (a) an acute bout of high-intensity exercise (n=29) or (b) a non-exercise control (n=29). Participants in the exercise group improved performance on inhibitory control in Stroop interference and on cognitive flexibility in Trail Making Test (TMT) Part-B compared with participants in the control group and increased BDNF immediately after exercise. There was a significant relationship between BDNF and TMT Part-B on the pre-post change following exercise. These findings provide support for the association between improved prefrontal-dependent cognitive performance and increased BDNF in response to acute exercise. We conclude that the changes in BDNF concentration may be partially responsible for prefrontal-dependent cognitive functioning following an acute bout of exercise.

  10. Acute effects of physical exercise on prefrontal cortex activity in older adults: a functional near-infrared spectroscopy study.

    PubMed

    Tsujii, Takeo; Komatsu, Kazutoshi; Sakatani, Kaoru

    2013-01-01

    We examined the acute effect of physical exercise on prefrontal cortex activity in older adults using functional near-infrared spectroscopy (NIRS). Fourteen older adults visited our laboratory twice: once for exercise and once for the control condition. On each visit, subjects performed working memory tasks before and after moderate intensity exercise with a cycling ergo-meter. We measured the NIRS response at the prefrontal cortex during the working memory task. We found that physical exercise improved behavioral performance of the working memory task compared with the control condition. Moreover, NIRS analysis showed that physical exercise enhanced the prefrontal cortex activity, especially in the left hemisphere, during the working memory task. These findings suggest that the moderate intensity exercise enhanced the prefrontal cortex activity associated with working memory performance in older adults.

  11. Diclofenac with or without an antiemetic for acute migraine headaches in adults

    PubMed Central

    Derry, Sheena; Rabbie, Roy; Moore, R Andrew

    2014-01-01

    Background Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter (OTC) analgesics. Diclofenac is an established analgesic, and new formulations using the potassium or epolamine salts, which can be dissolved in water, have been developed for rapid absorption, which may be beneficial in acute migraine. Co-therapy with an antiemetic should help to reduce the nausea and vomiting commonly associated with migraine. Objectives To determine the efficacy and tolerability of diclofenac, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, ClinicalTrials.gov, and reference lists for studies through 27 September 2011. Selection criteria We included randomised, double-blind, placebo- and/or active-controlled studies using self administered diclofenac to treat a migraine headache episode, with at least 10 participants per treatment arm. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or ‘risk ratio’) and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment. Main results Five studies (1356 participants) compared oral diclofenac with placebo, and one also compared it with sumatriptan; none combined diclofenac with a self administered antiemetic. Four studies treated attacks with single doses of medication, and two allowed an optional second dose for inadequate response. Only two studies, with three active treatment arms, provided data for pooled analysis of primary outcomes. For single doses of diclofenac

  12. The Relationship Between Risk Factors and Survival in Adult Acute Lymphoblastic Leukemia

    PubMed Central

    Allahyari, Abolghasem; Hashemi, Seyed-Mehdi; Nazemian, Fahimeh; Karimi, Mohammad; Kazemi, Mohammad-Reza; Sadeghi, Masoud

    2016-01-01

    Background Acute lymphoblastic leukemia (ALL) is aggressive cancer, especially in adults as only 20-40% is cured with current treatment regimens. Objectives The aim of this study is to evaluate prognostic factors and their effects on survival in ALL patients in the Northeast of Iran. Methods In a descriptive and retrospective study from 2009 to 2015, 48 ALL patients referred to hematology-oncology clinic. Age, sex, fever, blood group, type of ALL and consumption of amphotericin B, forms of cytogenetic, survival in the patients, WBC, hemoglobin, and platelet were checked in the first referral for every patient. The mean follow-up was 27.3 months in which 28 patients (59.3%) died. overall survival (OS) was plotted by GraphPad Prism 5 and the Log-rank test was used for analysis of survival with risk factors. Results The mean age for all the ALL patients at diagnosis was 32.3 years (range, 15-71 years), and 81.3% were male. Of all patients, 62.5% had fever and 25% consumed amphotericin B. 1-, 2-, 3-, 4-, 5-year OS rates were 62.2%, 52.7%, 40.6%, 39.1%, 22.2%, respectively. 75%, 29.2% and 39.6% of patients had WBC < 20 × 103/μl, Hb < 7 g/dL and platelet < 30 × 103/μL, respectively. There was a significant difference in survival based on age (P = 0.000). Conclusions Based on the results, age > 35 years is the most prognostic factor in ALL patients. Also, patients who received amphotericin B had lower life expectancy because these patients were suffering from fungal infection or due to lack of response to antibacterial drugs, they have been treated with amphotericin B.

  13. Characterization of LEF1 High Expression and Novel Mutations in Adult Acute Lymphoblastic Leukemia

    PubMed Central

    Liu, Juan; Li, Min; Song, Chunhua; Dovat, Sinisa; Li, Jianyong; Ge, Zheng

    2015-01-01

    Aberrant activation of the Wnt pathway plays a pathogenetic role in tumors and has been associated with adverse outcome in acute lymphoblastic leukemia (ALL). Lymphoid enhancer binding factor 1 (LEF1), a key mediator of Wnt signaling, has been linked to leukemic transformation, and LEF1 mutations have been identified in T-ALL. Here we found LEF1 is highly expressed in 25.0% adult ALL patients and LEF1 high expression was associated with high-risk leukemia factors (high WBC, Philadelphia chromosome positive, complex karyotype), shorter event-free survival (EFS), and high relapse rates in patients with B-ALL. LEF1 high expression is also associated with high mutation rate of Notch1 and JAK1 in T-ALL. We identified 2 novel LEF1 mutations (K86E and P106L) in 4 of 131 patients with ALL, and those patients with high-risk ALL (high WBC, complex karyotype). These results suggest a role for LEF1 mutations in leukemogenesis. We further explored the effect of the mutations on cell proliferation and found both mutations significantly promoted the proliferation of ALL cells. We also observed the effect of LEF1 and its mutations on the transcription of its targets, c-MYC and Cyclin D1. We found LEF1 increased the promoter activity of its targets c-MYC and Cyclin D1, and LEF1 K86E and P106L mutants further significantly enhanced this effect. We also observed that the c-MYC and Cyclin D1 mRNA levels were significantly increased in patients with LEF1 high expression compared with those with low expression. Taken together, our findings indicate high LEF1 expression and mutation are associated with high-risk leukemia and our results also revealed that LEF1 high expression and/or gain-of-function mutations are involved in leukemogenesis of ALL. PMID:25942645

  14. Acute Resveratrol Consumption Improves Neurovascular Coupling Capacity in Adults with Type 2 Diabetes Mellitus

    PubMed Central

    Wong, Rachel H.X.; Raederstorff, Daniel; Howe, Peter R.C.

    2016-01-01

    Background: Poor cerebral perfusion may contribute to cognitive impairment in type 2 diabetes mellitus (T2DM). We conducted a randomized controlled trial to test the hypothesis that resveratrol can enhance cerebral vasodilator function and thereby alleviate the cognitive deficits in T2DM. We have already reported that acute resveratrol consumption improved cerebrovascular responsiveness (CVR) to hypercapnia. We now report the effects of resveratrol on neurovascular coupling capacity (CVR to cognitive stimuli), cognitive performance and correlations with plasma resveratrol concentrations. Methods: Thirty-six T2DM adults aged 40–80 years were randomized to consume single doses of resveratrol (0, 75, 150 and 300 mg) at weekly intervals. Transcranial Doppler ultrasound was used to monitor changes in blood flow velocity (BFV) during a cognitive test battery. The battery consisted of dual-tasking (finger tapping with both Trail Making task and Serial Subtraction 3 task) and a computerized multi-tasking test that required attending to four tasks simultaneously. CVR to cognitive tasks was calculated as the per cent increase in BFV from pre-test basal to peak mean blood flow velocity and also as the area under the curve for BFV. Results: Compared to placebo, 75 mg resveratrol significantly improved neurovascular coupling capacity, which correlated with plasma total resveratrol levels. Enhanced performance on the multi-tasking test battery was also evident following 75 mg and 300 mg of resveratrol. Conclusion: a single 75 mg dose of resveratrol was able to improve neurovascular coupling and cognitive performance in T2DM. Evaluation of benefits of chronic resveratrol supplementation is now warranted. PMID:27420093

  15. Acute lethal graft-versus-host disease stimulates cellular proliferation in the adult rat liver.

    PubMed

    Klein, R M; Clancy, J; Stuart, S

    1982-11-01

    The present investigation was designed to analyse the effects of acute lethal graft-versus-host disease (GVHD) in adult (DA x LEW)F1 rats on cellular proliferation within the liver. The influence of the host thymus on GVHD-induced proliferation was also assessed. From 1-28 days after initiation of GVHD [3H]thymidine ([3H]-TdR) was injected i.v. and rats were killed one hour later. Percentage labelled cells (LI) of periportal infiltrating cells (PIC), hepatocytes (H), and sinusoidal lining cells (SC) were counted. Mean values for control rats were 0.3 +/- 0.1% (H), 0.4 +/- 0.1% (SC) and 0.2 +/- 0.1% (PIC). GVHD rats demonstrated a significant increase in LI of PIC (days 1-21), SC (days 2-17) and H (days 2-17). Most labelled cells in PIC were large lymphocytes. Peak LI values were 7.0 +/- 1.0% PIC (day 17), 6.8 +/- 0.9% SC (day 17), and 5.2 +/- 0.9% H (day 7), with all cellular compartments returning to near normal LI values by day 28. Stimulation of cellular proliferation occurred in all three liver cell compartments in neonatally thymectomized (TXM) rats. The intensity of GVHD-induced cell proliferation was significantly decreased at day 7 in all compartments and PIC was dramatically decreased at day 21 in TXM-GVHD rats as compared to non-TXM-GVHD rats. It is hypothesized that the general stimulation of hepatocyte cell proliferation in GVHD is related to the secretion of lymphokines by primarily donor and secondarily host T cells in the periportal infiltrate. PMID:7172201

  16. Oral processing effort, appetite and acute energy intake in lean and obese adults.

    PubMed

    Mattes, Richard D; Considine, Robert V

    2013-08-15

    Chewing reportedly contributes to satiation and satiety signals. Attempts to document and quantify this have led to small and inconsistent effects. The present trial manipulated oral processing effort though required chewing of gums of different hardness and measured appetitive sensations, energy intake, gastric emptying, GI transit time, and concentrations of glucose, insulin, GLP-1, ghrelin and pancreatic polypeptide. Sixty adults classified by sex and BMI (15 each of lean females, obese females, lean males and obese males) were tested in a randomized, controlled, cross-over trial with three arms. They chewed nothing, soft gum or hard gum for 15 min while sipping grape juice (10% of individual energy needs) containing acetaminophen and lactulose on one day each separated by 7 days. Electromyographic recordings and self-reports were obtained during and after chewing to quantify oral processing effort. Blood was sampled through an indwelling catheter and appetite ratings were obtained at baseline and at 0, 15, 30, 45, 60, 90, 120, 180 and 240 min after chewing initiation. Breath samples were collected at 10 min intervals for the first 2h and at 30 min intervals for the next 2h. No effects of chewing were observed for appetitive sensations or gut peptide concentrations. Energy intake tended to decline in lean and increase in obese participants so that daily energy intake differed significantly between the two groups when chewing either gum, while no difference was observed on the non-chewing day. Serum glucose and insulin were significantly lower at selected time points 90-240 min after chewing compared to baseline and the non-chewing day. These data indicate chewing effort does not affect appetitive sensations or gut peptide secretion, but may exert a small differential effect on acute energy intake in lean and obese individuals and lead to greater post-prandial declines of serum glucose and insulin. The efficacy of gum chewing as a substitute for eating for weight

  17. Pneumococcal disease in HIV-infected Malawian adults: acute mortality and long-term survival

    PubMed Central

    Gordon, Stephen B.; Chaponda, Mas; Walsh, Amanda L.; Whitty, Christopher J.M.; Gordon, Melita A.; Machili, C. Edward; Gilks, Charles F.; Boeree, Martin J.; Kampondeni, Sam; Read, Robert C.; Molyneux, Malcolm E.

