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1.
Increased oxidative stress in the mitochondria isolated from lymphocytes of bipolar disorder patients during depressive episodes.
Valvassori, SS, Bavaresco, DV, Feier, G, Cechinel-Recco, K, Steckert, AV, Varela, RB, Borges, C, Carvalho-Silva, M, Gomes, LM, Streck, EL, et al
Psychiatry research. 2018;:192-201
Abstract
The present study aims to investigate the oxidative stress parameters in isolated mitochondria, as well as looking at mitochondrial complex activity in patients with Bipolar Disorder (BD) during depressive or euthymic episodes. This study evaluated the levels of mitochondrial complex (I, II, II-III and IV) activity in lymphocytes from BD patients. We evaluated the following oxidative stress parameters: superoxide, thiobarbituric acid reactive species (TBARS) and carbonyl levels in submitochondrial particles of lymphocytes from bipolar patients. 51 bipolar patients were recruited into this study: 34 in the euthymic phase, and 17 in the depressive phase. Our results indicated that the depressive phase could increase the levels of mitochondrial superoxide, carbonyl and TBARS, and superoxide dismutase, and could decrease the levels of mitochondrial complex II activity in the lymphocytes of bipolar patients. It was also observed that there was a negative correlation between the Hamilton Depression Rating Scale (HDRS) and complex II activity in the lymphocytes of depressive bipolar patients. In addition, there was a positive correlation between HDRS and superoxide, superoxide dismutase, TBARS and carbonyl. Additionally, there was a negative correlation between complex II activity and oxidative stress parameters. In conclusion, our results suggest that mitochondrial oxidative stress and mitochondrial complex II dysfunction play important roles in the depressive phase of BD.
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2.
The sorafenib anti-relapse effect after alloHSCT is associated with heightened alloreactivity and accumulation of CD8+PD-1+ (CD279+) lymphocytes in marrow.
Lange, A, Jaskula, E, Lange, J, Dworacki, G, Nowak, D, Simiczyjew, A, Mordak-Domagala, M, Sedzimirska, M
PloS one. 2018;(1):e0190525
Abstract
We studied three FLT3 ITD acute myeloid leukemia (AML) patients who relapsed after allogeneic haematopoietic stem cell transplantation (alloHSCT) and received multikinase inhibitor (MKI) sorafenib as part of salvage therapy. MKI was given to block the effect of FLT3 ITD mutation which powers proliferation of blast cells. However, the known facts that sorafenib is more effective in patents post alloHSCT suggested that this MKI can augment the immune system surveillance on leukaemia. In the present study, we investigated in depth the effect of sorafenib on the alloreactivity seen post-transplant including that on leukaemia. The patients (i) responded to the treatment with cessation of blasts which lasted 1, 17 and 42+ months, (ii) developed skin lesions with CD3+ cell invasion of the epidermis, (iii) had marrow infiltrated with CD8+ lymphocytes which co-expressed PD-1 (programmed cell death protein 1 receptor, CD279) in higher proportions than those in the blood (163±32 x103 cells/μl vs 38±8 x103 cells/μl, p<0.001). The Lymphoprep fraction of marrow cells investigated for the expression of genes involved in lymphocyte activation showed in the patients with long lasting complete remission (CR) a similar pattern characterized by (i) a low expression of nitric oxide synthase 2 (NOS2) and colony stimulating factor 2 (CSF2) as well as that of angiopoietin-like 4 (ANGPTL4) (supporting the immune response and anti-angiogenic) genes, and (ii) higher expression of fibroblast growth factor 1 (FGF1) and collagen type IV alpha 3 chain (COL4A3) as well as toll like receptor 9 (TLR9) and interleukin-12 (IL-12) (pro-inflammatory expression profile) genes as compared with the normal individual. The positive effect in one patient hardly justified the presence of unwanted effects (progressive chronic graft-versus-host disease (cGvHD) and avascular necrosis of the femur), which were in contrast negligible in the other patient. The anti-leukemic and unwanted effects of sorafenib do not rely on each other.
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3.
Neutrophil-lymphocyte ratio, gamma-glutamyl transpeptidase, lipase, high-density lipoprotein as a panel of factors to predict acute pancreatitis in pregnancy.
