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Biochemia Medica Jun 2024Hairy cell leukemia (HCL) represents 2% of all leukemia cases, with men aged above 55 years being the most affected. The most common symptoms of this type of leukemia... (Review)
Review
Hairy cell leukemia (HCL) represents 2% of all leukemia cases, with men aged above 55 years being the most affected. The most common symptoms of this type of leukemia include splenomegaly, monocytopenia, and neutropenia. In the basic blood count examination, leukopenia with monocytopenia and granulocytopenia, as well as aplastic anemia and/or thrombocytopenia occur. The mutation of β-rapidly accelerated fibrosarcoma () proto-oncogene, which can be found in nearly 100% of patients, is an important feature of HCL. Immunophenotypic analysis of the HCL cells reveals high expression of B-lineage antigens, including CD19, CD20, and CD22. Additionally, CD11c, CD25, CD103, and CD123 belong to specific markers of HCL. Lactate dehydrogenase activity and β-2-microglobulin concentration are also important in the patient's assessment. The differential diagnosis between HCL, hairy cell leukemia variant (HCL-V) and splenic marginal zone lymphoma (SMZL) is of first importance. Currently, the main treatment for HCL involves the use of purine analogues, excluding pregnant women, individuals with severe infections, and those with relapsing HCL.
Topics: Humans; Male; Diagnosis, Differential; Leukemia, Hairy Cell; Mutation; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Sex Factors
PubMed: 38882583
DOI: 10.11613/BM.2024.020502 -
Frontiers in Immunology 2024Micronutrients, such as vitamins and trace minerals, are critical for supporting growth, performance, health and maintaining redox balance. Zinc (Zn), an essential... (Review)
Review
Micronutrients, such as vitamins and trace minerals, are critical for supporting growth, performance, health and maintaining redox balance. Zinc (Zn), an essential micronutrient, aids the functioning of innate and adaptive immune cells. This scoping review aims to assemble and evaluate the evidence available for the role of Zn within calf immunity. Relevant literature was identified within Web of Science, PubMed, and CABI using search terms specific to the major innate and adaptive immune cell populations. There was no evidence that Zn supplementation altered neutrophil, natural killer cell, or T-cell functions. However, there was limited evidence to support Zn supplementation with reduced monocyte numbers, but there was no evidence to associate the monocytopenia with improvements in monocyte function. There is moderate evidence to suggest that Zn supplementation was beneficial for maintaining epithelial barriers of integumental and mucosal surfaces. The evidence supports supplementation above the current industry recommendations for improving immunoglobulin (Ig) production, with the strongest results being observed for IgG and IgM. Moreover, Zn supplementation was associated with reduced proinflammatory cytokine production, which may reduce inflammation-associated hypophagia and warrants further investigation. Furthermore, Zn reduced the duration of clinical signs in animals facing respiratory disease and diarrhea. However, consensus is needed about the optimal dose, route, and Zn formulation most appropriate for supporting immunity. In conclusion, while the literature supports that Zn could enhance calf immunity, there is insufficient evidence to adequately determine the extent to which Zn impacts innate immune cell and T-cell functions. Determination of the immune cell functions susceptible to modification by Zn supplementation is an important knowledge gap for enhancing the understanding of Zn and calf immunity.
Topics: Zinc; Animals; Cattle; Dietary Supplements; Immunity, Innate; Adaptive Immunity
PubMed: 38799472
DOI: 10.3389/fimmu.2024.1387950 -
Toxicology Reports Dec 2023The genus (Passifloraceae) comprises about 500 species. The stands out because of its economic and medicinal importance. It is widely planted in tropical and...
The genus (Passifloraceae) comprises about 500 species. The stands out because of its economic and medicinal importance. It is widely planted in tropical and subtropical regions worldwide, especially in South America, the Caribbean, South Africa, and Asia. The aqueous extract of Passiflora edulis Sims f. edulis (Gulupa) leaves is used in traditional medicine for its soothing and tranquilizing effects on the central nervous system. Therefore, evaluating its safety for human use is a fundamental requirement to continue the development of new therapies within the framework of regulatory, preclinical, and clinical guidelines. Here, the sub-acute toxicity study was conducted following the Organization for Economic Cooperation and Development (OECD) guideline 407 for 28 days in Wistar albino rats. The study showed that 1000 mg/kg/day of the aqueous extract in 10 adult Wistar rats (five males and five females) was well tolerated. The hematological results are at normal levels. However, monocytopenia and eosinopenia were observed with a significant difference (P < 0,05) for both male and female rats treated with the aqueous extract of . The results show that liver and kidney function profiles were conserved. However, an increase in ALT is observed with significant differences between male and female rats treated with the extract compared to the controls. Study findings were limited to non-adverse histopathological results of a slightly increased incidence of focal periportal lymphocytic infiltrate in the liver and focal corticomedullary nephrocalcinosis in the kidney compared to control. Therefore, the aqueous extract of has a good safety profile in oral administration, was well tolerated, and did not cause any lethality or adverse effects in the sub-acute toxicity study in male and female rats. The NOAEL (no observed adverse effect level) for the 28-day subacute toxicity study was considered to be 1000 mg/kg.