    2016-01-01

    Objective HIV-infected patients in Africa are vulnerable to severe recurrent infection with Streptococcus pneumoniae, but no effective preventive strategy has been developed. We set out to determine which factors influence in-hospital mortality and long-term survival of Malawians with invasive pneumococcal disease. Design, setting and patients Acute clinical features, inpatient mortality and long-term survival were described among consecutively admitted hospital patients with S. pneumoniae in the blood or cerebrospinal fluid. Factors associated with inpatient mortality were determined, and patients surviving to discharge were followed to determine their long-term outcome. Results A total of 217 patients with pneumococcal disease were studied over an 18-month period. Among these, 158 out of 167 consenting to testing (95%) were HIV positive. Inpatient mortality was 65% for pneumococcal meningitis (n = 64), 20% for pneumococcaemic pneumonia (n = 92), 26% for patients with pneumococcaemia without localizing signs (n = 43), and 76% in patients with probable meningitis (n = 17). Lowered consciousness level, hypotension, and age exceeding 55 years at presentation were associated with inpatient death, but not long-term outcome in survivors. Hospital survivors were followed for a median of 414 days; 39% died in the community during the study period. Outpatient death was associated with multilobar chest signs, oral candidiasis, and severe anaemia as an inpatient. Conclusion Most patients with pneumococcal disease in Malawi have HIV co-infection. They have severe disease with a high mortality rate. At discharge, all HIV-infected adults have a poor prognosis but patients with multilobar chest signs or anaemia are at particular risk. PMID:12131218

  18. Intravenous immunoglobulin in the therapy of adult acute fulminant myocarditis: A retrospective study.

    PubMed

    Yu, Dan-Qing; Wang, Ying; Ma, Gui-Zhou; Xu, Rong-He; Cai, Zhi-Xiong; Ni, Chu-Min; Chen, Ping; Zhu, Zhi-Dan

    2014-01-01

    Acute fulminant myocarditis (AFM) is a serious heart disease with limited treatment. This observational retrospective study aimed to investigate whether intravenous immunoglobulin (IVIG) was able to improve left ventricular function and reduce the episodes of arrhythmia in adult patients with AFM. The medical records of all patients with AFM who were admitted to the Critical Care Unit of Guangdong General Hospital (Guangzhou, China) between January 2001 and December 2010 were reviewed. A cohort of 58 patients was included in the study. Of these 58, 32 patients were treated with IVIG (400 mg/kg per day) for five days, while the remaining patients did not receive IVIG therapy. The patients who received IVIG therapy had a higher left ventricular ejection fraction (LVEF) and a reduced left ventricular end-diastolic diameter (LVDD) compared with the non-IVIG therapy patients four weeks subsequent to the treatment (PLVEF=0.011 and PLVDD=0.048). The post-treatment incidence of ventricular tachycardia/ventricular fibrillation (VT/VF) and atrioventricular block (AVB) was reduced in the patients who received IVIG therapy compared with the baseline values (PVT/VF=0.025, PAVB=0.003); however, no significant differences were observed in the non-IVIG therapy patients (PVT/VF=0.564, PAVB=0.083) following treatment. There were two mortalities in the IVIG therapy group and seven in the non-IVIG therapy group (P=0.072). This retrospective study suggested that the use of IVIG for the treatment of AFM may be associated with improved left ventricular function and reduced episodes of fulminant arrhythmias. PMID:24348772

  19. Acute adult poisoning cases admitted to a university hospital in Tabriz, Iran.

    PubMed

    Islambulchilar, M; Islambulchilar, Z; Kargar-Maher, M H

    2009-04-01

    The aim of our study was to investigate the etiological and demographical characteristics of acute adult poisoning cases admitted to a university hospital in Tabriz, Iran. This retrospective study was performed on 1342 poisoning admissions to a university hospital from 2003 to 2005, by data collection from the medical records of patients. Poisonings were 5.40% of the total admissions. There was a predominance of female patients (55.7%) compared to male patients (44.3%) with a female-to-male ratio of 1.2:1. Most poisonings occurred in the age range of 11-20 years (38.9%). Drugs were the most common cause of poisonings (60.8%). Among the drug poisonings, benzodiazepines (40.31%) were the most frequent agents, followed by antidepressants (31.98%). The seasonal distribution in poisoning patients suggested a peak in spring (28%) and summer (27.5%). In 9.8% of cases accidental and in 90.2% intentional poisonings were evident. Most suicide attempts were made by women (58.51%) and unmarried people (51.4%).The mean duration of hospitalization was 3.02 +/- 2.8 days. There were 28 (2.3%) deaths; the majority (13 cases) was due to pesticides. This was a university hospital-based study, so these results may not be representative of the general population. Despite this drawback, these data still provide important information on the characteristics of the poisoning in this part of Iran. To prevent such poisonings, the community education about the danger of central nervous system-acting drugs and reducing the exposure period of people to pesticides are recommended. PMID:19734268

  20. Blood-brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat.

    PubMed

    Fernández-López, David; Faustino, Joel; Daneman, Richard; Zhou, Lu; Lee, Sarah Y; Derugin, Nikita; Wendland, Michael F; Vexler, Zinaida S

    2012-07-11

    The immaturity of the CNS at birth greatly affects injury after stroke but the contribution of the blood-brain barrier (BBB) to the differential response to stroke in adults and neonates is poorly understood. We asked whether the structure and function of the BBB is disrupted differently in neonatal and adult rats by transient middle cerebral artery occlusion. In adult rats, albumin leakage into injured regions was markedly increased during 2-24 h reperfusion but leakage remained low in the neonates. Functional assays employing intravascular tracers in the neonates showed that BBB permeability to both large (70 kDa dextran) and small (3 kDa dextran), gadolinium (III)-diethyltriaminepentaacetic acid tracers remained largely undisturbed 24 h after reperfusion. The profoundly different functional integrity of the BBB was associated with the largely nonoverlapping patterns of regulated genes in endothelial cells purified from injured and uninjured adult and neonatal brain at 24 h (endothelial transcriptome, 31,042 total probe sets). Within significantly regulated 1266 probe sets in injured adults and 361 probe sets in neonates, changes in the gene expression of the basal lamina components, adhesion molecules, the tight junction protein occludin, and matrix metalloproteinase-9 were among the key differences. The protein expression of collagen-IV, laminin, claudin-5, occludin, and zonula occludens protein 1 was also better preserved in neonatal rats. Neutrophil infiltration remained low in acutely injured neonates but neutralization of cytokine-induced neutrophil chemoattractant-1 in the systemic circulation enhanced neutrophil infiltration, BBB permeability, and injury. The markedly more integrant BBB in neonatal brain than in adult brain after acute stroke may have major implications for the treatment of neonatal stroke. PMID:22787045

  1. A Comprehensive Comparison of the Efficacy and Tolerability of Racecadotril with Other Treatments of Acute Diarrhea in Adults

    PubMed Central

    Fischbach, Wolfgang; Andresen, Viola; Eberlin, Marion; Mueck, Tobias; Layer, Peter

    2016-01-01

    Racecadotril is a guideline-recommended treatment to alleviate symptoms of acute diarrhea. A systematic review of randomized studies was performed comparing efficacy and safety of treatment with racecadotril to that with placebo or active treatments in adults. In five double-blind studies, racecadotril and placebo had comparable tolerability, but racecadotril was more effective. This was consistent across multiple efficacy parameters including duration of diarrhea, number of diarrheic stools, abdominal pain, and meteorism; it was also consistent across countries in Africa, Asia, and Europe. In six randomized studies in outpatients comparing racecadotril to loperamide, resolution of symptoms occurred with similar speed and efficacy; however, racecadotril treatment was associated with less rebound constipation and less abdominal discomfort. The seventh comparative study performed in geriatric nursing home residents reported a superior efficacy of racecadotril. In direct comparison with Saccharomyces boulardii treatment, racecadotril exhibited similar tolerability but was more efficacious. One study compared racecadotril to octreotide in patients with acute diarrhea requiring hospitalization, rehydration, and antibiotic treatment; in this cohort, octreotide was more efficacious than racecadotril. In conclusion, in adults with acute diarrhea, racecadotril is more efficacious than placebo or S. boulardii, similarly efficacious as loperamide and, in patients with moderate to severe disease as add-on to antibiotics, less than octreotide. The tolerability of racecadotril is similar to that of placebo or S. boulardii and better than that of loperamide, particularly with regard to risk of rebound constipation. Taken together, these data demonstrate that racecadotril is a suitable treatment to alleviate symptoms of acute diarrhea in adults. PMID:27790616

  2. In vitro inhibition of promyelocytic leukemia/retinoic acid receptor-alpha (PML/RARalpha) expression and leukemogenic activity by DNA/LNA chimeric antisense oligos.

    PubMed

    Caprodossi, Sara; Galluzzi, Luca; Biagetti, Simona; Della Chiara, Giulia; Pelicci, Pier Giuseppe; Magnani, Mauro; Fanelli, Mirco

    2005-01-01

    Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by the chromosomal translocation t(15:17) that leads to the expression of promyelocytic leukemia/retinoic acid receptor-alpha (PML/ RARalpha) oncofusion protein. The block of differentiation at the promyelocytic stage of the blasts and their increased survival induced by PML/RARalpha are the principal biological features of the disease. Therapies based on pharmacological doses of retinoic acid (RA, 10(-6) M) are able to restore APL cell differentiation in most cases, but not to achieve complete hematological remission because retinoic acid resistance occurs in many patients. In order to elaborate alternative therapeutic approaches, we focused our attention on the use of antisense oligonucleotides as gene-specific drug directed to PML/RARalpha mRNA target. We used antisense molecules containing multiple locked nucleic acid (LNA) modifications. The LNAs are nucleotide analogues that are able to form duplexes with complementary DNA or RNA sequences with highly increased thermal stability and are resistant to 3'-exonuclease degradation in vitro. The DNA/LNA chimeric molecules were designed on the fusion sequence of PML and RARalpha genes to specifically target the oncofusion protein. Cell-free and in vitro experiments using U937-PR9-inducible cell line showed that DNA/LNA oligonucleotides were able to interfere with PML/RARalpha expression more efficiently than the corresponding unmodified DNA oligo. Moreover, the treatment of U937-PR9 cells with these chimeric antisense molecules was able to abrogate the block of differentiation induced by PML/RARalpha oncoprotein. These data suggest a possible application of oligonucleotides containing LNA in an antisense therapeutic strategy for APL.

