Application of metabolomics in diagnostics and differentiation of meningitis: A narrative review with a critical approach to the literature.

Due to its high mortality rate associated with various life-threatening sequelae, meningitis poses a vital problem in contemporary medicine. Numerous algorithms, many of which were derived with the aid of artificial intelligence, were brought up in a strive for perfection in predicting the status of sepsis-related survival or exacerbation. This review aims to provide key insights on the contextual utilization of metabolomics. The aim of this the metabolomic approach set of methods can be used to investigate both bacterial and host metabolite sets from both the host and its microbes in several types of specimens - even in one's breath, mainly with use of two methods - Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR). Metabolomics, and has been used to elucidate the mechanisms underlying disease development and metabolic identification changes in a wide range of metabolite contents, leading to improved methods of diagnosis, treatment, and prognosis of meningitis. Mass spectrometry (MS) and Nuclear Magnetic Resonance (NMR) are the main analytical platforms used in metabolomics. Its high sensitivity accounts for the usefulness of metabolomics in studies into meningitis, its sequelae, and concomitant comorbidities. Metabolomics approaches are a double-edged sword, due to not only their flexibility, but also - high complexity, as even minor changes in the multi-step methods can have a massive impact on the results. Information on the differential diagnosis of meningitis act as a background in presenting the merits and drawbacks of the use of metabolomics in context of meningeal infections.

The Mother-Child Dyad Adipokine Pattern: A Review of Current Knowledge.

An important role in the network of interconnections between the mother and child is played by adipokines, which are adipose tissue hormones engaged in the regulation of metabolism. Alternations of maternal adipokines translate to the worsening of maternal insulin resistance as well as metabolic stress, altered placenta functions, and fetal development, which finally contribute to long-term metabolic unfavorable conditions. This paper is the first to summarize the current state of knowledge concerning the concentrations of individual adipokines in different biological fluids of maternal and cord plasma, newborn/infant plasma, milk, and the placenta, where it highlights the impact of adverse perinatal risk factors, including gestational diabetes mellitus, preeclampsia, intrauterine growth restriction, preterm delivery, and maternal obesity on the adipokine patterns in maternal-infant dyads. The importance of adipokine measurement and relationships in biological fluids during pregnancy and lactation is crucial for public health in the area of prevention of most diet-related metabolic diseases. The review highlights the huge knowledge gap in the field of hormones participating in the energy homeostasis and metabolic pathways during perinatal and postnatal periods in the mother-child dyad. An in-depth characterization is needed to confirm if the adverse outcomes of early developmental programming might be modulated via maternal lifestyle intervention.

Application of Metabolomics in Childhood Leukemia Diagnostics.

Metabolomics is a new field of science dealing with the study and analysis of metabolites formed in living cells. The biological fluids used in this test method are: blood, blood plasma, serum, cerebrospinal fluid, saliva and urine. The most popular methods of assessing the composition of metabolites include nuclear magnetic resonance spectroscopy and mass spectrometry (MS) in combination with gas chromatography-MS or liquid chromatography-MS. Metabolomics is used in many areas of medicine. The variability of biochemical processes in neoplastic cells in relation to healthy cells is the starting point for this type of research. The aim of the research currently being carried out is primarily to find biomarkers for quick diagnosis of the disease, assessment of its advancement and treatment effectiveness. The development of metabolomics may also contribute to the individualization of treatment of patients, adjusting drugs depending on the metabolic profile, and thus may improve the effectiveness of therapy, reduce side effects and help to improve the quality of life of patients. Here, we review the current and potential applications of metabolomics, focusing on its use as a biomarker method for childhood leukemia.

Kidney Dysfunction and Its Progression in Patients Hospitalized Duo to COVID-19: Contribution to the Clinical Course and Outcomes.

The disease caused by coronavirus SARS-CoV-2 (COVID-19) can affect almost all organs of the human body, including kidneys. We conducted a one-center study to comprehensively analyze the effects of kidney involvement on the course and outcomes in patients hospitalized with COVID-19, depending on the estimated glomerular filtration rate (eGFR) at admission. Out of the 1958 patients, 1342 (68.54%) had eGFR ≥ 60 mL/min/1.73 m2 (group A) and 616 (31.46%) had eGFR < 60 mL/min/1.73 m2 (group B). Group B was additionally divided into subgroups B1, B2, and B3 based on eGFR. We found that mortality rates during hospitalization, as well as after 90 and 180 days, were much higher in group B than group A. The highest mortality was observed in the B2 subgroup with eGFR of 15-29. The mortality of B patients was associated with comorbidities, respiratory dysfunction, immunological impairment, and more frequent development of AKI. AKI had a negative impact on patients' survival, regardless of the initial renal function. At discharge, 7.4% of patients had serum creatinine levels 30% higher, or more, as compared to admission. The disease course and outcomes in COVID-19 patients are associated with baseline eGFR; however, AKI during hospitalization is a more significant predictor of poor prognosis regardless of the initial renal function.