PubMed: 37955035
DOI: 10.1016/j.toxrep.2023.10.013 -
Frontiers in Immunology 2023Patients with septic shock caused by have mortality rates exceeding 50%, despite appropriate antibiotic therapy. Our objectives were to establish a rabbit model of...
Monoclonal antibodies neutralizing alpha-hemolysin, bicomponent leukocidins, and clumping factor A protected against -induced acute circulatory failure in a mechanically ventilated rabbit model of hyperdynamic septic shock.
BACKGROUND
Patients with septic shock caused by have mortality rates exceeding 50%, despite appropriate antibiotic therapy. Our objectives were to establish a rabbit model of septic shock and to determine whether a novel immunotherapy can prevent or halt its natural disease progression.
METHODS
Anesthetized rabbits were ventilated with lung-protective low-tidal volume, instrumented for advanced hemodynamic monitoring, and characterized for longitudinal changes in acute myocardial dysfunction by echocardiography and sepsis-associated biomarkers after intravenous challenge. To demonstrate the potential utility of this hyperdynamic septic shock model for preclinical drug development, rabbits were randomized for prophylaxis with anti-Hla/Luk/ClfA monoclonal antibody combination that neutralizes alpha-hemolysin (Hla), the bicomponent pore-forming leukocidins (Luk) including Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysin, and clumping factor A (ClfA), or an irrelevant isotype-matched control IgG (c-IgG), and then challenged with .
RESULTS
Rabbits challenged with , but not those with saline, developed a hyperdynamic state of septic shock characterized by elevated cardiac output (CO), increased stroke volume (SV) and reduced systemic vascular resistance (SVR), which was followed by a lethal hypodynamic state characterized by rapid decline in mean arterial pressure (MAP), increased central venous pressure, reduced CO, reduced SV, elevated SVR, and reduced left-ventricular ejection fraction, thereby reproducing the hallmark clinical features of human staphylococcal septic shock. In this model, rabbits pretreated with anti-Hla/Luk/ClfA mAb combination had 69% reduction in mortality when compared to those pretreated with c-IgG (<0.001). USA300-induced acute circulatory failure-defined as >70% decreased in MAP from pre-infection baseline-occurred in only 20% (2/10) of rabbits pretreated with anti-Hla/Luk/ClfA mAb combination compared to 100% (9/9) of those pretreated with c-IgG. Prophylaxis with anti-Hla/Luk/ClfA mAb combination halted progression to lethal hypodynamic shock, as evidenced by significant protection against the development of hyperlactatemia, hypocapnia, hyperkalemia, leukopenia, neutropenia, monocytopenia, lymphopenia, as well as biomarkers associated with acute myocardial injury.
CONCLUSION
These results demonstrate the potential utility of a mechanically ventilated rabbit model that reproduced hallmark clinical features of hyperdynamic septic shock and the translational potential of immunotherapy targeting virulence factors for the prevention of staphylococcal septic shock.
Topics: Humans; Animals; Rabbits; Staphylococcus aureus; Antibodies, Monoclonal; Hemolysin Proteins; Leukocidins; Shock, Septic; Respiration, Artificial; Stroke Volume; Ventricular Function, Left; Staphylococcal Infections; Shock; Immunoglobulin G
PubMed: 37781371
DOI: 10.3389/fimmu.2023.1260627 -
Yonsei Medical Journal Oct 2023Disseminated nontuberculous mycobacterial (D-NTM) disease occurs primarily in immunocompromised hosts. However, these cases have rarely been reported in South Korea.... (Observational Study)
Observational Study
PURPOSE
Disseminated nontuberculous mycobacterial (D-NTM) disease occurs primarily in immunocompromised hosts. However, these cases have rarely been reported in South Korea. This study aimed to describe the clinical manifestations, disease course, and underlying immune deficiencies of patients with D-NTM disease.
MATERIALS AND METHODS
We retrospectively reviewed the cases of D-NTM disease from January 2005 to December 2019 at a tertiary referral hospital in South Korea. D-NTM disease was defined as a bloodstream infection or infection of two or more non-contiguous body organs with species identification.