  3. Decitabine With or Without Bortezomib in Treating Older Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-03-14

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  4. Nucleocytoplasmic Shuttling of p62/SQSTM1 and Its Role in Recruitment of Nuclear Polyubiquitinated Proteins to Promyelocytic Leukemia Bodies*

    PubMed Central

    Pankiv, Serhiy; Lamark, Trond; Bruun, Jack-Ansgar; Øvervatn, Aud; Bjørkøy, Geir; Johansen, Terje

    2010-01-01

    p62, also known as sequestosome1 (SQSTM1), A170, or ZIP, is a multifunctional protein implicated in several signal transduction pathways. p62 is induced by various forms of cellular stress, is degraded by autophagy, and acts as a cargo receptor for autophagic degradation of ubiquitinated targets. It is also suggested to shuttle ubiquitinated proteins for proteasomal degradation. p62 is commonly found in cytosolic protein inclusions in patients with protein aggregopathies, it is up-regulated in several forms of human tumors, and mutations in the gene are linked to classical adult onset Paget disease of the bone. To this end, p62 has generally been considered to be a cytosolic protein, and little attention has been paid to possible nuclear roles of this protein. Here, we present evidence that p62 shuttles continuously between nuclear and cytosolic compartments at a high rate. The protein is also found in nuclear promyelocytic leukemia bodies. We show that p62 contains two nuclear localization signals and a nuclear export signal. Our data suggest that the nucleocytoplasmic shuttling of p62 is modulated by phosphorylations at or near the most important nuclear localization signal, NLS2. The aggregation of p62 in cytosolic bodies also regulates the transport of p62 between the compartments. We found p62 to be essential for accumulation of polyubiquitinated proteins in promyelocytic leukemia bodies upon inhibition of nuclear protein export. Furthermore, p62 contributed to the assembly of proteasome-containing degradative compartments in the vicinity of nuclear aggregates containing polyglutamine-expanded Ataxin1Q84 and to the degradation of Ataxin1Q84. PMID:20018885

  5. Nucleocytoplasmic shuttling of p62/SQSTM1 and its role in recruitment of nuclear polyubiquitinated proteins to promyelocytic leukemia bodies.

    PubMed

    Pankiv, Serhiy; Lamark, Trond; Bruun, Jack-Ansgar; Øvervatn, Aud; Bjørkøy, Geir; Johansen, Terje

    2010-02-19

    p62, also known as sequestosome1 (SQSTM1), A170, or ZIP, is a multifunctional protein implicated in several signal transduction pathways. p62 is induced by various forms of cellular stress, is degraded by autophagy, and acts as a cargo receptor for autophagic degradation of ubiquitinated targets. It is also suggested to shuttle ubiquitinated proteins for proteasomal degradation. p62 is commonly found in cytosolic protein inclusions in patients with protein aggregopathies, it is up-regulated in several forms of human tumors, and mutations in the gene are linked to classical adult onset Paget disease of the bone. To this end, p62 has generally been considered to be a cytosolic protein, and little attention has been paid to possible nuclear roles of this protein. Here, we present evidence that p62 shuttles continuously between nuclear and cytosolic compartments at a high rate. The protein is also found in nuclear promyelocytic leukemia bodies. We show that p62 contains two nuclear localization signals and a nuclear export signal. Our data suggest that the nucleocytoplasmic shuttling of p62 is modulated by phosphorylations at or near the most important nuclear localization signal, NLS2. The aggregation of p62 in cytosolic bodies also regulates the transport of p62 between the compartments. We found p62 to be essential for accumulation of polyubiquitinated proteins in promyelocytic leukemia bodies upon inhibition of nuclear protein export. Furthermore, p62 contributed to the assembly of proteasome-containing degradative compartments in the vicinity of nuclear aggregates containing polyglutamine-expanded Ataxin1Q84 and to the degradation of Ataxin1Q84.

  6. Clinical and molecular epidemiology of norovirus infection in adults with acute gastroenteritis in Ji'nan, China.

    PubMed

    Sai, Lintao; Wang, Gang; Shao, Lihua; Liu, Haihong; Zhang, Yajun; Qu, Chunmei; Ma, Lixian

    2013-11-01

    Acute gastroenteritis caused by human noroviruses (NoVs) has become an important public health problem worldwide. This study was carried out to investigate the rates of NoV infections and the genetic characteristics of NoVs in adult outpatients with acute gastroenteritis in Ji'nan, a large eastern city in China. A total of 480 fecal samples were collected from outpatients at the Shandong University Qilu Hospital between June 2010 and May 2011. Of the collected samples, 42 (42/480, 8.75 %) were positive for NoVs by RT-PCR, and seven different genotypes were identified: GI-1, GI-4, GII-1, GII-3, GII-4, GII-6 and GII-13, of which GII-4 was the most prevalent (29/42, 69.0 %). Phylogenetic and Simplot analyses showed that three recombinant strains were detected: two GII-4 polymerase/GII-3 capsid recombinants and one GII-6 polymerase/GII-4 capsid recombinant. This study indicated that NoV was a common causative agent of sporadic acute gastroenteritis in adults in Ji'nan, China, and that NoV GII-4 was the predominant strain during this period. Three recombinant strains were identified in which GII-6 polymerase/GII-4 capsid was detected for the first time in China.

  7. High Throughput Drug Sensitivity Assay and Genomics- Guided Treatment of Patients With Relapsed or Refractory Acute Leukemia

    ClinicalTrials.gov

    2016-05-19

    Acute Leukemia of Ambiguous Lineage; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia; Refractory Childhood Acute Lymphoblastic Leukemia

  8. Azacitidine, Mitoxantrone Hydrochloride, and Etoposide in Treating Older Patients With Poor-Prognosis Acute Myeloid Leukemia

    ClinicalTrials.gov

    2015-08-18

    Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  9. Comparative study of quality of life of adult survivors of childhood acute lymphocytic leukemia and Wilms’ tumor

    PubMed Central

    de Souza, Clélia Marta Casellato; Cristofani, Lilian Maria; Cornacchioni, Ana Lucia Beltrati; Odone, Vicente; Kuczynski, Evelyn

    2015-01-01

    Abstract Objective To analyze and compare the health-related quality of life of adult survivors of acute lymphocytic leukemia and Wilms’ tumor amongst themselves and in relation to healthy participants. Methods Ninety participants aged above 18 years were selected and divided into three groups, each comprising 30 individuals. The Control Group was composed of physically healthy subjects, with no cancer history; and there were two experimental groups: those diagnosed as acute lymphocytic leukemia, and those as Wilms’ Tumor. Quality of life was assessed over the telephone, using the Medical Outcomes Study 36-Item Short Form Health Survey. Results Male survivors presented with better results as compared to female survivors and controls in the Vitality domain, for acute lymphocytic leukemia (p=0.042) and Wilms’ tumor (p=0.013). For acute lymphocytic leukemia survivors, in Social aspects (p=0.031), Mental health (p=0.041), and Emotional aspects (p=0.040), the latter also for survivors of Wilms’ tumor (p=0.040). The best results related to the Functional capacity domain were recorded for the experimental group that had a late diagnosis of acute lymphocytic leukemia. There were significant differences between groups except for the Social and Emotional domains for self-perceived health, with positive responses that characterized their health as good, very good, and excellent. Conclusion Survivors of acute lymphocytic leukemia showed no evidence of relevant impairment of health-related quality of life. The Medical Outcomes Study 36-Item Short Form Health Survey (via telephone) can be a resource to access and evaluate survivors. PMID:26537509

  10. Targeted Therapy in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myelogenous Leukemia

    ClinicalTrials.gov

    2016-07-28

    Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia With Myelodysplasia-Related Changes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Adult Acute Lymphoblastic Leukemia

  11. Promyelocytic leukemia nuclear bodies associate with transcriptionally active genomic regions

    PubMed Central

    Wang, Jayson; Shiels, Carol; Sasieni, Peter; Wu, Pei Jun; Islam, Suhail A.; Freemont, Paul S.; Sheer, Denise

    2004-01-01

    The promyelocytic leukemia (PML) protein is aggregated into nuclear bodies that are associated with diverse nuclear processes. Here, we report that the distance between a locus and its nearest PML body correlates with the transcriptional activity and gene density around the locus. Genes on the active X chromosome are more significantly associated with PML bodies than their silenced homologues on the inactive X chromosome. We also found that a histone-encoding gene cluster, which is transcribed only in S-phase, is more strongly associated with PML bodies in S-phase than in G0/G1 phase of the cell cycle. However, visualization of specific RNA transcripts for several genes showed that PML bodies were not themselves sites of transcription for these genes. Furthermore, knock-down of PML bodies by RNA interference did not preferentially change the expression of genes closely associated with PML bodies. We propose that PML bodies form in nuclear compartments of high transcriptional activity, but they do not directly regulate transcription of genes in these compartments. PMID:14970191

  12. Flavopiridol in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2013-06-03

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia

  13. Sorafenib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2013-01-08

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); 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 Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia

  14. Recovery-oriented care in older-adult acute inpatient mental health settings in Australia: an exploratory study.

    PubMed

    McKenna, Brian; Furness, Trentham; Dhital, Deepa; Ireland, Susan

    2014-10-01

    Recovery-oriented care acknowledges the unique journey that consumers lead with the aim of regaining control of their lives in order to live a good life. Recovery has become a dominant policy-directed model of many mental health care organizations, but in older-adult acute mental health inpatient settings, nurses do not have a clear description of how to be recovery-oriented. The aims of this study were to determine the extent to which elements of existing nursing practice resemble the domains of recovery-oriented care and provide a baseline understanding of practice in preparation for transformation to recovery-oriented mental health care provision. An exploratory, qualitative research design was used to meet the research aims. A purposive sample of mental health nurses (N = 12) participated in focus groups in three older-adult inpatient settings in Australia. A general inductive approach was used to analyze the qualitative data. The mental health nurses in this study readily discussed aspects of their current practice within the recovery domains. They described pragmatic ways to promote a culture of hope, collaborative partnerships, meaningful engagement, autonomy and self-determination, and community participation and citizenship. Nurses also discussed challenges and barriers to recovery-oriented care in older-adult acute mental health settings. This study identified a reasonable baseline understanding of practice in preparation for transformation to recovery-oriented older-adult mental healthcare provision. A concerted drive focused on recovery education is required to effectively embed a recovery-orientated paradigm into older-adult mental health settings.

