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Cancers Nov 20195-Fluorouracil (5-FU) is an antimetabolite chemotherapy widely used for the treatment of various cancers. However, many cancer patients experience hematological side...
5-Fluorouracil (5-FU) is an antimetabolite chemotherapy widely used for the treatment of various cancers. However, many cancer patients experience hematological side effects following 5-FU treatment. Here, we investigated the protective effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a mitigator against 5-FU-induced hematologic toxicity, including neutropenia, monocytopenia, thrombocytopenia, and thrombocytosis, in Balb/c mice injected with 5-FU (100 mg/kg, i.p.). Administration of PLAG significantly and dose-dependently reduced the duration of neutropenia and improved the nadirs of absolute neutrophil counts (ANCs). Moreover, while the ANCs of all mice in the control fell to the severely neutropenic range, none of the mice in the PLAG 200 and 400 mg/kg-treated groups experienced severe neutropenia. Administration of PLAG significantly delayed the mean first day of monocytopenia and reduced the duration of monocytopenia. PLAG also effectively reduced extreme changes in platelet counts induced by 5-FU treatment, thus preventing 5-FU-induced thrombocytopenia and thrombocytosis. PLAG significantly decreased plasma levels of the chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, interleukin (IL)-6, and C-reactive protein (CRP), which were elevated consistently with the occurrence time of neutropenia, monocytopenia, and thrombocytopenia. When compared with olive oil and palmitic linoleic hydroxyl glycerol (PLH), only PLAG effectively mitigated 5-FU-induced hematological toxicity, indicating that it has a distinctive mechanism of action. In conclusion, PLAG may have therapeutic potential as a mitigator for 5-FU-induced neutropenia and other hematological disorders.
PubMed: 31752148
DOI: 10.3390/cancers11111811 -
PloS One 2019Elephant endotheliotropic herpesvirus-hemorrhagic disease (EEHV-HD) is the primary cause of acute, highly fatal, hemorrhagic diseases in young Asian elephants. Although...
Elephant endotheliotropic herpesvirus-hemorrhagic disease (EEHV-HD) is the primary cause of acute, highly fatal, hemorrhagic diseases in young Asian elephants. Although monocytopenia is frequently observed in EEHV-HD cases, the role monocytes play in EEHV-disease pathogenesis is unknown. This study seeks to explain the responses of monocytes/macrophages in the pathogenesis of EEHV-HD. Samples of blood, frozen tissues, and formalin-fixed, paraffin-embedded (FFPE) tissues from EEHV1A-HD, EEHV4-HD, co-infected EEHV1A and 4-HD, and EEHV-negative calves were analyzed. Peripheral blood mononuclear cells (PBMCs) from the persistent EEHV4-infected and EEHV-negative calves were also studied. The results showed increased infiltration of Iba-1-positive macrophages in the inflamed tissues of the internal organs of elephant calves with EEHV-HD. In addition, cellular apoptosis also increased in the tissues of elephants with EEHV-HD, especially in the PBMCs, compared to the EEHV-negative control. In the PBMCs of persistent EEHV4-infected elephants, cytokine mRNA expression was high, particularly up-regulation of TNF-α and IFN-γ. Moreover, viral particles were observed in the cytoplasm of the persistent EEHV4-infected elephant monocytes. Our study demonstrated for the first time that apoptosis of the PBMCs increased in cases of EEHV-HD. Furthermore, this study showed that monocytes may serve as a vehicle for viral dissemination during EEHV infection in Asian elephants.
Topics: Animals; Apoptosis; Cytokines; Elephants; Female; Gene Expression Regulation; Herpesviridae; Herpesviridae Infections; Macrophages; Male; Monocytes; RNA, Messenger
PubMed: 31491031
DOI: 10.1371/journal.pone.0222158 -
Open Forum Infectious Diseases Jul 2019Data regarding invasive pulmonary aspergillosis (IPA) following respiratory viral infections (RVIs) in patients with leukemia and/or hematopoietic stem cell...
BACKGROUND
Data regarding invasive pulmonary aspergillosis (IPA) following respiratory viral infections (RVIs) in patients with leukemia and/or hematopoietic stem cell transplantation (LHSCT) are limited.
METHODS
We conducted a retrospective case-control study of post-RVI IPA (2006-2016). Cases were patients who underwent LHSCT and had RVI due to respiratory syncytial virus (RSV), influenza virus (INF), or parainfluenza virus (PIV) followed by culture-documented IPA within 6 weeks. Controls had IPA only.
