A Rare Case of Methemoglobinemia after Ifosfamide Infusion in a 3-Year-Old Patient Treated for T-ALL.

Methemoglobinemia is a potentially life-threatening, rare condition in which the oxygen-carrying capacity of hemoglobin is diminished. We present the case of a 3-year-old boy treated for T-cell acute lymphoblastic leukemia (T-ALL) who developed methemoglobinemia (MetHb 57.1%) as a side effect of ifosfamide administration. Due to his critical condition, the patient was transferred to the intensive care unit (ICU). The therapy included methylene blue administration, an exchange transfusion, catecholamine infusion, and steroids. Improving the general condition allowed for continuing chemotherapy without ifosfamide and completion of the HR2 block. Vigilance for methemoglobinemia as a very rare side effect should be widespread when using ifosfamide in the treatment protocols.

The Role of Selected Interleukins in the Development and Progression of Multiple Sclerosis-A Systematic Review.

Multiple sclerosis is a disabling inflammatory disorder of the central nervous system characterized by demyelination and neurodegeneration. Given that multiple sclerosis remains an incurable disease, the management of MS predominantly focuses on reducing relapses and decelerating the progression of both physical and cognitive decline. The continuous autoimmune process modulated by cytokines seems to be a vital contributing factor to the development and relapse of multiple sclerosis. This review sought to summarize the role of selected interleukins in the pathogenesis and advancement of MS. Patients with MS in the active disease phase seem to exhibit an increased serum level of IL-2, IL-4, IL-6, IL-13, IL-17, IL-21, IL-22 and IL-33 compared to healthy controls and patients in remission, while IL-10 appears to have a beneficial impact in preventing the progression of the disease. Despite being usually associated with proinflammatory activity, several studies have additionally recognized a neuroprotective role of IL-13, IL-22 and IL-33. Moreover, selected gene polymorphisms of IL-2R, IL-4, IL-6, IL-13 and IL-22 were identified as a possible risk factor related to MS development. Treatment strategies of multiple sclerosis that either target or utilize these cytokines seem rather promising, but more comprehensive research is necessary to gain a clearer understanding of how these cytokines precisely affect MS development and progression.

Iron Overload in Children with Acute Lymphoblastic and Acute Myeloblastic Leukemia-Experience of One Center.

Transfusions of packed red blood cells (PRBCs), given due to an oncological disease and its acute complications, are an indispensable part of anticancer therapy. However, they can lead to post-transfusion iron overload. The study aim was to evaluate the role of ferritin as a nonspecific marker of leukemic growth and marker of transfusion-related iron overload. We performed a longitudinal study of PRBC transfusions and changes in ferritin concentrations during the oncological treatment of 135 patients with childhood acute lymphoblastic and acute myeloblastic leukemia (ALL and AML, median age 5.62 years). At the diagnosis, 41% of patients had a ferritin level over 500 ng/mL, and 14% of patients had a ferritin level over 1000 ng/mL. At the cessation of the treatment, 80% of the children had serum ferritin (SF) over 500 ng/mL, and 31% had SF over 1000 ng/mL. There was no significant difference between SF at the beginning of the treatment between ALL and AML patients, but children with AML finished treatment with statistically higher SF. AML patients had also statistically higher number of transfusions. We found statistically significant positive correlations between ferritin and age, and weight and units of transfused blood. Serum ferritin at the moment of diagnosis can be a useful marker of leukemic growth, but high levels of SF are connected with iron overload in both AML and ALL.

Effects of Combinatory In Vitro Treatment with Immune Checkpoint Inhibitors and Cytarabine on the Anti-Cancer Immune Microenvironment in De Novo AML Patients.

Despite substantial progress in the diagnostic and therapeutic procedures, acute myeloid leukaemia (AML) still constitutes a significant problem for patients suffering from its relapses. A comprehensive knowledge of the disease's molecular background has led to the development of targeted therapies, including immune checkpoint inhibitors, and demonstrated beneficial effects on several types of cancer. Here, we aimed to assess in vitro the potential of the immune checkpoint blockage for supporting anti-cancer responses to the AML backbone therapy with cytarabine. PBMCs of AML patients were collected at admission and, following the therapy, eight complete remission (CR) and eight non-responders (NR) subjects were selected. We assessed the effects of the in vitro treatment of the cells with cytarabine and the immune checkpoint inhibitors: anti-CTLA-4, anti-PD-1, anti-PD-L1. The study protocol allowed us to evaluate the viability of the cancer and the immune cells, proliferation status, phenotype, and cytokine release. Anti-PD-L1 antibodies were found to exert the most beneficial effect on the activation of T cells, with a concomitant regulation of the immune balance through Treg induction. There was no direct influence on the blast cells; however, the modulation of the PD-1/PD-L1 axis supported the expansion of lymphocytes. Changes in the response between CR and NR patients might result from the differential expression of PD-1 and PD-L1, with lower levels in the latter group. The tested blockers appear to support the anti-cancer immune responses rather than directly improve the effects of cytarabine. In conclusion, checkpoint proteins' modulators might improve the anti-cancer responses in the tumour environment.