  15. Exploratory study of the decongestive effect of Rhinopront syrup in adults and in children with acute rhinitis.

    PubMed

    Lebacq, E; Gline, J P; Joue, P; Stockis, A; Calderon, P; Van Schoor, O; Deroubaix, X; Schwegler, F

    1994-10-01

    The decongestive effect of Rhinopront syrup was assessed in 18 adults and 18 children with acute rhinitis, by comparison to a matching placebo syrup and to a commercial standard decongestant (Triaminic tablets or drops). The evolution of symptoms following single dose administration of each treatment was estimated both by objective measurements of nasal resistance using bilateral rhinomanometry and by subjective evaluation of nasal congestion and aspect of the mucosa. In children, the treatment was continued over the next 4 days and the global clinical efficacy of the formulations was subjectively evaluated by the parents. In adult patients, a significant decrease in nasal resistance was obtained after a single dose of Rhinopront (15 g). The effect was already important after 0.5 h and reached a minimum of approximately 50% of baseline within 1 to 2 h; the drop in nasal resistance was significantly less intense for Triaminic (p < 0.05; 0.5-1-h period) and for the placebo (p < 0.05; 0.5-2-h period). In children, the scatter of rhinomanometric measurements precluded the observation of any significant within- or between-group differences; however, a significantly lower nasal congestion score was observed for Rhinopront than placebo, between 4 and 10 h after single dose administration (1 g per year of age). The present work suggests that Rhinopront is an effective nasal decongestant in adults and children with acute congestive rhinitis and supports the adequacy of the proposed twice-daily dosing rate.

  16. Bone Marrow MicroRNA-335 Level Predicts the Chemotherapy Response and Prognosis of Adult Acute Myeloid Leukemia

    PubMed Central

    Yingchun, Li; Rong, Zhang; Kun, Yao; Ying, Yang; Zhuogang, Liu

    2015-01-01

    Abstract The aim of this study was to investigate the role of microRNA-335 (miR-335) in determining the treatment response and prognosis in adult acute myeloid leukemia (AML) patients receiving the cytarabine (Ara-C)-based chemotherapy. A total of 204 adult AML patients were collected. The miR-335 levels in serum and bone marrow samples from these patients were determined. All patients received Ara-C-based standard induction chemotherapy regimens. The treatment response to Ara-C-based chemotherapy was evaluated. All patients were followed for prognostic analyses. The levels of miR-335 in bone marrow and serum samples from adult AML patients achieving complete response were significantly higher than those without. The serum miR-335 level was not associated with the chemotherapy response and prognosis in these AML patients. In contrast, high bone marrow miR-335 level was significantly associated with a poor treatment response and also predicted a worse prognosis indicated by the relapse-free survival and overall survival periods in adult AML patients receiving Ara-C-based chemotherapy. Our finding suggests that bone marrow miR-335 level may be used as a marker to predict the chemotherapy response and prognosis in adult AML patients. PMID:26287405

  17. Ibuprofen with or without an antiemetic for acute migraine headaches in adults

    PubMed Central

    Rabbie, Roy; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers do not seek professional help, relying instead on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce symptoms commonly associated with migraine headaches. Objectives To determine efficacy and tolerability of ibuprofen, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 22 April 2010. Selection criteria We included randomised, double-blind, placebo- or active-controlled studies using self-administered ibuprofen to treat a migraine headache episode, with at least 10 participants per treatment arm. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and number needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. Main results Nine studies (4373 participants, 5223 attacks) compared ibuprofen with placebo or other active comparators; none combined ibuprofen with a self-administered antiemetic. All studies treated attacks with single doses of medication. For ibuprofen 400 mg versus placebo, NNTs for 2-hour pain-free (26% versus 12% with placebo), 2-hour headache relief (57% versus 25%) and 24-hour sustained headache relief (45% versus 19%) were 7.2, 3.2 and 4.0, respectively. For ibuprofen 200 mg versus placebo, NNTs for 2-hour pain-free (20% versus 10%) and 2-hour headache relief (52% versus 37%) were 9.7 and 6.3, respectively. The higher dose was significantly better for 2-hour headache relief than the lower dose. Soluble formulations of ibuprofen 400 mg were better than standard tablets for 1-hour, but not 2-hour headache relief

  18. Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults

    PubMed Central

    Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting commonly associated with migraine. Objectives To determine the efficacy and tolerability of paracetamol (acetaminophen), alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 4 October 2010. Selection criteria We included randomised, double-blind, placebo- or active-controlled studies using self-administered paracetamol to treat a migraine headache episode, with at least 10 participants per treatment arm. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. Main results Ten studies (2769 participants, 4062 attacks) compared paracetamol 1000 mg, alone or in combination with an antiemetic, with placebo or other active comparators, mainly sumatriptan 100 mg. For all efficacy outcomes paracetamol was superior to placebo, with NNTs of 12, 5.2 and 5.0 for 2-hour pain-free and 1- and 2-hour headache relief, respectively, when medication was taken for moderate to severe pain. Nausea, photophobia and phonophobia were reduced more with paracetamol than with placebo at 2 hours (NNTs of 7 to 11); more individuals were free of any functional disability at 2 hours with paracetamol (NNT 10); and fewer participants needed rescue medication over 6 hours (NNT 6). Paracetamol 1000 mg plus metoclopramide 10 mg was not significantly different from oral sumatriptan

  19. [Double-blind controlled study of the efficacy of nifuroxazide versus placebo in the treatment of acute diarrhea in adults].

    PubMed

    Bourée, P; Chaput, J C; Krainik, F; Michel, H; Trépo, C

    1989-05-01

    In a double-blind, controlled randomized trial, 88 adult patients with acute diarrhea (more than three watery stools per day) received either 400 mg of nifuroxazide twice daily or placebo for 5 days. The mean duration of diarrhea in the nifuroxazide group was 2.09 days versus 3.26 days in the placebo group (p less than 0.004). The number of bowel movements per day diminished and mucus disappeared more quickly in patients treated by nifuroxazide than in patients of the placebo group. Nifuroxazide was well tolerated and no side effects were observed. Nifuroxazide is an effective therapy for acute diarrhea and can be prescribed from the onset of diarrhea without waiting for stool culture results which can be late or negative. PMID:2666238

  20. Lenalidomide in Treating Older Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-07-25

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  1. Risk-Based Classification System of Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-10-24

    Adult B Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Childhood B Acute Lymphoblastic Leukemia; Childhood T Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  2. [Treatment of acute coronary syndrome in older adults and high-risk patients."When the going gets tough…"].

    PubMed

    Bassanelli, Giorgio; Morici, Nuccia; De Luca, Leonardo; De Servi, Stefano; Savonitto, Stefano

    2015-10-01

    The increasing life expectancy in older adults and the better survival of patients with multiple pathologies require the capability to treat complex clinical conditions with an increased risk of iatrogenic complications. Nevertheless, recent improvements in the pharmacological and interventional treatment of acute coronary syndrome (ACS) have promoted a shift from therapeutic nihilism to a more active management of complex ACS cases. Despite the paucity of specific randomized clinical trials, observational studies seem to show benefit of an early invasive treatment in these patients. This approach requires close cooperation of clinical intensivists, interventional cardiologists and cardiovascular surgeons either in a specialized heart center or in a network of hospitals. PMID:26442976

  3. Tipifarnib and Bortezomib in Treating Patients With Acute Leukemia or Chronic Myelogenous Leukemia in Blast Phase

    ClinicalTrials.gov

    2015-04-14

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Blastic Phase; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  4. Salmonella myocarditis in a young adult patient presenting with acute pulmonary edema, rhabdomyolysis, and multi-organ failure.

    PubMed

    Al-aqeedi, Rafid Fayadh; Kamha, Ahmed; Al-aani, Fuad K; Al-ani, Ahmed A

    2009-12-01

    The mortality and morbidity of salmonella infections is seriously underestimated. Salmonella myocarditis is an unusual complication of salmonella sepsis in adults. Cases that do occur may be associated with high morbidity and mortality. We present a rare case of salmonella myocarditis with multi-organ failure in a previously healthy young adult man who was brought to the emergency room with fever, diarrhea, shortness of breath, and altered sensorium, discovered to have acute pulmonary edema and respiratory compromise for which he was assisted with mechanical ventilation for 8 days. Blood culture grew Salmonella typhi. Biochemically he exhibited myocardial, hepatic, and muscular enzymatic surge with renal failure, features of rhabdomyolysis, and disseminated intravascular coagulation. The patient showed a progressive improvement on treatment with ceftriaxone for 2 weeks in addition to decongestive therapy. He was discharged in good condition afterward. PMID:19944325

  5. (-)-Epigallocatechin-3-gallate (EGCG) modulates neurological function when intravenously infused in acute and, chronically injured spinal cord of adult rats.

    PubMed

    Renno, Waleed M; Al-Khaledi, Ghanim; Mousa, Alyaa; Karam, Shaima M; Abul, Habib; Asfar, Sami

    2014-02-01

    Spinal cord injury (SCI) causes severe and long lasting motor and sensory deficits, chronic pain, and autonomic dysreflexia. (-)-epigallocatechin-3-gallate (EGCG) has shown to produce neuroprotective effect in a broad range of neurodegenerative disease animal models. This study designed to test the efficacy of intravenous infusion of EGCG for 36 h, in acutely injured rats' spinal cord: within first 4 h post-injury and, in chronically SC injured rats: after one year of injury. Functional outcomes measured using standard BBB scale, The Louisville Swim Scale (LSS) and, pain behavior assessment tests. 72 Female adult rats subjected to moderate thoracic SCI using MASCIS Impactor, blindly randomized as the following: (I) Acute SCI + EGCG (II) Acute SCI + saline. (III) Chronic SCI + EGCG. (IV) Chronic SCI + saline and, sham SCI animals. EGCG i.v. treatment of acute and, chronic SCI animals resulted in significantly better recovery of motor and sensory functions, BBB and LSS (P < 0.005) and (P < 0.05) respectively. Tactile allodynia, mechanical nociception (P < 0.05) significantly improved. Paw withdrawal and, tail flick latencies increase significantly (P < 0.05). Moreover, in the EGCG treated acute SCI animals the percentage of lesion size area significantly reduced (P < 0.0001) and, the number of neurons in the spinal cord increased (P < 0.001). Percent areas of GAP-43 and GFAP immunohistochemistry showed significant (P < 0.05) increase. We conclude that the therapeutic window of opportunity for EGCG to depict neurological recovery in SCI animals, is viable up to one year post SCI when intravenously infused for 36 h. PMID:24071567

  6. (-)-Epigallocatechin-3-gallate (EGCG) modulates neurological function when intravenously infused in acute and, chronically injured spinal cord of adult rats.