RESULTS
We identified 54 cases and 142 controls. Among cases, 29 (54%) had PIV infection, 14 (26%) had INF infection, and 11 (20%) had RSV infection. The median time to IPA after RVI was 7 days. A greater percentage of cases (37 [69%]) than controls (52 [37%]) underwent allogeneic HSCT ( < .0001). Cases were more likely to be nonneutropenic (33 [61%] vs 56 [39%]; = .009) and in hematologic remission (27 [50%] vs 39 [27%]; = .003) before IPA. Cases were more likely to have monocytopenia (45 [83%] vs 99 [70%]; = .05) and less likely to have severe neutropenia (21 [39%] vs 86 [61%]; = .007) at IPA diagnosis. Prior use of an -active triazole was more common in cases (27 of 28 [96%] vs 50 of 74 [68%]; = .0017). Median time to empirical antifungal therapy initiation was 2 days in both groups. Crude 42-day mortality rates did not differ between cases (22%) and controls (27%), but the 42-day mortality rate was higher among cases with IPA after RSV infection (45%) than among those with IPA following INF or PIV infection (13%; = .05).
CONCLUSIONS
IPA had comparable outcomes when it followed RVI in patients who underwent LHSCT, and post-RVI IPA occurred more frequently in patients with prior allogeneic HSCT and was associated with leukemia relapse and neutropenia.
PubMed: 31338382
DOI: 10.1093/ofid/ofz247 -
Journal of Clinical Immunology Aug 2019WHIM syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and... (Review)
Review
WHIM syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow; monocytopenia and lymphopenia, especially B lymphopenia, also commonly occur. WHIM syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and β-arrestin-dependent responses. Accordingly, CXCR4 antagonists have shown promise as mechanism-based treatments in phase 1 clinical trials. This review is based on analysis of all 105 published cases of WHIM syndrome and covers current concepts, recent advances, unresolved enigmas and controversies, and promising future research directions.
Topics: Adaptive Immunity; Alleles; Combined Modality Therapy; Diagnosis, Differential; Disease Management; Disease Susceptibility; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Immunity, Innate; Mutation; Phenotype; Precision Medicine; Primary Immunodeficiency Diseases; Warts
PubMed: 31313072
DOI: 10.1007/s10875-019-00665-w -
International Journal of Molecular... Jun 2019The PI3K/Akt pathway plays a crucial role in the survival, proliferation, and migration of macrophages, which may impact the development of atherosclerosis. Changes in... (Review)
Review
The PI3K/Akt pathway plays a crucial role in the survival, proliferation, and migration of macrophages, which may impact the development of atherosclerosis. Changes in Akt isoforms or modulation of the Akt activity levels in macrophages significantly affect their polarization phenotype and consequently atherosclerosis in mice. Moreover, the activity levels of Akt signaling determine the viability of monocytes/macrophages and their resistance to pro-apoptotic stimuli in atherosclerotic lesions. Therefore, elimination of pro-apoptotic factors as well as factors that antagonize or suppress Akt signaling in macrophages increases cell viability, protecting them from apoptosis, and this markedly accelerates atherosclerosis in mice. In contrast, inhibition of Akt signaling by the ablation of Rictor in myeloid cells, which disrupts mTORC2 assembly, significantly decreases the viability and proliferation of blood monocytes and macrophages with the suppression of atherosclerosis. In addition, monocytes and macrophages exhibit a threshold effect for Akt protein levels in their ability to survive. Ablation of two Akt isoforms, preserving only a single Akt isoform in myeloid cells, markedly compromises monocyte and macrophage viability, inducing monocytopenia and diminishing early atherosclerosis. These recent advances in our understanding of Akt signaling in macrophages in atherosclerosis may have significant relevance in the burgeoning field of cardio-oncology, where PI3K/Akt inhibitors being tested in cancer patients can have significant cardiovascular and metabolic ramifications.
Topics: Animals; Apoptosis; Atherosclerosis; Blood Cells; Cell Survival; Humans; Macrophage Activation; Macrophages; Phosphatidylinositol 3-Kinases; Protein Isoforms; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 31159424
DOI: 10.3390/ijms20112703 -
Journal of Clinical Medicine Research Jun 2019Thyroid storm (TS) is very rare, however, a life-threatening medical condition requiring emergency treatment. Since TS is rare, published case reports and seven...