Significance of Th17 and Treg in Treatment Efficacy and Outcome in Pediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia represents a malignant proliferation of lymphoid cells blocked at an early stage of cell differentiation. It is the most common cancer occurring in children. Despite favorable prognosis, the survival rate of patients with poor treatment response or relapse remains dismal. The interaction between leukemic cells and the tumor immune microenvironment is pivotal in mediating tumor progression. In this study we evaluated associations between Treg and Th17 lymphocytes and the clinical presentation of ALL pediatric patients to validate their value in monitoring treatment outcome. The peripheral blood and bone marrow aspirates from 35 pediatric patients with ALL and 48 healthy control subjects were selected for the experiment. We demonstrated the numbers of Th17 lymphocytes and Tregs were increased in the bone marrow of ALL patients at the moment of diagnosis compared to the healthy control group, with the latter significantly decreasing during the course of ALL treatment. Patients with lower Th17 were found to demonstrate higher risk of blasts prevalence in bone marrow at day 33. ALL patients with lower WBC demonstrated higher frequency of Tregs. In summary, we identified a significant role of Th17 and Treg lymphocytes in ALL of pediatric patients and their contribution to disease-related parameters.

Diagnostic Value and Prognostic Significance of Nucleated Red Blood Cells (NRBCs) in Selected Medical Conditions.

Nucleated red blood cells (NRBCs) are premature erythrocyte precursors that reside in the bone marrow of humans of all ages as an element of erythropoiesis. They rarely present in healthy adults' circulatory systems but can be found circulating in fetuses and neonates. An NRBC count is a cost-effective laboratory test that is currently rarely used in everyday clinical practice; it is mostly used in the diagnosis of hematological diseases/disorders relating to erythropoiesis, anemia, or hemolysis. However, according to several studies, it may be used as a biomarker in the diagnosis and clinical outcome prognosis of preterm infants or severely ill adult patients. This would allow for a quick diagnosis of life-threatening conditions and the prediction of a possible change in a patient's condition, especially in relation to patients in the intensive care unit. In this review, we sought to summarize the possible use of NRBCs as a prognostic marker in various disease entities. Research into the evaluation of the NRBCs in the pediatric population most often concerns neonatal hypoxia, the occurrence and consequences of asphyxia, and overall neonatal mortality. Among adults, NRBCs can be used to predict changes in clinical condition and mortality in critically ill patients, including those with sepsis, trauma, ARDS, acute pancreatitis, or severe cardiovascular disease.

Intravenous Immunoglobulin-Induced Aseptic Meningitis-A Narrative Review of the Diagnostic Process, Pathogenesis, Preventative Measures and Treatment.

Intravenous immunoglobulins (IVIGs) are widely used in the treatment of numerous diseases in both adult and pediatric populations. Higher doses of IVIGs usually serve as an immunomodulatory factor, common in therapy of children with immune thrombocytopenic purpura. Considering the broad range of IgG applications, the incidence of side effects in the course of treatment is inevitable. Aseptic meningitis, an uncommon but significant adverse reaction of IVIG therapy, can prove a diagnostic obstacle. As of April 2022, forty-four cases of intravenous immunoglobulin-induced aseptic meningitis have been reported in the English-language literature. This review aims to provide a thorough overview of the diagnostic process, pathophysiology, possible preventative measures and adequate treatment of IVIG-induced aseptic meningitis.

Circulating Hematopoietic (HSC) and Very-Small Embryonic like (VSEL) Stem Cells in Newly Diagnosed Childhood Diabetes type 1 - Novel Parameters of Beta Cell Destruction/Regeneration Balance and Possible Prognostic Factors of Future Disease Course.

