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Nature Reviews. Neuroscience Oct 2023Stress-linked psychiatric disorders, including anxiety and major depressive disorder, are associated with systemic inflammation. Recent studies have reported... (Review)
Review
Stress-linked psychiatric disorders, including anxiety and major depressive disorder, are associated with systemic inflammation. Recent studies have reported stress-induced alterations in haematopoiesis that result in monocytosis, neutrophilia, lymphocytopenia and, consequently, in the upregulation of pro-inflammatory processes in immunologically relevant peripheral tissues. There is now evidence that this peripheral inflammation contributes to the development of psychiatric symptoms as well as to common co-morbidities of psychiatric disorders such as metabolic syndrome and immunosuppression. Here, we review the specific brain and spinal regions, and the neuronal populations within them, that respond to stress and transmit signals to peripheral tissues via the autonomic nervous system or neuroendocrine pathways to influence immunological function. We comprehensively summarize studies that have employed retrograde tracing to define neurocircuits linking the brain to the bone marrow, spleen, gut, adipose tissue and liver. Moreover, we highlight studies that have used chemogenetic or optogenetic manipulation or intracerebroventricular administration of peptide hormones to control somatic immune responses. Collectively, this growing body of literature illustrates potential mechanisms through which stress signals are conveyed from the CNS to immune cells to regulate stress-relevant behaviours and comorbid pathophysiology.
Topics: Humans; Depressive Disorder, Major; Adipose Tissue; Anxiety; Inflammation; Immunity
PubMed: 37626176
DOI: 10.1038/s41583-023-00729-2 -
Cancers Jul 2023Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematological disorders characterized by both proliferative and dysplastic features. According to the 2022... (Review)
Review
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematological disorders characterized by both proliferative and dysplastic features. According to the 2022 International Consensus Classification (ICC), MDS/MPN consists of clonal monocytosis of undetermined significance (CMUS), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with SF3B1 mutation (MDS/MPN-T-SF3B1), MDS/MPN with ring sideroblasts and thrombocytosis not otherwise specified (MDS/MPN-RS-T-NOS), and MDS/MPN-NOS. These disorders exhibit a diverse range of genetic alterations involving various transcription factors (e.g., ), signaling molecules (e.g., , ), splicing factors (e.g., , ), and epigenetic regulators (e.g., , , ), as well as specific cytogenetic abnormalities (e.g., 8 trisomies, 7 deletions/monosomies). Clinical studies exploring therapeutic options for higher-risk MDS/MPN overlap syndromes mostly involve hypomethylating agents, but other treatments such as lenalidomide and targeted agents such as JAK inhibitors and inhibitors targeting PARP, histone deacetylases, and the Ras pathway are under investigation. While these treatment modalities can provide partial disease control, allogeneic bone marrow transplantation (allo-BMT) is the only potentially curative option for patients. Important prognostic factors correlating with outcomes after allo-BMT include comorbidities, splenomegaly, karyotype alterations, and the bone marrow blasts percentage at the time of transplantation. Future research is imperative to optimizing therapeutic strategies and enhancing patient outcomes in MDS/MPN neoplasms. In this review, we summarize MDS/MPN diagnostic criteria, biology, and current and future treatment options, including bone marrow transplantation.
PubMed: 37568631
DOI: 10.3390/cancers15153815 -
Frontiers in Immunology 2023Serotonin is involved in leukocyte recruitment during inflammation. Deficiency of the serotonin transporter (SERT) is associated with metabolic changes in humans and...
INTRODUCTION
Serotonin is involved in leukocyte recruitment during inflammation. Deficiency of the serotonin transporter (SERT) is associated with metabolic changes in humans and mice. A possible link and interaction between the inflammatory effects of serotonin and metabolic derangements in SERT-deficient mice has not been investigated so far.
METHODS
SERT-deficient ( ) and wild type (WT) mice were fed a high-fat diet, starting at 8 weeks of age. Metabolic phenotyping (metabolic caging, glucose and insulin tolerance testing, body and organ weight measurements, qPCR, histology) and assessment of adipose tissue inflammation (flow cytometry, histology, qPCR) were carried out at the end of the 19-week high-fat diet feeding period. In parallel, and WT mice received a control diet and were analyzed either at the time point equivalent to high-fat diet feeding or as early as 8-11 weeks of age for baseline characterization.