BACKGROUND
Thyroid storm (TS) is very rare, however, a life-threatening medical condition requiring emergency treatment. Since TS is rare, published case reports and seven unpublished cases of TS diagnosed at the researchers' facilities were analyzed to make diagnostic criteria for TS in Japan. There are no reports on differences in backgrounds between Graves' disease patients with and without TS, from a single research facility.
METHODS
We retrospectively picked up patients who had been diagnosed as having Graves' disease with and without TS, at National Center for Global Health and Medicine Kohnodai Hospital, between January 2010 and October 2018. According to the guideline for the diagnosis of Graves' disease and TS presented by the Japan Thyroid Association, we diagnosed patients as having Graves' disease with and without TS. We obtained clinical and laboratory data by using electronical medical records and database after showing the opt-out.
RESULTS
We found 69 Graves' disease patients without TS, and five Graves' disease patients with TS. Graves' disease patients with TS were significantly younger than those without TS. Graves' disease patients with TS included a significantly higher percentage of male patients than those without TS. Body temperature and pulse rate in patients with TS were significantly higher than those without TS. Serum thyroid hormone levels and the titer of third-generation thyroid stimulating hormone receptor antibody in patients with TS were significantly higher than in those without TS. Neutrophilic leukocytosis together with eosinopenia, monocytopenia and lymphocytopenia were observed in patients with TS. Serum alkaline phosphatase level was significantly higher in patients with TS than in those without TS. Serum levels of triglyceride, high-density lipoprotein-cholesterol, and low-density lipoprotein-cholesterol in patients with TS were significantly lower than those without TS.
CONCLUSIONS
Our study demonstrated significant clinical, biochemical, hematological, endocrinological and immunological differences in Graves' disease patients with TS compared to those without TS.
PubMed: 31143313
DOI: 10.14740/jocmr3833 -
PeerJ 2019Largemouth bass () are an economically important freshwater fish species that have been investigated for both the short and long-term effects of stress, secondary to...
BACKGROUND
Largemouth bass () are an economically important freshwater fish species that have been investigated for both the short and long-term effects of stress, secondary to angling. Limited data has been published on the hematological parameters of this species and blood sample stability is a notable limitation of hematologic field studies. A relatively novel technique using 10% neutral buffered formalin preserves heparinized whole blood and maintains blood cell stability beyond one month in striped bass. The objective of this study was to evaluate the differences in hematological parameters between tournament-caught and captive-raised largemouth bass using whole blood preservation with neutral buffered formalin.
METHODS
Two populations of largemouth bass ( = 26 wild; = 29 captive) underwent coccygeal venipuncture to collect heparinized whole blood for packed cell volume, total solids, and manual differential. Formalin preservation of heparinized whole blood facilitated manual hemocytometer analysis. Results were compared between the populations (tournament-caught, and captive-raised) with Wilcoxon rank sum test, a Hotelling's test, and Bonferroni simultaneous 95% confidence intervals to determine significance.
RESULTS
The mean packed cell volume (44.9 ± 5.4%) and total solids (7.2 ± 1.1 g/dL) were significantly higher, while the total leukocyte count (7.08 ± 1.86 × 10/µL) was significantly lower in the wild tournament-caught population of largemouth bass, as compared to the captive-raised counterparts (PCV 34.4 ± 7.2%; TS 5.2 ± 1.0 g/dL; WBC 16.43 ± 8.37 × 10/µL). The wild population demonstrated a significantly distinct leukogram characterized by a neutropenia (24.1 ± 12.7%), lymphocytosis (67.7 ± 13.0%), and monocytopenia (8.3 ± 2.9%), while the erythrocyte and thrombocyte counts were not significantly different between populations.
DISCUSSION
Numerous factors have been demonstrated to influence hematologic parameters in fish including age, size, sex, temperature, environmental oxygen level, population density, and infection. The wild population endured stress during angling capture, live-well hypoxia, transport, and extended air exposures at weigh in, which may have caused a stress leukopenia as well as osmoregulatory dysfunction and subsequent hemoconcentration. Further evaluation of seasonal impact as well as increased sample size is warranted to enhance our understanding of largemouth bass hematology.
CONCLUSION
This study concluded that wild largemouth bass captured via tournament angling have higher packed cell volume and total solids, and lower total leukocyte counts, compared to captive-reared individuals. Through the completion of this study, we demonstrated the successful use of 10% neutral buffered formalin to preserve heparinized whole blood for precise hemocytometer cell counts in a new teleost species, the largemouth bass.
PubMed: 30976464
DOI: 10.7717/peerj.6669 -
Orphanet Journal of Rare Diseases Feb 2019Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic...