AIMS/HYPOTHESIS: We aimed to evaluate hematopoietic stem cells (HSC) and very small embryonic-like stem cells (VSEL) mobilization to establish their role in residual beta cell function maintenance and partial remission occurrence in children newly diagnosed with type 1 diabetes. METHODS: We recruited 59 type 1 diabetic patients (aged 6-18 years) monitored for 2 years, and 31 healthy children as a control group. HSC and VSEL levels were assessed at disease onset in PBMC isolated from whole peripheral blood with the use of flow cytometry. An assessment of beta cell function was based on C-peptide secretion. Studied groups were stratified on the basis of VSEL, HSC and/or C-peptide median levels in regard to beta cell function and partial remission. RESULTS: Patients with higher stimulated C-peptide secretion at disease onset demonstrated lower levels of HSC (p < 0.05), while for VSEL and VSEL/HSC ratio higher values were observed (p < 0.05). Accordingly, after 2 years follow-up, patients with higher C-peptide secretion presented lower initial levels of HSC and higher VSEL/HSC ratio (p < 0.05). Patients with lower values of HSC levels demonstrated a tendency for better partial remission prevalence in the first 3 to 6 months after diagnosis. CONCLUSIONS: These clinical observations indicate a possible significant role of HSC and VSEL in maintaining residual beta cell function in type 1 diabetic patients.

Intraventricular Flow Simulations in Singular Right Ventricles Reveal Deteriorated Washout and Low Vortex Formation.

PURPOSE: Patients with a functionally univentricular heart represent one of the most common severe cardiac lesions with a prevalence of 3 per 10,000 live births. Hemodynamics of the singular ventricle is a major research topic in cardiology and there exists a relationship between fluid dynamical features and cardiac behavior in health and disease. The aim of the present work was to compare intraventricular flow in single right ventricle (SRV) patients and subjects with healthy left hearts (LV) through patient-specific CFD simulations. METHODS: Three-dimensional real-time echocardiographic images were obtained for five SRV patients and two healthy subjects and CFD simulations with a moving mesh methodology were performed. Intraventricular vortex formation and vortex formation time (VFT) as well as the turbulent kinetic energy (TKE) and ventricular washout were evaluated. RESULTS: The results show significantly lower values for the VFT and the TKE in SRV patients compared with healthy LV subjects. Furthermore, vortex formation does not progress to the apex in SRV patients. These findings were confirmed by a significantly lower washout in SRV patients. CONCLUSIONS: The study pinpoints the intriguing role of intraventricular flows to characterize performance of SRVs that goes beyond standard clinical metrics such as ejection fraction.

Effects of Pegylated Interferon Alpha and Ribavirin (pegIFN-α/RBV) Therapeutic Approach on Regulatory T Cells in HCV-Monoinfected and HCV/HIV-Coinfected Patients.

Approximately 25% of HIV-infected patients are co-infected with HCV. Notably, the burden of HCV infection (e.g., viral persistence, viral load, or HCV-related liver symptoms) is more pronounced in the presence of HIV co-infection. However, to date, the underlying immune mechanisms accounting for accelerated disease progression in HIV/HCV-coinfected individuals have not been described in sufficient detail. We hypothesized that regulatory T cells (Treg) bearing potent immunosuppressive capacities could not only play a substantial role in the pathogenesis of HCV/HIV coinfection but also modulate the response to the standard anti-viral therapy. MATERIALS AND METHODS: To this end, we studied alterations in frequencies of Treg cells in correlation with other Treg-related and virus-related parameters in both HCV and HCV/HIV-infected patients subjected to standard pegIFN-α/RBV therapy. RESULTS: Notably, we found that pegIFN-α/RBV therapy significantly increased levels of Treg cells in HCV-infected but not in HIV/HCV-coinfected individuals. Furthermore, HIV/HCV-coinfection was demonstrated to inhibit expansion of regulatory T cells during anti-viral treatment; thus, it might probably be responsible for viral persistence and HCV-related liver damage. CONCLUSIONS: Therapy with pegIFN-α/RBV demonstrated a significant effect on regulatory T cells in the course of HIV and/or HCV infection indicating a crucial role in the anti-viral immune response.

Differential Response of MDA-MB-231 and MCF-7 Breast Cancer Cells to In Vitro Inhibition with CTLA-4 and PD-1 through Cancer-Immune Cells Modified Interactions.