RESULTS
After 19 weeks of high-fat diet, and WT mice displayed similar whole-body and fat pad weights despite increased relative weight gain due to lower starting body weight in . In obese animals insulin resistance and liver steatosis were enhanced as compared to WT animals. Leukocyte accumulation and mRNA expression of cytokine signaling mediators were increased in epididymal adipose tissue of obese mice. These effects were associated with higher adipose tissue mRNA expression of the chemokine monocyte chemoattractant protein 1 and presence of monocytosis in blood with an increased proportion of pro-inflammatory Ly6C+ monocytes. By contrast, mice fed a control diet did not display adipose tissue inflammation.
DISCUSSION
Our observations suggest that SERT deficiency in mice is associated with inflammatory processes that manifest as increased adipose tissue inflammation upon chronic high-fat diet feeding due to enhanced leukocyte recruitment.
Topics: Humans; Animals; Mice; Diet, High-Fat; Serotonin Plasma Membrane Transport Proteins; Serotonin; Inflammation; Obesity; Adipose Tissue; Weight Gain; RNA, Messenger
PubMed: 37520561
DOI: 10.3389/fimmu.2023.1184010 -
Kidney Medicine Feb 2024Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy affecting the bone marrow and resulting in peripheral blood monocytosis. Kidney and urinary tract... (Review)
Review
Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy affecting the bone marrow and resulting in peripheral blood monocytosis. Kidney and urinary tract involvement is common and can present dramatically with life-threatening consequences. Kidney involvement can be the result of direct or indirect mechanisms, including prerenal azotemia, glomerular disease, tubulointerstitial involvement, and renovascular disorders. Urinary tract involvement, electrolyte and acid-base disorders, as well as nephrotoxicity from treatment of the disorder can also occur. Given this multifactorial pathogenesis involving several mechanisms concomitantly, nephrologists must exercise heightened awareness and maintain a low threshold for kidney biopsy. There is a pressing need for future research endeavors to elucidate and target the manifestations of CMML that involve the kidneys with the ultimate goal of augmenting overall prognosis and therapeutic outcomes.
PubMed: 38313809
DOI: 10.1016/j.xkme.2023.100769 -
Blood Mar 2024The World Health Organization (WHO) classification of hematolymphoid tumors and the International Consensus Classification (ICC) of 2022 introduced major changes to the...
The World Health Organization (WHO) classification of hematolymphoid tumors and the International Consensus Classification (ICC) of 2022 introduced major changes to the definition of chronic myelomonocytic leukemia (CMML). To assess its qualitative and quantitative implications for patient care, we started with 3311 established CMML cases (according to WHO 2017 criteria) and included 2130 oligomonocytosis cases fulfilling the new CMML diagnostic criteria. Applying both 2022 classification systems, 356 and 241 of oligomonocytosis cases were newly classified as myelodysplastic (MD)-CMML (WHO and ICC 2022, respectively), most of which were diagnosed as myelodysplastic syndrome (MDS) according to the WHO 2017 classification. Importantly, 1.5 times more oligomonocytosis cases were classified as CMML according to WHO 2022 than based on ICC, because of different diagnostic criteria. Genetic analyses of the newly classified CMML cases showed a distinct mutational profile with strong enrichment of MDS-typical alterations, resulting in a transcriptional subgroup separated from established MD and myeloproliferative CMML. Despite a different cytogenetic, molecular, immunophenotypic, and transcriptional landscape, no differences in overall survival were found between newly classified and established MD-CMML cases. To the best of our knowledge, this study represents the most comprehensive analysis of routine CMML cases to date, both in terms of clinical characterization and transcriptomic analysis, placing newly classified CMML cases on a disease continuum between MDS and previously established CMML.
Topics: Humans; Consensus; Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukocytosis; World Health Organization; Prognosis; Organic Chemicals
PubMed: 38064663
DOI: 10.1182/blood.2023021199 -
Leukemia Sep 2023In a registry-based analysis of 135 patients with "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-TK; FIP1L1::PDGFRA, n = 78;...