    PubMed

    Renno, Waleed M; Al-Khaledi, Ghanim; Mousa, Alyaa; Karam, Shaima M; Abul, Habib; Asfar, Sami

    2014-02-01

    Spinal cord injury (SCI) causes severe and long lasting motor and sensory deficits, chronic pain, and autonomic dysreflexia. (-)-epigallocatechin-3-gallate (EGCG) has shown to produce neuroprotective effect in a broad range of neurodegenerative disease animal models. This study designed to test the efficacy of intravenous infusion of EGCG for 36 h, in acutely injured rats' spinal cord: within first 4 h post-injury and, in chronically SC injured rats: after one year of injury. Functional outcomes measured using standard BBB scale, The Louisville Swim Scale (LSS) and, pain behavior assessment tests. 72 Female adult rats subjected to moderate thoracic SCI using MASCIS Impactor, blindly randomized as the following: (I) Acute SCI + EGCG (II) Acute SCI + saline. (III) Chronic SCI + EGCG. (IV) Chronic SCI + saline and, sham SCI animals. EGCG i.v. treatment of acute and, chronic SCI animals resulted in significantly better recovery of motor and sensory functions, BBB and LSS (P < 0.005) and (P < 0.05) respectively. Tactile allodynia, mechanical nociception (P < 0.05) significantly improved. Paw withdrawal and, tail flick latencies increase significantly (P < 0.05). Moreover, in the EGCG treated acute SCI animals the percentage of lesion size area significantly reduced (P < 0.0001) and, the number of neurons in the spinal cord increased (P < 0.001). Percent areas of GAP-43 and GFAP immunohistochemistry showed significant (P < 0.05) increase. We conclude that the therapeutic window of opportunity for EGCG to depict neurological recovery in SCI animals, is viable up to one year post SCI when intravenously infused for 36 h.

  7. Lineage switch from acute myeloid leukemia to acute lymphoblastic leukemia: report of an adult case and review of the literature.

    PubMed

    Lounici, A; Cony-Makhoul, P; Dubus, P; Lacombe, F; Merlio, J P; Reiffers, J

    2000-12-01

    Lineage switch from AML to ALL is an extremely rare phenomenon, and we report the case of an adult diagnosed with AML at 46 years of age who relapsed with ALL. At initial diagnosis, blast cell morphology and immunophenotyping were consistent with the diagnosis of M4-AML. Complete remission was achieved, and the patient underwent autologous BMT. At relapse, six months after ABMT, blast cells were different from those seen at initial diagnosis, for morphology (L2-ALL), cytochemistry, and immunophenotyping. The karyotype was normal at both diagnosis and relapse. No evidence of bcr-abl fusion genes was found by RT-PCR. Monoclonal IgH and TCR gamma gene rearrangement were evidenced by PCR analysis at relapse but not on blast cells at AML diagnosis.

  8. Effects of age, but not sex, on elevated startle during withdrawal from acute morphine in adolescent and adult rats.

    PubMed

    Radke, Anna K; Gewirtz, Jonathan C; Carroll, Marilyn E

    2015-08-01

    Investigations into animal models of drug withdrawal have largely found that emotional signs of withdrawal (e.g. anxiety, anhedonia, and aversion) in adolescents are experienced earlier and less severely than in their adult counterparts. The majority of these reports have examined withdrawal from ethanol or nicotine. To expand our knowledge about the emotional withdrawal state in adolescent rats, we used potentiation of the acoustic startle reflex after an acute dose of morphine (10 mg/kg, subcutaneously) as a measure of opiate withdrawal. Startle was measured at four time points after morphine injection (2, 3, 4, and 5 h) in 28-day-old and 90-day-old male and female rats. The results of this experiment revealed that peak potentiation of the startle reflex occurred at 3 h in the adolescent rats and at 5 h in the adult rats, and that the magnitude of withdrawal was larger in the adults. No sex differences were observed. Overall, these results affirm that, similar to withdrawal from ethanol and nicotine, opiate withdrawal signs are less severe in adolescent than in adult rats.

  9. Effects of age, but not sex, on elevated startle during withdrawal from acute morphine in adolescent and adult rats

    PubMed Central

    Radke, Anna K.; Gewirtz, Jonathan C.; Carroll, Marilyn E.

    2015-01-01

    Investigations into animal models of drug withdrawal have largely found that emotional signs of withdrawal (e.g., anxiety, anhedonia, and aversion) in adolescents are experienced earlier and less severely than in their adult counterparts. The majority of these reports have examined withdrawal from ethanol or nicotine. In order to expand our knowledge about the emotional withdrawal state in adolescent rats, we used potentiation of the acoustic startle reflex after an acute dose of morphine (10 mg/kg, s.c.) as a measure of opioid withdrawal. Startle was measured at four time points after morphine injection (2, 3, 4, and 5 h) in 28 and 90 day old male and female rats. The results of this experiment revealed that peak potentiation of the startle reflex occurred at 3 h in the adolescent rats and at 5 h in the adult rats, and that the magnitude of withdrawal was larger in the adults. No sex differences were observed. Overall, these results affirm that, similar to withdrawal from ethanol and nicotine, opiate withdrawal signs are less severe in adolescent than in adult rats. PMID:26154436

  10. Acute stress differentially affects aromatase activity in specific brain nuclei of adult male and female quail.

    PubMed

    Dickens, Molly J; Cornil, Charlotte A; Balthazart, Jacques

    2011-11-01

    The rapid and temporary suppression of reproductive behavior is often assumed to be an important feature of the adaptive acute stress response. However, how this suppression operates at the mechanistic level is poorly understood. The enzyme aromatase converts testosterone to estradiol in the brain to activate reproductive behavior in male Japanese quail (Coturnix japonica). The discovery of rapid and reversible modification of aromatase activity (AA) provides a potential mechanism for fast, stress-induced changes in behavior. We investigated the effects of acute stress on AA in both sexes by measuring enzyme activity in all aromatase-expressing brain nuclei before, during, and after 30 min of acute restraint stress. We show here that acute stress rapidly alters AA in the male and female brain and that these changes are specific to the brain nuclei and sex of the individual. Specifically, acute stress rapidly (5 min) increased AA in the male medial preoptic nucleus, a region controlling male reproductive behavior; in females, a similar increase was also observed, but it appeared delayed (15 min) and had smaller amplitude. In the ventromedial and tuberal hypothalamus, regions associated with female reproductive behavior, stress induced a quick and sustained decrease in AA in females, but in males, only a slight increase (ventromedial) or no change (tuberal) in AA was observed. Effects of acute stress on brain estrogen production, therefore, represent one potential way through which stress affects reproduction.

  11. The acute effect of maximal exercise on central and peripheral arterial stiffness indices and hemodynamics in children and adults.

    PubMed

    Melo, Xavier; Fernhall, Bo; Santos, Diana A; Pinto, Rita; Pimenta, Nuno M; Sardinha, Luís B; Santa-Clara, Helena

    2016-03-01

    This study compared the effects of a bout of maximal running exercise on arterial stiffness in children and adults. Right carotid blood pressure and artery stiffness indices measured by pulse wave velocity (PWV), compliance and distensibility coefficients, stiffness index α and β (echo-tracking), contralateral carotid blood pressure, and upper and lower limb and central/aortic PWV (applanation tonometry) were taken at rest and 10 min after a bout of maximal treadmill running in 34 children (7.38 ± 0.38 years) and 45 young adults (25.22 ± 0.91 years) having similar aerobic potential. Two-by-two repeated measures analysis of variance and analysis of covariance were used to detect differences with exercise between groups. Carotid pulse pressure (PP; η(2) = 0.394) increased more in adults after exercise (p < 0.05). Compliance (η(2) = 0.385) decreased in particular in adults and in those with high changes in distending pressure, similarly to stiffness index α and β. Carotid PWV increased more in adults and was related to local changes in PP but not mean arterial pressure (MAP). Stiffness in the lower limbs decreased (η(2) = 0.115) but apparently only in those with small MAP changes (η(2) = 0.111). No significant exercise or group interaction effects were found when variables were adjusted to height. An acute bout of maximal exercise can alter arterial stiffness and hemodynamics in the carotid artery and within the active muscle beds. Arterial stiffness and hemodynamic response to metabolic demands during exercise in children simply reflect their smaller body size and may not indicate a particular physiological difference compared with adults. PMID:26842667

  12. Entinostat and Clofarabine in Treating Patients With Newly Diagnosed, Relapsed, or Refractory Poor-Risk Acute Lymphoblastic Leukemia or Bilineage/Biphenotypic Leukemia

    ClinicalTrials.gov

    2014-07-16

    Acute Leukemias of Ambiguous Lineage; Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  13. Clinical characteristics and genetic diversity of noroviruses in adults with acute gastroenteritis in Beijing, China in 2008-2009.

    PubMed

    Tian, Geng; Jin, Miao; Li, Huiying; Li, Quanrui; Wang, Jing; Duan, Zhao-jun

    2014-07-01

    Norovirus (NoV) infections that cause acute gastroenteritis are commonly observed during colder months. This study was conducted to investigate the clinical features and molecular epidemiology of NoVs in adult outpatients with acute gastroenteritis in Beijing, China from August 2008 to July 2009. Five hundred nineteen patients were enrolled, their stool specimens were collected, and 136 (26.2%) were positive for NoV. The elderly were found to be more susceptible to NoVs than other age groups. The greatest number of gastroenteritis cases associated with occurred in October. Six GI and eleven GII NoV genotypes were isolated; among these, the GII.4 genotype was most prevalent (70/140 and 50% were the 2006b variant). The elderly were more susceptible to the GII.4 genotype than to other genotypes. Greater numbers of neutrophils in the peripheral blood were observed in the NoV infected group than in uninfected control group. However, the levels of neutrophils and leukocytes in the non-GII.4 patients infected with NoV were higher than those of the GII.4-infected patients. The data highlight the role of NoV as a primary agent responsible for gastroenteritis in adults in Beijing, China.

  14. Magnetic resonance imaging of femoral marrow predicts outcome in adult patients with acute myeloid leukaemia in complete remission.

    PubMed

    Takagi, Shojiro; Tanaka, Osamu

    2002-04-01

    Accurate assessment of residual disease is important for the prediction of outcome in patients with acute leukaemia in complete remission (CR). To investigate whether abnormalities on magnetic resonance (MR) images of femoral marrow in adult patients with acute myeloid leukaemia (AML) in CR can predict outcome, 28 newly diagnosed patients with AML underwent MR imaging when bone marrow aspiration or biopsy was performed to verify the state of CR after induction therapy. MR abnormalities on short TI (inversion time) inversion recovery (STIR) techniques persisted in all four patients who did not achieve CR. In 13 CR patients abnormalities on STIR images resolved, to result in normal appearance at the time CR was achieved. All 13 patients remained in CR for 3-104 months (median, 73 months). In the other 11 CR patients, STIR abnormalities persisted at the time CR was achieved. Seven of them relapsed between 1 and 28 months (median, 3 months) after MR evaluation. Disease-free survival of patients with persistent abnormal STIR images was significantly shorter than that of patients with normal STIR images (P < 0.01). MR imaging of femoral marrow may predict outcome in adult patients with AML in CR. PMID:11918535

  15. Magnetic resonance imaging of femoral marrow predicts outcome in adult patients with acute myeloid leukaemia in complete remission.