Zhang, L, Wang, Y, Han, J, Shen, H, Zhao, M, Cai, S
Medicine. 2018;(26):e11189
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Abstract
Acute pancreatitis in pregnancy (APIP) is a rare but dangerous complication. APIP has common symptoms with acute abdomen. Assessment of an acute abdomen is more complicated during pregnancy because the gravid uterus could mask most of symptomatic signs. It has been a challenge to diagnose APIP by physical examination or diagnostic imaging. Case studies on APIP are also limited for analysis on the risk factors associated with the disease. This retrospective study evaluated a series of risk factors from a relatively substantial number of APIP cases to determine early predictors or prognosis markers for APIP.Fifty-nine APIP patients together with 179 random normal pregnant women in Shengjing Affiliated Hospital of China Medical University were included for this retrospective study. Medical parameters of blood test in biochemistry and hematology were compared between 2 groups using t test. Multivariate logistic regression analysis was performed to investigate the relationship between various factors and APIP using Statistical Applied Software (SAS student version).Compared with normal pregnant women, APIP patients have elevated values in alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, creatinine, C-reactive protein, direct bilirubin, fibrin degradation products, gamma-glutamyl transpeptidase (GGT), glucose, lipase, pH and decreased values in albumin, fibrinogen, high-density lipoprotein (HDL), hemoglobin, low-density lipoprotein cholesterol (LDL-D), and total proteins from their blood tests. In addition, APIP patients have decreased numbers in red cells but increased numbers in white blood cells and increased ratio of neutrophil/lymphocyte (N/L). Among these factors, N/LR, GGT, lipase, and HDL are significantly associated with APIP. This study suggests that the combination of those factors serve as a panel of indicators for early-onset prognosis of APIP.GGT, lipase, HDL, and N/LR can serve as a panel of factors to predict APIP. More case studies are important to further evaluate the predicting power of this panel factors in APIP.
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Peripheral Lymphocytes, Obesity, and Metabolic Syndrome in Young Adults: An Immunometabolism Study.
Rodríguez, CP, González, MC, Aguilar-Salinas, CA, Nájera-Medina, O
Metabolic syndrome and related disorders. 2018;(7):342-349
Abstract
BACKGROUND Obesity is characterized by a low-intensity chronic inflammatory process in which immune system cells interact in a complex network, which affects systemic metabolic processes. This raises interest in analyzing possible changes in the proportions of immune system cells in individuals with obesity with and without metabolic syndrome (MS), in relation to their body composition. METHODS Circulating cells were analyzed with flow cytometry in young adults: monocytes, granulocytes, lymphocytes (T, B, and natural killer [NK]), TCD4+CD62-, TCD8+CD28-, and naive and memory cells of TCD3+ and TCD4+. Body composition was obtained by bioelectrical impedance analysis and dual-energy X-ray absorptiometry, and metabolic parameters. RESULTS A total of 169 persons were evaluated: 20% presented normal body mass index (BMI); 49% was overweight, and 31% had obesity; 28% had MS. It was observed that with an increase in BMI and visceral adipose tissue increase (VATI), body composition and biochemical variables were negatively altered. With regard to cell subpopulations, total lymphocytes increased and granulocytes and NK lymphocytes decreased in patients with MS and VATI. Memory cells increased with BMI and VATI. In individuals with MS, monocytes, and NK lymphocytes comprised a negative association with VAT, fat mass, and skeletal muscle mass (SMM). In individuals with MS and VATI, a negative correlation was observed between monocytes and SMM. CONCLUSIONS Significant changes were detected in the subpopulations of lymphocytes, suggesting that weight gain, SMM, and VAT accumulation gave rise to immunological changes at the peripheral level, and the presence of increased memory cells could be related to low-intensity chronic inflammation.
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Cirrhotic patients with minimal hepatic encephalopathy have increased capacity to eliminate superoxide and peroxynitrite in lymphocytes, associated with cognitive impairment.