In a registry-based analysis of 135 patients with "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-TK; FIP1L1::PDGFRA, n = 78; PDGFRB, diverse fusions, n = 26; FGFR1, diverse, n = 9; JAK2, diverse, n = 11; ETV6::ABL1, n = 11), we sought to evaluate the disease-defining characteristics. In 81/135 (60%) evaluable patients, hypereosinophilia (>1.5 × 10/l) was observed in 40/44 (91%) FIP1L1::PDGFRA and 7/7 (100%) ETV6::ABL1 positive patients but only in 13/30 (43%) patients with PDGFRB, FGFR1, and JAK2 fusion genes while 9/30 (30%) patients had no eosinophilia. Monocytosis >1 × 10/l was identified in 27/81 (33%) patients, most frequently in association with hypereosinophilia (23/27, 85%). Overall, a blast phase (BP) was diagnosed in 38/135 (28%) patients (myeloid, 61%; lymphoid, 39%), which was at extramedullary sites in 18 (47%) patients. The comparison between patients with PDGFRA/PDGFRB vs. FGFR1, JAK2, and ETV6::ABL1 fusion genes revealed a similar occurrence of primary BP (17/104, 16% vs. 8/31 26%, p = 0.32), a lower frequency (5/87, 6% vs. 8/23, 35%, p = 0.003) of and a later progression (median 87 vs. 19 months, p = 0.053) into secondary BP, and a better overall survival from diagnosis of BP (17.1 vs. 1.7 years, p < 0.0008). We conclude that hypereosinophilia with or without monocytosis and various phenotypes of BP occur at variable frequencies in MLN-TK.
Topics: Humans; Receptor, Platelet-Derived Growth Factor beta; Receptor, Platelet-Derived Growth Factor alpha; Oncogene Proteins, Fusion; Myeloproliferative Disorders; Eosinophilia; Lymphoma; Gene Fusion
PubMed: 37454239
DOI: 10.1038/s41375-023-01958-1 -
Journal of Lipid Research Mar 2024Finasteride is commonly prescribed to treat benign prostate hyperplasia and male-pattern baldness in cis men and, more recently, trans individuals. However, the effect...
Finasteride is commonly prescribed to treat benign prostate hyperplasia and male-pattern baldness in cis men and, more recently, trans individuals. However, the effect of finasteride on cardiovascular disease remains elusive. We evaluated the role of finasteride on atherosclerosis using low-density lipoprotein (LDL) receptor-deficient (Ldlr) mice. Next, we examined the relevance to humans by analyzing the data deposited between 2009 and 2016 in the National Health and Nutrition Examination Survey. We show that finasteride reduces total plasma cholesterol and delays the development of atherosclerosis in Ldlr mice. Finasteride reduced monocytosis, monocyte recruitment to the lesion, macrophage lesion content, and necrotic core area, the latter of which is an indicator of plaque vulnerability in humans. RNA sequencing analysis revealed a downregulation of inflammatory pathways and an upregulation of bile acid metabolism, oxidative phosphorylation, and cholesterol pathways in the liver of mice taking finasteride. Men reporting the use of finasteride showed lower plasma levels of cholesterol and LDL-cholesterol than those not taking the drug. Our data unveil finasteride as a potential treatment to delay cardiovascular disease in people by improving the plasma lipid profile.
Topics: Humans; Male; Animals; Mice; Finasteride; Cardiovascular Diseases; Nutrition Surveys; Atherosclerosis; Cholesterol; Receptors, LDL; Mice, Knockout
PubMed: 38272355
DOI: 10.1016/j.jlr.2024.100507 -
Frontiers in Immunology 2023Live attenuated vaccines produced by sequential passages in splenectomized calves have historically been used to control acute bovine babesiosis in endemic areas...
INTRODUCTION
Live attenuated vaccines produced by sequential passages in splenectomized calves have historically been used to control acute bovine babesiosis in endemic areas worldwide. However, several constraints prevent the widespread use of these vaccines, including the need for several splenectomized calves to produce vaccine batches, and potential inconsistent parasite attenuation, which contraindicates their use for highly -susceptible adult cattle. Thus, the use of vaccines based on well-defined culture attenuated strains emerges as a more sustainable and efficient alternative. Previous work demonstrated that the culture attenuated strain Att-S74-T3Bo is non-tick transmissible and able to safely protect calves against needle challenge with a virulent strain.