    PubMed

    Takagi, Shojiro; Tanaka, Osamu

    2002-04-01

    Accurate assessment of residual disease is important for the prediction of outcome in patients with acute leukaemia in complete remission (CR). To investigate whether abnormalities on magnetic resonance (MR) images of femoral marrow in adult patients with acute myeloid leukaemia (AML) in CR can predict outcome, 28 newly diagnosed patients with AML underwent MR imaging when bone marrow aspiration or biopsy was performed to verify the state of CR after induction therapy. MR abnormalities on short TI (inversion time) inversion recovery (STIR) techniques persisted in all four patients who did not achieve CR. In 13 CR patients abnormalities on STIR images resolved, to result in normal appearance at the time CR was achieved. All 13 patients remained in CR for 3-104 months (median, 73 months). In the other 11 CR patients, STIR abnormalities persisted at the time CR was achieved. Seven of them relapsed between 1 and 28 months (median, 3 months) after MR evaluation. Disease-free survival of patients with persistent abnormal STIR images was significantly shorter than that of patients with normal STIR images (P < 0.01). MR imaging of femoral marrow may predict outcome in adult patients with AML in CR.

  16. Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia

    ClinicalTrials.gov

    2014-11-06

    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); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  17. Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-05-18

    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); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  18. Bilateral acute pyogenic conjunctivitis with iritis induced by unilateral topical application of bacterial peptidoglycan muramyl dipeptide in adult rabbits.

    PubMed

    Langford, Marlyn P; Foreman, Bridgett D; Srur, Lana; Ganley, James P; Redens, Thomas B

    2013-11-01

    The factors responsible for the conjunctivitis and iritis associated with acute ocular infection and post enteric inflammatory disease are not fully known. The pro-inflammatory activity of unilateral topical application of muramyl dipeptide (MDP; the smallest bio-active Gram-positive and Gram-negative bacterial cell wall component) was investigated in adult rabbits. The resultant bilateral conjunctivitis/iritis and pyogenic responses were characterized. Bilateral symptoms were graded by slit lamp examinations; tear fluid, Schirmer tests (tear production), blood and aqueous humor (AH) samples were obtained from MDP-treated and untreated rabbits. MDP concentration, gamma-glutamyltranspeptidase activity (GGT; key enzyme in glutathione recapture, xenobiotic detoxification, eicosanoid synthesis and neutrophil function), protein concentration, and tear cell density, cytology, and immunofluorescent antibody reactivity to GGT and calreticulin (CRT; MDP-binding protein) were determined. MDP was cleared from ipsilateral tears and serum by 6 h, but was undetected in mock-treated contralateral tears. Bilateral signs of acute transient pyogenic conjunctivitis, characterized by tearing, lid edema, conjunctival hyperemia, chemosis and leukocytic infiltrate with iritis (erythema and aqueous flare) were detected. Milder symptoms occurred in the mock-treated contralateral eyes. Bilateral symptoms, tear production, tear protein, GGT activity, and mucopurulent discharge (containing up to 2.5-5.0 × 10(6) cells/mL) were elevated 4-8 h post MDP and resolved to near pre-treatment levels by 24 h. Tear GGT activity and protein levels were higher in MDP-treated and mock-treated contralateral eyes than in eyes of untreated adult rabbits (p's < 0.001). Elevated tear GGT activity was associated with histopathology and increased vascular and epithelial permeability to serum protein, GGT-positive epithelia cells, macrophages and heterophils. Repeat MDP applications induced recurrent

  19. Efficacy of Compound Kushen Injection in Combination with Induction Chemotherapy for Treating Adult Patients Newly Diagnosed with Acute Leukemia

    PubMed Central

    Tu, Honglei; Lei, Bo; Meng, Shan; Liu, Hailing; Wei, Yongchang; He, Aili; Zhang, Wanggang

    2016-01-01

    We assessed the clinical effectiveness and safety of CKI (compound Kushen injection) plus standard induction chemotherapy for treating adult acute leukemia (AL). We randomly assigned 332 patients with newly diagnosed AL to control (n = 165, receiving DA (daunorubicin and cytarabine) or hyper-CVAD (fractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone)) or treatment (n = 167, receiving CKI and DA or hyper-CVAD) groups. Posttreatment, treatment group CD3+, CD4+, CD4+/CD8+, natural killer (NK) cell, and immunoglobulin (IgG, IgA, and IgM) levels were significantly higher than those of the control group (p < 0.05), and CD8+ levels were lower in the treatment group than in the control group (p < 0.05). Treatment group interleukin- (IL-) 4 and IL-10 levels were significantly higher compared to the control posttreatment (both p < 0.05) as were complete remission, overall response, and quality of life (QoL) improvement rates (p < 0.05). The control group had more incidences of grade 3/4 hematologic and nonhematologic toxicity (p < 0.05). Responses to induction chemotherapy, QoL improvement, and adverse events incidence between control group patients with acute myeloid leukemia and acute lymphocytic leukemia were not significantly different. CKI plus standard induction chemotherapy is effective and safe for treating AL, possibly by increasing immunologic function. PMID:27738441

  20. The burden of acute traumatic spinal cord injury among adults in the united states: an update.

    PubMed

    Selvarajah, Shalini; Hammond, Edward R; Haider, Adil H; Abularrage, Christopher J; Becker, Daniel; Dhiman, Nitasha; Hyder, Omar; Gupta, Deepak; Black, James H; Schneider, Eric B

    2014-02-01

    The current incidence estimate of 40 traumatic spinal cord injuries (TSCI) per million population/year in the United States (U.S.) is based on data from the 1990s. We sought to update the incidence and epidemiology of TSCI in U.S adults by using the Nationwide Emergency Department Sample (NEDS), the largest all-payer emergency department (ED) database in the United States. Adult ED visits between 2007 and 2009 with a principal diagnosis of TSCI were identified using International Classification of Diseases (ICD)-9 codes (806.0-806.9 and 952.0-952.9). We describe TSCI cumulative incidence, mortality, discharge disposition, and hospital charges weighted to the U.S. population. The estimated 3-year cumulative incidence of TSCI was 56.4 per million adults. Cumulative incidence of TSCI in older adults increased from 79.4 per million older adults in 2007 to 87.7 by the end of 2009, but remained steady among younger adults. Overall, falls were the leading cause of TSCI (41.5%). ED charges rose by 20% over the study period, and death occurred in 5.7% of patients. Compared with younger adults, older adults demonstrated higher adjusted odds of mortality in the ED (adjusted odds ratio [AOR]=4.4; 95% confidence interval [CI]: 1.1-16.6), mortality during hospitalization (AOR=5.9; 95% CI: 4.7-7.4), and being discharged to chronic care (AOR=3.7; 95% CI: 3.0-4.5). The incidence of TSCI is higher than previously reported with a progressive increase among older adults who also experience worse outcomes compared with younger adults. ED-related TSCI charges are also increasing. These updated national estimates support the development of customized prevention strategies based on age-specific risk factors.

  1. Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France

    PubMed Central

    Labopin, Myriam; Ruggeri, Annalisa; Gorin, Norbert Claude; Gluckman, Eliane; Blaise, Didier; Mannone, Lionel; Milpied, Noel; Yakoub-Agha, Ibrahim; Deconinck, Eric; Michallet, Mauricette; Fegueux, Nathalie; Socié, Gerard; Nguyen, Stephanie; Cahn, Jean Yves; de Revel, Thierry; Garnier, Federico; Faucher, Catherine; Taright, Namik; Kenzey, Chantal; Volt, Fernanda; Bertrand, Dominique; Mohty, Mohamad; Rocha, Vanderson

    2014-01-01

    Double cord blood transplantation extends the use of cord blood to adults for whom a single unit is not available, but the procedure is limited by its cost. To evaluate outcomes and cost-effectiveness of double compared to single cord blood transplantation, we analyzed 134 transplants in adults with acute leukemia in first remission. Transplants were performed in France with reduced intensity or myeloablative conditioning regimens. Costs were estimated from donor search to 1 year after transplantation. A Markov decision analysis model was used to calculate quality-adjusted life-years and cost-effectiveness ratio within 4 years. The overall survival at 2 years after single and double cord blood transplants was 42% versus 62%, respectively (P=0.03), while the leukemia-free-survival was 33% versus 53%, respectively (P=0.03). The relapse rate was 21% after double transplants and 42% after a single transplant (P=0.006). No difference was observed for non-relapse mortality or chronic graft-versus-host-disease. The estimated costs up to 1 year after reduced intensity conditioning for single and double cord blood transplantation were € 165,253 and €191,827, respectively. The corresponding costs after myeloablative conditioning were € 192,566 and € 213,050, respectively. Compared to single transplants, double cord blood transplantation was associated with supplementary costs of € 21,302 and € 32,420 up to 4 years, but with increases in quality-adjusted life-years of 0.616 and 0.484, respectively, and incremental cost-effectiveness ratios of € 34,581 and €66,983 in the myeloablative and reduced intensity conditioning settings, respectively. Our results showed that for adults with acute leukemia in first complete remission in France, double cord transplantation is more cost-effective than single cord blood transplantation, with better outcomes, including quality-adjusted life-years. PMID:24143000

  2. Allogeneic hematopoietic stem cell transplantation in adult acute lymphoblastic leukemia: potential benefit of medium-dose etoposide conditioning.

    PubMed

    Imamura, Masahiro; Shigematsu, Akio

    2015-01-01

    The outcomes of adult acute lymphoblastic leukemia (ALL) patients with chemotherapy or autologous hematopoietic stem cell transplantation (HSCT) are unsatisfactory. Therefore, allogeneic (allo) HSCT has been applied to those patients in first complete remission (CR1), and has shown a long-term survival rate of approximately 50 %. In terms of myeloablative conditioning (MAC) regimen, higher dose of cyclophosphamide (CY) and total body irradiation (TBI) (the standard CY + TBI) has been generally applied to allo HSCT. Other MAC regimens such as busulfan-based or etoposide-based regimens have also been used. Among those, medium-dose etoposide (ETP) in addition to the standard CY + TBI conditioning regimen appears to be promising for allo HSCT in adult ALL when transplanted in ALL patients aged under 50 years in CR1 and also in CR2, showing an excellent outcome without increasing relapse or transplant-related mortality (TRM) rates. By contrast, reduced-intensity conditioning (RIC) regimens have also been applied to adult ALL patients and favorable outcomes have been obtained; however, relapse and TRM rates remain high. Therefore, an allo HSCT conditioning regimen which deserves further study for adult ALL patients aged under 50 years in CR1 and CR2 appears to be medium-dose ETP + CY + TBI and RIC is suitable for patients aged over 50 years or for younger patients with comorbid conditions. On the contrary, new therapeutic strategies for adult ALL patients are increasingly utilized with better outcomes; namely, various tyrosine kinase inhibitors for Philadelphia chromosome (Ph)-positive ALL, human leukocyte antigen-haploidentical HSCT, and pediatric-inspired regimens for Ph-negative ALL. Therefore, the optimal treatment modality should be selected considering patient's age, Ph-positivity, donor availability, risk classification, efficacy, and safety. PMID:26322249

  3. Impetigo presenting as an acute necrotizing swelling of the lower lip in an adult patient.

    PubMed

    Ghafoor, Mohammed; Halsnad, Moorthy; Fowell, Christopher; Millar, Brian G

    2012-06-01

    The authors present an unusual case of an acute swelling of the lower lip and septicemia in a 35-year-old, recent immigrant male arriving from India. The patient presented in our emergency department with a 48-hour history of a worsening, painful swelling of the lower lip. On presentation, he was pyrexial and the lip was found to be acutely inflamed with honey-colored crusting, pustular lesions, and induration . A diagnosis of impetigo leading to necrosis of the lip was established, a rare phenomenon potentially resulting in significant tissue destruction. Appropriate medical management achieved a good outcome and prevented disabling tissue loss of the orofacial region.