Giménez-Garzó, C, Urios, A, Agustí, A, Mangas-Losada, A, García-García, R, Escudero-García, D, Kosenko, E, Ordoño, JF, Tosca, J, Giner-Durán, R, et al
Free radical research. 2018;(1):118-133
Abstract
Patients with minimal hepatic encephalopathy (MHE) show increased oxidative stress in blood. We aimed to assess whether MHE patients show alterations in different types of blood cells in (a) basal reactive oxygen and nitrogen species levels; (b) capacity to metabolise these species. To assess the mechanisms involved in the altered capacity to metabolise these species we also analysed: (c) peroxynitrite formation and d) peroxynitrite reaction with biological molecules. Levels of reactive oxygen and nitrogen species were measured by flow cytometry in blood cell populations from cirrhotic patients with and without MHE and controls, under basal conditions and after adding generators of superoxide (plumbagin) or nitric oxide (NOR-1) to assess the capacity to eliminate them. Under basal conditions, MHE patients show reduced superoxide and peroxynitrite levels and increased nitric oxide (NO) and nitrotyrosine levels. In patients without MHE plumbagin strongly increases cellular superoxide, moderately peroxynitrite and reduces NO levels. In MHE patients, plumbagin increases slightly superoxide and strongly peroxynitrite levels and affects slightly NO levels. NOR-1 increases NO levels much less in patients with than without MHE. These data show that the mechanisms and the capacity to eliminate cellular superoxide, NO and peroxynitrite are enhanced in MHE patients. Superoxide elimination is enhanced through reaction with NO to form peroxynitrite which, in turn, is eliminated by enhanced reaction with biological molecules, which could contribute to cognitive impairment in MHE. The data show that basal free radical levels do not reflect the oxidative stress status in MHE.
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Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society.
Ehl, S, Astigarraga, I, von Bahr Greenwood, T, Hines, M, Horne, A, Ishii, E, Janka, G, Jordan, MB, La Rosée, P, Lehmberg, K, et al
The journal of allergy and clinical immunology. In practice. 2018;(5):1508-1517
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome requiring aggressive immunosuppressive therapy. Following 2 large international studies mainly targeting pediatric patients with familial disease and patients without underlying chronic or malignant disease, the HLH-94 protocol is recommended as the standard of care when using etoposide-based therapy by the Histiocyte Society. However, in clinical practice, etoposide-based therapy has been widely used beyond the study inclusion criteria, including older patients and patients with underlying diseases (secondary HLH). Many questions remain around these extended indications and published reports do not address several practical issues. To tackle these concerns, the HLH Steering Committee of the Histiocyte Society decided to issue guidance for use of the HLH-94 protocol. The group convened in a structured consensus finding process to define recommendations that are based largely on expert opinion backed up by available data from the literature. The recommendations address all main elements of HLH-94 including corticosteroids, cyclosporin, etoposide, intrathecal therapy, and hematopoietic stem cell transplantation (HSCT) and consider various forms of HLH and all age groups. Aspects covered include indications, applications, dosing, side effects, duration of therapy, salvage therapy, and HSCT. These recommendations aim to provide a framework to guide treatment decisions in this severe disease.
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Acute glutamine ingestion modulates lymphocytic responses to exhaustive exercise in the heat.
Zheng, C, Chen, XK, Zhou, Y
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2018;(3):213-220
Abstract
The purpose of this study was to determine if acute intake of glutamine modulates homeostatic, hematologic, immune, and inflammatory responses to exhaustive exercise in the heat. Thirteen healthy, untrained young men participated in this randomized, double-blind, placebo-controlled, crossover study. They served as their own control and completed 2 trials of treadmill exercise at 40% maximal oxygen uptake to exhaustion in a hot environment (temperature, 38.0 ± 1.0 °C; relative humidity, 60.0% ± 5.0%; oxygen, 20.8%) following placebo (PLA) and glutamine (GLN) consumption. Heart rate, gastrointestinal temperature, forehead temperature, the rating of perceived exertion, and body weight were measured. Blood samples were collected before and after exercise. After exhaustive exercise in the heat (PLA vs. GLN: 42.0 ± 9.5 vs. 39.6 ± 7.8 min, p > 0.05), significant changes in homeostatic, hematologic, and immune parameters (elevated natural killer (NK) cells and neutrophils, and reduced CD4+/CD8+ ratio and CD19+ lymphocytes) were found in the control group owing to the time effect (p < 0.05). Moreover, a condition × time interaction effect was observed for the absolute count of CD3+ (F = 4.26, p < 0.05) and CD3+CD8+ T lymphocytes (F = 4.27, p < 0.05), which were elevated following acute glutamine intervention. While a potential interaction effect was also observed for the absolute count of CD3+CD4+ T lymphocytes (F = 3.21, p = 0.08), no condition or interaction effects were found for any other outcome measures. The results of this study suggest that acute glutamine ingestion evokes CD3+ and CD3+CD8+ T lymphocytosis but does not modulate neutrophil and NK cell leukocytosis and immune disturbances after exhaustive exercise in the heat.
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8.
Altered microRNA expression profile in the peripheral lymphoid compartment of multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw.