Drugs targeting immune checkpoint molecules have been found effective in melanoma, lung cancer, and other malignancies treatment. Recent studies on breast cancer demonstrated the significance of inhibitory anti-CTLA-4 and anti-PD-1 in the regulation of disease progression. However, seemingly the same types of breast cancer do not always respond unambiguously to immunotherapy. Thus, here we set out to analyze the in vitro effects of inhibiting CTLA-4 and PD-1 on interactions between co-cultured lymphocytes and two selected breast adenocarcinoma cell lines. Breast cancer cells were co-cultured with lymphocytes to evaluate the effects of CTLA-4 and PD-1 inhibition. Proliferation, cell cycle, and viability assessment were measured in cancer cells. IFN-gamma, IL-10, perforin, granzyme B production, and CTLA-4 and PD-1 expression were analyzed in lymphocytes. We found that administration of anti-CTLA-4 improved the anti-cancer activity of T cells with reduced proliferation and viability of MDA-MB-231. Lack of response was observed in the context of MCF-7. In addition, differential expression of checkpoint proteins was found between studied cancer cells lines. Inhibition of molecules was followed by IL-10 and IFN-gamma decrease in lymphocytes co-cultured with MDA-MB-231, not demonstrated in reference to MCF-7. Furthermore, CTLA-4 blockage was associated with reduction of CTLA-4+ and PD-1+ lymphocytes in MDA-MB-231, with a significant increase in MCF-7, reduced by anti-PD-1. Altogether, our study revealed that anti-CTLA-4 and anti-PD-1 treatment can improve lymphocytes effects on breast cancer cells. Favorable effects seemed to be related to breast cancer cells features as differential responses were reported. Novel blocking antibodies strategies should be tested for more effective cancer inhibition.

Estimation of left ventricular stroke work based on a large cohort of healthy children.

Left ventricular stroke work is an important prognostic marker to analyze cardiac function. Standard values for children are, however, missing. For clinicians, standards can help to improve the treatment decision of heart failures. For engineers, they can help to optimize medical devices. In this study, we estimated the left ventricular stroke work for children based on modeled pressure-volume loops. A lumped parameter model was fitted to clinical data of 340 healthy children. Reference curves for standard values were created over age, weight, and height. Left ventricular volume was measured with 3D echocardiography, while maximal ventricular pressure was approximated with a regression model from the literature. For validation of this method, we used 18 measurements acquired by a conductance catheter in 11 patients. The method demonstrated a low absolute mean difference of 0.033 J (SD: 0.031 J) for stroke work between measurement and estimation, while the percentage error was 21.66 %. According to the resulting reference curves, left ventricular stroke work of newborns has a median of 0.06 J and increases to 1.15 J at the age of 18 years. Stroke work increases over weight and height in a similar trend. The percentile curves depict the distribution. We demonstrate how reference curves can be used for quantification of differences and comparison in patients.

One Ligand, One Metal, Seven Oxidation States: Stable Technetium Complexes with the "Kläui Ligand".

A series of technetium complexes with (η5-cyclopentadienyl)tris(dimethyl phosphito-P)cobaltate(III), also known as the "Kläui ligand" {LOMe}-, has been prepared. The products span seven different oxidation states (+1 to +7) of the radioactive transition metal and comprise nitrosyl, halide, oxido and nitrido complexes. All members of this series ([TcI(NO)Cl(PPh3)(LOMe)], [TcII(NO)Cl2(LOMe)], [TcIIICl2(PPh3)(LOMe)], [TcIVCl3(LOMe)], [TcVOCl2(LOMe)], [TcVNCl(PPh3)(LOMe)], [TcVINCl2(LOMe)], and [TcVIIO3(LOMe)] are air- and water-stable compounds, which recommends this class of technetium complexes as potential candidates for nuclear medical imaging procedures.

Understanding Ni(II)-Mediated C(sp3)-H Activation: Tertiary Ureas as Model Substrates.

We report a mechanistic study of C(sp3)-H bond activation mediated by nickel. Cyclometalated Ni(II) ureate [(PEt3)Ni(κ3- C,N,N-(CH2)N(Cy)(CO)N((N)-quinolin-8-yl))] was synthesized and isolated from the urea precursor, (Me)(Cy)N(CO)N(H)(quinolin-8-yl), via C(sp3)-H activation. We investigated the effects of solvents and base additives on the rate of C-H activation. Kinetic isotope effect experiments showed that C-H activation is rate determining. Through deuterium labeling and protonation studies, we also showed that C-H activation can be reversible. We extended this reaction to a range of ureas with primary and secondary C(sp3)-H bonds, which activate readily to form analogous nickelated products. Finally, we showed that carboxylate additives assist with both ligand dissociation and initial N-H bond activation, consistent with a concerted metalation-deprotonation mechanism.