  4. Novel biomarkers for early diagnosis of acute kidney injury after cardiac surgery in adults

    PubMed Central

    Kališnik, Jurij Matija

    2016-01-01

    Acute kidney injury after cardiac surgery with cardiopulmonary bypass is a common and serious complication and it is associated with increased morbidity and mortality. Diagnosis of acute kidney injury is based on the serum creatinine levels which rise several hours to days after the initial injury. Thus, novel biomarkers that will enable faster diagnosis are needed in clinical practice. There are numerous urine and serum proteins that indicate kidney injury and are under extensive research. Despite promising basic research results and assembled data, which indicate superiority of some biomarkers to creatinine, we are still awaiting clinical application. PMID:27212976

  5. Impetigo presenting as an acute necrotizing swelling of the lower lip in an adult patient.

    PubMed

    Ghafoor, Mohammed; Halsnad, Moorthy; Fowell, Christopher; Millar, Brian G

    2012-06-01

    The authors present an unusual case of an acute swelling of the lower lip and septicemia in a 35-year-old, recent immigrant male arriving from India. The patient presented in our emergency department with a 48-hour history of a worsening, painful swelling of the lower lip. On presentation, he was pyrexial and the lip was found to be acutely inflamed with honey-colored crusting, pustular lesions, and induration . A diagnosis of impetigo leading to necrosis of the lip was established, a rare phenomenon potentially resulting in significant tissue destruction. Appropriate medical management achieved a good outcome and prevented disabling tissue loss of the orofacial region. PMID:22677026

  6. Acute and Chronic Electroconvulsive Seizures (ECS) Differentially Regulate the Expression of Epigenetic Machinery in the Adult Rat Hippocampus

    PubMed Central

    Pusalkar, Madhavi; Ghosh, Shreya; Jaggar, Minal; Husain, Basma Fatima Anwar; Galande, Sanjeev

    2016-01-01

    Background: Electroconvulsive seizure treatment is a fast-acting antidepressant therapy that evokes rapid transcriptional, neurogenic, and behavioral changes. Epigenetic mechanisms contribute to altered gene regulation, which underlies the neurogenic and behavioral effects of electroconvulsive seizure. We hypothesized that electroconvulsive seizure may modulate the expression of epigenetic machinery, thus establishing potential alterations in the epigenetic landscape. Methods: We examined the influence of acute and chronic electroconvulsive seizure on the gene expression of histone modifiers, namely histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone (lysine) demethylases as well as DNA modifying enzymes, including DNA methyltransferases, DNA demethylases, and methyl-CpG-binding proteins in the hippocampi of adult male Wistar rats using quantitative real time-PCR analysis. Further, we examined the influence of acute and chronic electroconvulsive seizure on global and residue-specific histone acetylation and methylation levels within the hippocampus, a brain region implicated in the cellular and behavioral effects of electroconvulsive seizure. Results: Acute and chronic electroconvulsive seizure induced a primarily unique, and in certain cases bidirectional, regulation of histone and DNA modifiers, and methyl-CpG-binding proteins, with an overlapping pattern of gene regulation restricted to Sirt4, Mll3, Jmjd3, Gadd45b, Tet2, and Tet3. Global histone acetylation and methylation levels were predominantly unchanged, with the exception of a significant decline in H3K9 acetylation in the hippocampus following chronic electroconvulsive seizure. Conclusions: Electroconvulsive seizure treatment evokes the transcriptional regulation of several histone and DNA modifiers, and methyl-CpG-binding proteins within the hippocampus, with a predominantly distinct pattern of regulation induced by acute and chronic electroconvulsive seizure. PMID

  7. Comparison of outcomes after unrelated cord blood and unmanipulated haploidentical stem cell transplantation in adults with acute leukemia.

    PubMed

    Ruggeri, A; Labopin, M; Sanz, G; Piemontese, S; Arcese, W; Bacigalupo, A; Blaise, D; Bosi, A; Huang, H; Karakasis, D; Koc, Y; Michallet, M; Picardi, A; Sanz, J; Santarone, S; Sengelov, H; Sierra, J; Vincent, L; Volt, F; Nagler, A; Gluckman, E; Ciceri, F; Rocha, V; Mohty, M

    2015-09-01

    Outcomes after unmanipulated haploidentical stem cell transplantation (Haplo) and after unrelated cord blood transplantation (UCBT) are encouraging and have become alternative options to treat patients with high-risk acute leukemia without human leukocyte antigen (HLA) matched donor. We compared outcomes after UCBT and Haplo in adults with de novo acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Median follow-up was 24 months. Analysis was performed separately for patients with AML, n=918 (Haplo=360, UCBT=558) and ALL, n=528 (Haplo=158 and UCBT=370). UCBT was associated with delayed engraftment and higher graft failure in both AML and ALL recipients. In multivariate analysis, UCBT was associated with lower incidence of chronic graft-vs-host disease both in the AML group (hazard ratio (HR)=0.63, P=0.008) and in the ALL group (HR=0.58, P=0.01). Not statistically significant differences were observed between Haplo and UCBT for relapse incidence (HR=0.95, P=0.76 for AML and HR=0.82, P=0.31 for ALL), non-relapse mortality (HR=1.16, P=0.47 for AML and HR=1.23, P=0.23 for ALL) and leukemia-free survival (HR 0.78, P=0.78 for AML and HR=1.00, P=0.84 for ALL). There were no statistically differences on main outcomes after unmanipulated Haplo and UCBT, and both approaches are valid for acute leukemia patients lacking a HLA matched donor. Both strategies expand the donor pool for patients in need.

  8. Eltrombopag Olamine in Improving Platelet Recovery in Older Patients With Acute Myeloid Leukemia Undergoing Chemotherapy

    ClinicalTrials.gov

    2016-02-17

    Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid 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(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Secondary Acute Myeloid Leukemia

  9. Acute and fractionated exposure to high-LET (56)Fe HZE-particle radiation both result in similar long-term deficits in adult hippocampal neurogenesis.

    PubMed

    Rivera, Phillip D; Shih, Hung-Ying; Leblanc, Junie A; Cole, Mara G; Amaral, Wellington Z; Mukherjee, Shibani; Zhang, Shichuan; Lucero, Melanie J; Decarolis, Nathan A; Chen, Benjamin P C; Eisch, Amelia J

    2013-12-01

    Astronauts on multi-year interplanetary missions will be exposed to a low, chronic dose of high-energy, high-charge particles. Studies in rodents show acute, nonfractionated exposure to these particles causes brain changes such as fewer adult-generated hippocampal neurons and stem cells that may be detrimental to cognition and mood regulation and thus compromise mission success. However, the influence of a low, chronic dose of these particles on neurogenesis and stem cells is unknown. To examine the influence of galactic cosmic radiation on neurogenesis, adult-generated stem and progenitor cells in Nestin-CreER(T2)/R26R-YFP transgenic mice were inducibly labeled to allow fate tracking. Mice were then sham exposed or given one acute 100 cGy (56)Fe-particle exposure or five fractionated 20 cGy (56)Fe-particle exposures. Adult-generated hippocampal neurons and stem cells were quantified 24 h or 3 months later. Both acute and fractionated exposure decreased the amount of proliferating cells and immature neurons relative to sham exposure. Unexpectedly, neither acute nor fractionated exposure decreased the number of adult neural stem cells relative to sham expsoure. Our findings show that single and fractionated exposures of (56)Fe-particle irradiation are similarly detrimental to adult-generated neurons. Implications for future missions and ground-based studies in space radiation are discussed. PMID:24320054

  10. Acute and Fractionated Exposure to High-LET 56Fe HZE-Particle Radiation Both Result in Similar Long-Term Deficits in Adult Hippocampal Neurogenesis

    PubMed Central

    Rivera, Phillip D.; Shih, Hung-Ying; LeBlanc, Junie A.; Cole, Mara G.; Amaral, Wellington Z.; Mukherjee, Shibani; Zhang, Shichuan; Lucero, Melanie J.; DeCarolis, Nathan A.; Chen, Benjamin P. C.; Eisch, Amelia J.

    2014-01-01

    Astronauts on multi-year interplanetary missions will be exposed to a low, chronic dose of high-energy, high-charge particles. Studies in rodents show acute, nonfractionated exposure to these particles causes brain changes such as fewer adult-generated hippocampal neurons and stem cells that may be detrimental to cognition and mood regulation and thus compromise mission success. However, the influence of a low, chronic dose of these particles on neurogenesis and stem cells is unknown. To examine the influence of galactic cosmic radiation on neurogenesis, adult-generated stem and progenitor cells in Nestin-CreERT2/R26R-YFP transgenic mice were inducibly labeled to allow fate tracking. Mice were then sham exposed or given one acute 100 cGy 56Fe-particle exposure or five fractionated 20 cGy 56Fe-particle exposures. Adult-generated hippocampal neurons and stem cells were quantified 24 h or 3 months later. Both acute and fractionated exposure decreased the amount of proliferating cells and immature neurons relative to sham exposure. Unexpectedly, neither acute nor fractionated exposure decreased the number of adult neural stem cells relative to sham expsoure. Our findings show that single and fractionated exposures of 56Fe-particle irradiation are similarly detrimental to adult-generated neurons. Implications for future missions and ground-based studies in space radiation are discussed. PMID:24320054

  11. Augmented hyper-CVAD based on dose-intensified vincristine, dexamethasone, and asparaginase in adult acute lymphoblastic leukemia salvage therapy.