Musolino, C, Oteri, G, Allegra, A, Mania, M, D'Ascola, A, Avenoso, A, Innao, V, Allegra, AG, Campo, S
Annals of hematology. 2018;(7):1259-1269
Abstract
Bisphosphonates are formidable inhibitors of osteoclast-mediated bone resorption employed for therapy of multiple myeloma (MM) subjects with osteolytic lesions. Osteonecrosis of the jaw (ONJ) is an uncommon drug-induced adverse event of these agents. MicroRNAs (miRNAs) are a group of small, noncoding RNAs nucleotides, which are essential post-transcriptional controllers of gene expression. They have a central role in the normal bone development. The goal of our study was to investigate 18 miRNAs, whose targets were previously validated and described in MM subjects without ONJ, in peripheral lymphocytes of MM subjects with bisphosphonate-induced ONJ. Utilizing reverse transcription quantitative polymerase chain reaction, we evaluated miRNAs in five healthy subjects and in five MM patients with ONJ. Our experimental data revealed that a diverse miRNA signature for ONJ subjects emerged with respect to control subjects. Using the filter for in silico analysis, among the 18 miRNAs, we recognized 14 dysregulated miRNAs. All these miRNAs were significantly over-expressed in patients vs controls (MIR-16-1, MIR-21, MIR-23A, MIR-28, MIR-101-1, MIR-124-1, MIR-129, MIR-139, MIR-145, MIR-149, MIR-202, MIR-221, MIR-424, MIR-520). Among them, six were strongly upregulated (fourfold upregulated and more). These miRNAs target numerous pathways and genes implicated in calcium ion binding, bone resorption, mineralization of bone matrix, and differentiation and maintenance of bone tissue. A modified microRNA expression profile after zoledronate therapy could participate to the onset of ONJ. Targeting these miRNAs could provide a new opportunity for the prevention or treatment of ONJ.
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Pre-Dialysis Neutrophil-Lymphocyte Ratio, a Novel and Strong Short-Term Predictor of All-Cause Mortality in Patients With Diabetic Nephropathy: Results From a Single-Center Study.
Sato, H, Takeuchi, Y, Matsuda, K, Kagaya, S, Saito, A, Fukami, H, Ojima, Y, Nagasawa, T
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2017;(4):370-377
Abstract
Neutrophil-lymphocyte ratio (NLR) is an inflammatory marker affecting the prognosis of end-stage renal disease (ESRD) patients. This study aimed to evaluate NLR levels predicting all-cause mortality in ESRD patients with diabetic nephropathy (DN), which have not been evaluated. We recruited 151 isolated DN patients who started hemodialysis between January 2009 and December 2014 at the Japanese Red Cross Ishinomaki Hospital. The primary outcomes were 1- and 3-year survival rates. The association between NLR and survival rate was evaluated using the Kaplan-Meier method and Cox proportional hazard regression analysis. Patients with an NLR ≥ 3.5 had a significantly higher mortality rate than did those with an NLR < 3.5 (log rank P = 0.02). The area under the curve (AUC) of 1-year survival for NLR was significantly larger than that for other commonly used nutritional and inflammatory variables. NLR was a more accurate predictor than other well-known markers.
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Assessment of DNA damage in blood lymphocytes of bakery workers by comet assay.
Kianmehr, M, Hajavi, J, Gazeri, J
Toxicology and industrial health. 2017;(9):726-735
Abstract
The comet assay is widely used in screening and identification of genotoxic effects of different substances on people in either their working or living environment. Exposure to fuel smoke leads to DNA damage and ultimately different types of cancer. Using a comet assay, the present study aimed to assess peripheral blood lymphocyte DNA damage in people working in bakeries using natural gas, kerosene, diesel, or firewood for fuel compared to those in the control group. The subjects of this study were 55 people in total who were divided into four experimental groups, each of which comprised of 11 members (based on the type of fuel used), and one control group comprised of 11 members. Using CometScore, the subjects' peripheral blood lymphocytes were examined for DNA damage. All bakers, that is, experimental subjects, showed significantly greater peripheral blood lymphocyte DNA damage compared to the individuals in the control group. There was greater peripheral blood lymphocyte DNA damage in bakers who had been using firewood for fuel compared to those using other types of fuel to such an extent that tail moments (µm) for firewood-burning bakers was 4.40 ± 1.98 versus 1.35 ± 0.84 for natural gas, 1.85 ± 1.33 for diesel, and 2.19 ± 2.20 for kerosene. The results indicated that burning firewood is the greatest inducer of peripheral blood lymphocytes DNA damage in bakers. Nonetheless, there was no significant difference in peripheral blood lymphocyte DNA damage among diesel and kerosene burning bakers.