BACKGROUND
Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies. Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing.
RESULTS
In order to evaluate a possible neurological involvement in WHIM syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8-51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6).
CONCLUSIONS
Taken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.
Topics: Adolescent; Adult; Cerebellum; Child; Female; Gain of Function Mutation; Humans; Immunologic Deficiency Syndromes; Magnetic Resonance Imaging; Mental Disorders; Middle Aged; Nervous System Malformations; Primary Immunodeficiency Diseases; Receptors, CXCR4; Warts; Young Adult
PubMed: 30819232
DOI: 10.1186/s13023-019-1030-8 -
BMJ Case Reports Jan 2019A 26-year-old man with history of schizophrenia was admitted for neutropaenia. He was started on clozapine 3 months prior to admission. As a result he had weekly...
A 26-year-old man with history of schizophrenia was admitted for neutropaenia. He was started on clozapine 3 months prior to admission. As a result he had weekly monitoring of his blood counts and on day of admission was noted to have an absolute neutrophil count (ANC) of 450 cells/μL. He was admitted for clozapine-induced agranulocytosis. Clozapine was held and the patient was started on granulocyte colony-stimulating factor (G-CSF) filgrastim and received two doses without any signs of ANC recovery. On further review, it was noted that the absolute monocyte count (AMC) was also low and tracked with the trend of ANC. We then theorised that the impact of clozapine was on a haematopoietic precursor (colony-forming unit granulocyte-macrophage, CFU-GM) which gives rise to both monocytic and myeloid lineages. Therefore, sargramostim GM-CSF was started. After two doses, the ANC and AMC started trending up and by the third dose, both counts had fully recovered. He was discharged from the hospital and there are no plans to rechallenge with clozapine. Thus, we demonstrate a case of monocytopenia accompanying clozapine-induced agranulocytosis with successful use of GM-CSF. At least in this case, the target of the clozapine injury appears to be the CFU-GM, explaining the rapid and full response to GM-CSF after lack of response to G-CSF.
Topics: Adult; Agranulocytosis; Clozapine; Filgrastim; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Monocytes; Neutropenia; Recombinant Proteins; Schizophrenia; Treatment Outcome
PubMed: 30661042
DOI: 10.1136/bcr-2018-226016 -
Frontiers in Immunology 2018Infection with causes a chronic parasitic disease that progress to severe liver and gastrointestinal damage, and eventually death. During its development into mammalian...
Infection with causes a chronic parasitic disease that progress to severe liver and gastrointestinal damage, and eventually death. During its development into mammalian hosts, immature schistosomula transit through the lung vasculature before they reach the liver to mature into adult worms. A low grade inflammatory reaction is induced during this process. However, molecules that are required for efficient leukocyte accumulation in the lungs of -infected subjects are unknown. In addition, specific leukocyte subsets that mediate pulmonary response during migration through the lung remain to be elucidated. β integrins are fundamental regulators of leukocyte trans-endothelial migration and function. Therefore, we investigated their role during experimental schistosomiasis. Mice that express low levels of CD18 (the common β integrin subunit) and wild type C57BL/6 mice were subcutaneously infected with cercariae. Cellular profiles of lungs and livers were evaluated in different time points after infection by flow cytometry. Low levels of CD18 affected the accumulation of patrolling Ly6C, intermediate Ly6C monocytes, monocyte-derived macrophages and monocyte-derived dendritic cells in the lungs 7 days after infection. This correlated with increased TNF-α levels. Strikingly, low CD18 expression resulted in monocytopenia both in the peripheral blood and bone marrow during acute infection. After 48 days, worm burdens were higher in the hepatic portal system of CD18 mice, which also displayed reduced hepatic accumulation of patrolling Ly6C and intermediate Ly6C, but not inflammatory Ly6C monocytes. Higher parasite burden resulted in increased granulomatous lesions in the liver, increased egg deposition and enhanced mortality. Overall, our data point for a fundamental role of CD18 for monocyte hematopoiesis during infection, which promotes an efficient host response against experimental schistosomiasis.
Topics: Animals; Antigens, Ly; CD18 Antigens; Cell Movement; Disease Resistance; Hematopoiesis; Humans; Immunity, Innate; Leukocytes, Mononuclear; Lung; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Models, Animal; Mutation; Parasite Egg Count; Schistosoma mansoni; Schistosomiasis mansoni
PubMed: 30233576
DOI: 10.3389/fimmu.2018.01970