    PubMed

    Faderl, Stefan; Thomas, Deborah Ann; O'Brien, Susan; Ravandi, Farhad; Garcia-Manero, Guillermo; Borthakur, Gautam; Ferrajoli, Alessandra; Verstovsek, Srdan; Ayoubi, Mohamed; Rytting, Michael; Feliu, Jennie; Kantarjian, Hagop M

    2011-02-01

    The prognosis of adult patients with relapsed acute lymphoblastic leukemia (ALL) remains poor. Recent studies in adolescents and young adults reported better outcomes when therapy was intensified. Based on hyper-CVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) as a backbone, we designed an augmented version with intensified doses of vincristine, dexamethasone, and asparaginase (L-asparaginase in the first 62 patients and pegaspargase in the remainder) starting from course 1. Ninety patients have been enrolled, with a median age of 34 years (range, 14-70 years). Most patients (78%) had pre-B ALL and were in first salvage (76%), with a first remission duration of 12.6 months (range, 1-78 months). Ten patients had primary refractory disease. Of 88 evaluable patients, 41 (47%) achieved complete remission (CR), with a median time to CR of 29 days (range, 18-80 days). Eight patients (9%) died within the first 30 days. Median CR duration, progression-free survival, and overall survival were 5, 6.2, and 6 months, respectively. Median overall survival of CR patients was 10.2 months (range, 1.4-69.5+ months). Twenty-eight patients (32%) proceeded to stem cell transplantation. Myelosuppression-associated complications were frequent. Pegaspargase was equally effective and easier to administer than L-asparaginase. Augmented hyper-CVAD may be suitable to be studied in younger adults with untreated ALL. PMID:21454191

  12. Acute social defeat stress increases the conditioned rewarding effects of cocaine in adult but not in adolescent mice.

    PubMed

    Montagud-Romero, S; Aguilar, M A; Maldonado, C; Manzanedo, C; Miñarro, J; Rodríguez-Arias, M

    2015-08-01

    Stressful experiences modify activity in areas of the brain involved in the rewarding effects of psychostimulants. In the present study we evaluated the influence of acute social defeat (ASD) on the conditioned rewarding effects of cocaine in adolescent (PND 29-32) and adult (PND 50-53) male mice in the conditioned place preference (CPP) paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1mg/kg or 25mg/kg of cocaine. The effects of social defeat on corticosterone levels were also evaluated. Adult mice exposed to ASD showed an increase in the conditioned reinforcing effects of cocaine. Only these mice developed cocaine-induced CPP with the subthreshold dose of cocaine, and they needed a higher number of extinction sessions for the 25mg/kg cocaine-induced CPP to be extinguished. In adolescent mice, on the other hand, ASD reduced the conditioned reinforcing effects of cocaine, since CPP was not produced with the lower dose of cocaine and was extinguished faster when they were conditioned with 25mg/kg. Adult mice exposed to social defeat displayed higher levels of corticosterone than their controls and adolescent mice. Our results confirm that the effect of social defeat stress on the acquisition and reinstatement of the CPP induced by cocaine varies depending on the age at which this stress is experienced.

  13. Acute Effect of Manganese on Hypothalamic Luteinizing Hormone Releasing Hormone Secretion in Adult Male Rats: Involvement of Specific Neurotransmitter Systems

    PubMed Central

    Prestifilippo, Juan Pablo; Fernández-Solari, Javier; De Laurentiis, Andrea; Mohn, Claudia Ester; de la Cal, Carolina; Reynoso, Roxana; Dees, W. Les; Rettori, Valeria

    2008-01-01

    Manganese chloride (MnCl2) is capable of stimulating luteinizing hormone releasing hormone (LHRH) secretion in adult male Sprague-Dawley rats through the activation of the hypothalamic nitric oxide/cyclic guanosine monophosphate (cGMP)/protein kinase G pathway. The present study aimed to determine the involvement of specific neurotransmitters involved in this action. Our results indicate that dopamine, but not glutamic acid and prostaglandinds, mediates the MnCl2 stimulated secretion of LHRH from medial basal hypothalami in vitro, as well as increases the activity of nitric oxide synthase. Furthermore, a biphasic response was observed in that gamma aminobutyric acid (GABA) release was also increased, which acts to attenuate the MnCl2 action to stimulate LHRH secretion. Although it is clear that manganese (Mn+2) can acutely induce LHRH secretion in adult males, we suggest that the additional action of MnCl2 to release GABA, a LHRH inhibitor, may ultimately contribute to suppressed reproductive function observed in adult animals following exposure to high chromic levels of Mn+2. PMID:18603625

  14. Acute pulmonary function response to ozone in young adults as a function of body mass index

    EPA Science Inventory

    Recent studies have shown enhanced responsiveness to ozone in obese mice. Adiposity has not been examined as a possible modulator of ozone response in humans. We therefore examined the relationship between body mass index and the acute spirometric response to ozone (O(3)) exposur...

  15. Acute Exercise Improves Prefrontal Cortex but not Hippocampal Function in Healthy Adults.

    PubMed

    Basso, Julia C; Shang, Andrea; Elman, Meredith; Karmouta, Ryan; Suzuki, Wendy A

    2015-11-01

    The effects of acute aerobic exercise on cognitive functions in humans have been the subject of much investigation; however, these studies are limited by several factors, including a lack of randomized controlled designs, focus on only a single cognitive function, and testing during or shortly after exercise. Using a randomized controlled design, the present study asked how a single bout of aerobic exercise affects a range of frontal- and medial temporal lobe-dependent cognitive functions and how long these effects last. We randomly assigned 85 subjects to either a vigorous intensity acute aerobic exercise group or a video watching control group. All subjects completed a battery of cognitive tasks both before and 30, 60, 90, or 120 min after the intervention. This battery included the Hopkins Verbal Learning Test-Revised, the Modified Benton Visual Retention Test, the Stroop Color and Word Test, the Symbol Digit Modalities Test, the Digit Span Test, the Trail Making Test, and the Controlled Oral Word Association Test. Based on these measures, composite scores were formed to independently assess prefrontal cortex- and hippocampal-dependent cognition. A three-way mixed Analysis of Variance was used to determine whether differences existed between groups in the change in cognitive function from pre- to post-intervention testing. Acute exercise improved prefrontal cortex- but not hippocampal-dependent functioning, with no differences found between delay groups. Vigorous acute aerobic exercise has beneficial effects on prefrontal cortex-dependent cognition and these effects can last for up to 2 hr after exercise.

  16. The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies.

    PubMed

    Marmura, Michael J; Silberstein, Stephen D; Schwedt, Todd J

    2015-01-01

    The study aims to provide an updated assessment of the evidence for individual pharmacological therapies for acute migraine treatment. Pharmacological therapy is frequently required for acutely treating migraine attacks. The American Academy of Neurology Guidelines published in 2000 summarized the available evidence relating to the efficacy of acute migraine medications. This review, conducted by the members of the Guidelines Section of the American Headache Society, is an updated assessment of evidence for the migraine acute medications. A standardized literature search was performed to identify articles related to acute migraine treatment that were published between 1998 and 2013. The American Academy of Neurology Guidelines Development procedures were followed. Two authors reviewed each abstract resulting from the search and determined whether the full manuscript qualified for review. Two reviewers studied each qualifying full manuscript for its level of evidence. Level A evidence requires at least 2 Class I studies, and Level B evidence requires 1 Class I or 2 Class II studies. The specific medications - triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan [oral, nasal spray, injectable, transcutaneous patch], zolmitriptan [oral and nasal spray]) and dihydroergotamine (nasal spray, inhaler) are effective (Level A). Ergotamine and other forms of dihydroergotamine are probably effective (Level B). Effective nonspecific medications include acetaminophen, nonsteroidal anti-inflammatory drugs (aspirin, diclofenac, ibuprofen, and naproxen), opioids (butorphanol nasal spray), sumatriptan/naproxen, and the combination of acetaminophen/aspirin/caffeine (Level A). Ketoprofen, intravenous and intramuscular ketorolac, flurbiprofen, intravenous magnesium (in migraine with aura), and the combination of isometheptene compounds, codeine/acetaminophen and tramadol/acetaminophen are probably effective (Level B). The antiemetics prochlorperazine

  17. Dasatinib, Cytarabine, and Idarubicin in Treating Patients With High-Risk Acute Myeloid Leukemia

    ClinicalTrials.gov

    2016-04-08

    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); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

  18. Effect of neonatal handling on adult rat spatial learning and memory following acute stress.

    PubMed

    Stamatakis, A; Pondiki, S; Kitraki, E; Diamantopoulou, A; Panagiotaropoulos, T; Raftogianni, A; Stylianopoulou, F

    2008-03-01

    Brief neonatal handling permanently alters hypothalamic-pituitary-adrenal axis function resulting in increased ability to cope with stress. Since stress is known to affect cognitive abilities, in the present study we investigated the effect of brief (15 min) handling on learning and memory in the Morris water maze, following exposure to an acute restraint stress either before training or recall. Exposure of non-handled rats to the acute stress prior to training resulted in quicker learning of the task, than in the absence of the stressor. When acute stress preceded acquisition, male handled rats showed an overall better learning performance, and both sexes of handled animals were less impaired in the subsequent memory trial, compared to the respective non-handled. In addition, the number of neurons immunoreactive for GR was higher in all areas of Ammon's horn of the handled rats during the recall. In contrast, the number of neurons immunoreactive for MR was higher in the CA1 and CA2 areas of the non-handled males. When the acute restraint stress was applied prior to the memory test, neonatal handling was not effective in preventing mnemonic impairment, as all animal groups showed a similar deficit in recall. In this case, no difference between handled and non-handled rats was observed in the number of GR positive neurons in the CA2 and CA3 hippocampal areas during the memory test. These results indicate that early experience interacts with sex and acute stress exposure in adulthood to affect performance in the water maze. Hippocampal corticosterone receptors may play a role in determining the final outcome.

  19. Acute stress differentially affects spatial configuration learning in high and low cortisol-responding healthy adults

    PubMed Central

    Meyer, Thomas; Smeets, Tom; Giesbrecht, Timo; Quaedflieg, Conny W. E. M.; Merckelbach, Harald

    2013-01-01

    Background Stress and stress hormones modulate memory formation in various ways that are relevant to our understanding of stress-related psychopathology, such as posttraumatic stress disorder (PTSD). Particular relevance is attributed to efficient memory formation sustained by the hippocampus and parahippocampus. This process is thought to reduce the occurrence of intrusions and flashbacks following trauma, but may be negatively affected by acute stress. Moreover, recent evidence suggests that the efficiency of visuo-spatial processing and learning based on the hippocampal area is related to PTSD symptoms. Objective The current study investigated the effect of acute stress on spatial configuration learning using a spatial contextual cueing task (SCCT) known to heavily rely on structures in the parahippocampus. Method Acute stress was induced by subjecting participants (N = 34) to the Maastricht Acute Stress Test (MAST). Following a counterbalanced within-subject approach, the effects of stress and the ensuing hormonal (i.e., cortisol) activity on subsequent SCCT performance were compared to SCCT performance following a no-stress control condition. Results Acute stress did not impact SCCT learning overall, but opposing effects emerged for high versus low cortisol responders to the MAST. Learning scores following stress were reduced in low cortisol responders, while high cortisol-responding participants showed improved learning. Conclusions The effects of stress on spatial configuration learning were moderated by the magnitude of endogenous cortisol secretion. These findings suggest a possible mechanism by which cortisol responses serve an adaptive function during stress and trauma, and this may prove to be a promising route for future research in this area. PMID:2367176