METHODS AND RESULTS
Herein we evaluated safety and efficacy of Att-S74-T3Bo in preventing acute babesiosis in adult (>1.5 year of age) cattle. Results demonstrated that Att-S74-T3Bo vaccination of adult animals (n=5) induced self-limiting signs of acute infection and protected the vaccinated animals against challenge with the homologous virulent strain Vir-S74-T3Bo. Att-S74-T3Bo-vaccinated adult cattle developed significant (P<0.05) monocytosis, with concomitant neutropenia and CD4 leukopenia, in peripheral blood early after vaccination. Also, vaccinated animals developed a specific signature of pro- and anti-inflammatory cytokine expression in peripheral blood and significant levels of IgM, total IgG, IgG1, and IgG2 against the immunodominant antigen RAP-1 CT. Strikingly, none of the vaccinated animals showed any signs of acute babesiosis after challenge with Vir-S74-T3Bo. In contrast, control adult cattle (n=5) showed pathognomonic symptoms of acute babesiosis, and significant decrease (P<0.05) in lymphocytes, monocytes, and neutrophils, starting on day 7 post-challenge. All control animals developed severe acute disease and were euthanized on days 10 through 12 days post-challenge.
DISCUSSION AND CONCLUSION
Evidence from this study indicates that Att-S74-T3Bo safely protects highly susceptible adult cattle against challenge with a homologous virulent strain of . In conclusion, Att-S74-T3Bo may be considered as a potential efficient and sustainable attenuated candidate vaccine strain to control acute bovine babesiosis in highly susceptible adult cattle. Future studies should focus on increasing the number of animals vaccinated, duration of immunity, and efficacy of this attenuated strain against heterologous virulent parasite strains.
Topics: Cattle; Animals; Babesia bovis; Babesiosis; Babesia; Vaccination; Immunoglobulin G; Vaccines, Attenuated; Cattle Diseases
PubMed: 37583702
DOI: 10.3389/fimmu.2023.1219913 -
African Journal of Laboratory Medicine 2023Automated haematology analysers such as the Sysmex XN-3000 (Sysmex Corporation, Kobe, Japan) utilise white blood cell (WBC) flags to identify quantitative and...
BACKGROUND
Automated haematology analysers such as the Sysmex XN-3000 (Sysmex Corporation, Kobe, Japan) utilise white blood cell (WBC) flags to identify quantitative and qualitative abnormalities. Owing to clinical and biological factors, the sensitivity and specificity of the flags vary when compared to microscopy, the gold-standard method for assessing peripheral blood smear (PBS) morphology.
OBJECTIVE
This study assessed the performance of the Sysmex XN-3000 haematology analyser in comparison to PBS microscopy for the detection of WBC abnormalities.
METHODS
We collected 250 random full blood count samples from the haematology laboratory at Inkosi Albert Luthuli Central Hospital, Durban, KwaZulu-Natal, South Africa, from March 2022 to April 2022. The performance of the automated WBC flags of the Sysmex XN-3000 was assessed in comparison to PBS microscopy, and the impact of established clinical variables on the performance of the flags was determined.
RESULTS
The sensitivity of the 'blast' flag was 96.3%, and the specificity was 84.9%. The efficiency of the flag was adversely impacted by low white cell counts (< 1.5 × 10/L; < 0.001), chemotherapy ( = 0.002), malignancy ( = 0.02), and infection ( = 0.02). The 'abnormal lymphocyte' flag demonstrated a sensitivity of 90% and a specificity of 96.2%, and its performance was adversely impacted by chemotherapy exposure ( = 0.03). Three cases (1.2%) erroneously flagged as 'monocytosis' demonstrated blasts on microscopy.
CONCLUSION
In our setting, PBS microscopy remains necessary to confirm blasts, abnormal lymphocytes, and monocytosis in patients with malignancy, current chemotherapy exposure, low white cell counts, and infection.
WHAT THIS STUDY ADDS
This study adds evidence that PBS morphology remains the gold standard for confirming WBC abnormalities in patients with a history of malignancy, chemotherapy, and leucopenia.
PubMed: 38094982
DOI: 10.4102/ajlm.v12i1.2140