RESULTS
Of the 53342 mycobacterial samples from 23338 patients, extrapulmonary NTM was detected in 104 patients, and 3 (2.9%) were diagnosed with D-NTM disease. was isolated from two patients, while subspecies was identified in one. The patients were aged between 18 and 25 years, and two patients were male. All patients were immunocompromised - one received lung transplantation, one was diagnosed with anhidrotic ectodermal dysplasia with T-cell immune deficiency, and one had monocytopenia and mycobacterial infection syndrome associated with mutations. All patients underwent a standard macrolide-based regimen for >5 months, and their sputum tested negative. However, one patient died of bacterial sepsis, while the other two survived.
CONCLUSION
D-NTM disease is rare in a tertiary referral center in South Korea. They occur primarily in immunocompromised patients at a relatively young age. Careful investigation of the underlying immune status is required when treating patients with D-NTM disease.
Topics: Humans; Male; Adolescent; Young Adult; Adult; Female; Tertiary Care Centers; Retrospective Studies; Republic of Korea; Anti-Bacterial Agents
PubMed: 37727920
DOI: 10.3349/ymj.2023.0046 -
The Journal of Clinical Investigation Oct 2023BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUNDWarts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a primary immunodeficiency disorder caused by heterozygous gain-of-function CXCR4 mutations. Myelokathexis is a kind of neutropenia caused by neutrophil retention in bone marrow and in WHIM syndrome is associated with lymphopenia and monocytopenia. The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODSIn this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). The treatment order was randomized for each patient.RESULTSPlerixafor was nonsuperior to G-CSF for TISS (P = 0.54). In exploratory endpoints, plerixafor was noninferior to G-CSF for maintaining neutrophil counts of more than 500 cells/μL (P = 0.023) and was superior to G-CSF for maintaining lymphocyte counts above 1,000 cells/μL (P < 0.0001). Complete regression of a subset of large wart areas occurred on plerixafor in 5 of 7 patients with major wart burdens at baseline. Transient rash occurred on plerixafor, and bone pain was more common on G-CSF. There were no significant differences in drug preference or quality of life or the incidence of drug failure or serious adverse events.CONCLUSIONPlerixafor was not superior to G-CSF in patients with WHIM for TISS, the primary endpoint. Together with wart regression and hematologic improvement, the infection severity results support continued study of plerixafor as a potential treatment for WHIM syndrome.TRIAL REGISTRATIONClinicaltrials.gov NCT02231879.FUNDINGThis study was funded by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases.
Topics: Humans; Immunologic Deficiency Syndromes; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Cross-Over Studies; Quality of Life; Heterocyclic Compounds; Primary Immunodeficiency Diseases; Warts; Receptors, CXCR4
PubMed: 37561579
DOI: 10.1172/JCI164918 -
Cancers Jul 2023The absolute monocyte count (AMC) is associated with mortality in a variety of medical conditions. Its prognostic impact in myelodysplastic syndromes (MDSs) is less well...
The absolute monocyte count (AMC) is associated with mortality in a variety of medical conditions. Its prognostic impact in myelodysplastic syndromes (MDSs) is less well studied. Therefore, we investigated its potential prognostic value in a cohort from the Düsseldorf MDS registry in relationship to the revised international prognostic scoring system (IPSS-R). An AMC below the population's median (<0.2 × 10/L) was associated with several adverse disease features such as lower haemoglobin levels, lower count of neutrophils and platelets, and a higher percentage of blasts in the bone marrow. MDS patients with an AMC < 0.2 × 10/L had a significantly higher risk of progression into acute myeloid leukemia (AML). In a univariate, proportional hazards model the effect of the AMC as a continuous variable was modelled via p-splines. We found a U-shaped effect with the lowest hazard around 0.3 × 10/L. Accordingly, an AMC within the last quartile of the population (0.4 × 10/L) was associated with a reduced overall survival independently of IPSS-R, but not with the risk of secondary AML. Considering monocytopenia as a risk factor for AML progression in MDS may provide an additional argument for allogeneic transplantation or the use of hypomethylating agents in patients who are not clear candidates for those treatments according to current prognostic scoring systems and/or recommendations. Further studies are needed to assess the prognostic impact of the AMC in the context of prognostic scoring systems, considering the molecular risk profile, and to identify the mechanisms responsible for the higher mortality in MDS patients with a subtle monocytosis.
PubMed: 37509235
DOI: 10.3390/cancers15143572 -
Scientific Reports Jul 2023Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants...
Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants and young children. Cytochrome P450 2B6 (CYP2B6) is the major catalyst and CYP2C19 is the minor enzyme in bioactivation and inactivation pathways of cyclophosphamide. CYP-mediated metabolism may contribute to the variable pharmacokinetics of cyclophosphamide and its toxic byproducts leading to insufficient response to the therapy and development of clinically significant side effects. The aim of the study was to reveal the contribution of pharmacogenetic variability in CYP2B6 and CYP2C19 to the treatment efficacy and cyclophosphamide-induced side effects in pediatric neuroblastoma patients under cyclophosphamide therapy (N = 50). Cyclophosphamide-induced hematologic toxicities were pivotal in all patients, whereas only moderate hepatorenal toxicity was developed. The patients' CYP2B6 metabolizer phenotypes were associated with the occurrence of lymphopenia, thrombocytopenia, and monocytopenia as well as of liver injury, but not with kidney or urinary bladder (hemorrhagic cystitis) toxicities. Furthermore, the patients' age (< 1.5 years, P = 0.03) and female gender (P ≤ 0.02), but not CYP2B6 or CYP2C19 metabolizer phenotypes appeared as significant prognostic factors in treatment outcomes. Our results may contribute to a better understanding of the impact of CYP2B6 variability on cyclophosphamide-induced side effects.
Topics: Humans; Child; Female; Child, Preschool; Infant; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cyclophosphamide; Neuroblastoma; Drug-Related Side Effects and Adverse Reactions
PubMed: 37479763
DOI: 10.1038/s41598-023-38983-0 -
Cureus Jun 2023Background Enteric fever is a systemic infection in humans caused by the Gram-negative bacilli serovars Typhi and Paratyphi Although the diagnosis typically involves...
Background Enteric fever is a systemic infection in humans caused by the Gram-negative bacilli serovars Typhi and Paratyphi Although the diagnosis typically involves the isolation of serovars, it is often determined based on laboratory findings and clinical observations. However, due to the wide variety and the non-specific character of clinical features, making a definitive diagnosis presents numerous challenges. Therefore, the aim of this study was to find the predictive hematological and biochemical parameters which would serve in the diagnosis, prognosis, and treatment of typhoid fever cases. Methodology A cross-sectional study was conducted from November 2020 to September 2021 on1076consented volunteerparticipants. Stool culture and identification tests enabled us to distinguish three groups including 423 Typhi positive patients, 115 Paratyphi positive patients, and 538 negative participants. Biochemical and hematological parameters were evaluated using standard methods from commercial kits and Sysmex KX-21N automated hematology analyzer, respectively. A multiple logistic regression analysis was performed to identify the validity of the hematological and biochemical characteristics for enteric fever diagnosis. Results Multiple logistic regression showed hyper creatininemia, hypoalbuminemia, hyper total proteinemia, hyper alkaline phosphatase (ALP), hyper alanine aminotransferase (ALT), hyper total bilirubinemia, hyper conjugated bilirubinemia, hyper triglyceridemia, hyper C-reactive protein (CRP), leukopenia, thrombocytopenia, lymphopenia, monocytopenia, low hemoglobin, low hematocrit, low mean corpuscular volume (MCV), low mean corpuscular hemoglobin (MCH), low platelet, low platelet crit level, high platelet distribution width (PDW) level, high erythrocyte sedimentation rate 1 (ESR1) level as significant biological abnormalities associated (odds ratio {OR} > 1; p < 0.05) with enteric fever infection. Similarly, hyper ESR2 was an independent predictor (OR > 1; p < 0.05) of Typhi infection. However, a negative and significant association (OR < 1; p < 0.05) was recorded between enteric fever infection and high mean platelet volume (MPV). Conclusion Overall the results of the biochemical and hematological profiles can serve as potential diagnostic markers for typhoid fever. These markers can also be useful in the appropriate management of those with enteric fever, preventing severity and limiting outcomes of mortality.
PubMed: 37461754
DOI: 10.7759/cureus.40498 -
Children (Basel, Switzerland) Jun 2023Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection caused by hyperactivation of the immune system.
BACKGROUND
Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe complication of SARS-CoV-2 infection caused by hyperactivation of the immune system.
METHODS
this is a retrospective analysis of clinical data, biochemical parameters, and immune cell subsets in 40 MIS-C patients from hospital admission to outpatient long-term follow-up.
RESULTS
MIS-C patients had elevated inflammatory markers, associated with T- and NK-cell lymphopenia, a profound depletion of dendritic cells, and altered monocyte phenotype at disease onset, while the subacute phase of the disease was characterized by a significant increase in T- and B-cell counts and a rapid decline in activated T cells and terminally differentiated B cells. Most of the immunological parameters returned to values close to the normal range during the remission phase (20-60 days after hospital admission). Nevertheless, we observed a significantly reduced ratio between recently generated and more differentiated CD8+ T- and B-cell subsets, which partially settled at longer-term follow-up determinations.
CONCLUSIONS
The characterization of lymphocyte distribution in different phases of MIS-C may help to understand the course of diseases that are associated with dysregulated immune responses and to calibrate prompt and targeted treatments.
PubMed: 37371300
DOI: 10.3390/children10061069