Time-dependent changes in extra-domain A-fibronectin concentration and relative amounts of fibronectin-fibrin complexes in plasma of patients with peripheral arterial disease after endovascular revascularisation.

Fibronectin (FN) may be involved in time- and stage-dependent and inter-related controlled processes of inflammation, coagulation, and wound healing accompanying peripheral arterial disease (PAD). In the present study, FN and FN-containing extra-domain A (EDA-FN), macromolecular FN-fibrin complexes, and FN monomer were analysed in the plasma of 142 PAD patients, including 37 patients with restenosis, for 37 months after revascularisation. FN concentration increased significantly in the plasma of PAD patients within 7 to 12 months after revascularisation, whereas the high concentration of EDA-FN was maintained up to 24 months, significantly higher in the group 7 to 12 months after revascularisation with recurrence of stenosis and lower in the PAD groups 1 to 3 months and 4 to 6 months after revascularisation with comorbid diabetes and ulceration, respectively. The relative amounts of FN-fibrin complexes up to 1600 kDa and FN monomer were significantly higher, within intervals of 4 to 24 months and 4 to 6 months after revascularisation, respectively. Moreover, the relative amounts of 750 to 1600 kDa FN-fibrin complexes within 13 to 24 months after revascularisation were higher in comparison with those in the group without restenosis. In conclusion, high levels of EDA-FN and FN-fibrin complexes could have potential diagnostic value in the management of PAD patients after revascularisation, predicting restenosis risk.

Analysis of Soluble Molecular Fibronectin-Fibrin Complexes and EDA-Fibronectin Concentration in Plasma of Patients with Atherosclerosis.

Atherosclerosis, a chronic vascular disease, leads to molecular events bound with interplaying processes of inflammation and coagulation. In the present study, fibronectin (FN), FN containing extra domain A (EDA-FN), frequency of occurrence, and relative amounts of soluble plasma FN-fibrin complexes were analyzed in 80 plasma samples of patients suspected of coronary artery disease based on clinical evaluation and changes in arteries found by computed tomographic coronary angiography. The study showed that in the plasma of the patients' group with high risk of coronary artery disease EDA-FN concentration was significantly higher (3.5 ± 2.5 mg/L; P < 0.025) and the molecular FN-fibrin complexes of 1000 kDa and higher occurred more often than in the groups of patients with mild risk of coronary artery disease and the normal age-matched. The increased level of EDA-FN and occurrence of FN-fibrin complexes could have a potential diagnostic value in the diagnosis and management of patients with coronary artery disease.

Occurrence of fibronectin-fibrin complexes in plasma of patients with multimorbidity due to the inflamm-aging phenomenon.

BACKGROUND: Multimorbidity is the co-occurrence of chronic diseases associated with low-grade chronic inflammation of connective tissue. AIM OF STUDY: Frequency of occurrence and relative amounts of fibronectin (FN) complexes with fibrin (FN-fibrin) and FN monomer were analyzed in 130 plasma samples of 18 to 94-year-old multimorbid patients in relation to concentrations of FN and extra domain A (EDA)-FN, and C-reactive protein (CRP) as well as to age, number of coexisting chronic diseases and presence of specified diseases. RESULTS: Immunoblotting revealed, besides FN dimer, the presence of FN monomer, and 750-, 1000-, and 1300-kDa FN-fibrin complexes in the multimorbid plasmas. The FN-fibrin complexes appeared more frequently and in higher relative amounts, but FN monomer less frequently and in a lower relative amount in the groups of elderly multimorbid patients, with a higher number of coexisting diseases and with dominance of cardiovascular diseases and osteoarthrosis, and with CRP concentration of 3-5mg/l. In contrast, the normal plasma contained only the FN-fibrin complex of 750 kDa in a lower relative amount, but with an increasing amount with normal aging. Moreover, FN concentration increased and EDA-FN decreased with the number of co-existing diseases and aging of patients, although both concentration values were lower than in the age-matched normal groups. FN concentration was the lowest in the exacerbation of a chronic disease and EDA-FN in the stable chronic disease groups. CONCLUSION: The alterations in plasma FN molecular status were associated with micro-inflammation and micro-coagulation, as well as multimorbidity of subjects and their physiological aging.

Identification of soluble supramolecular FN-fibrin complexes in human plasma.

SDS-agarose FN immunoblotting of 257 normal and pathological human plasma samples revealed the ladder pattern of multiple plasma FN bands which corresponded to FN monomer and dimer, and 5 FN-fibrin bands with increasing molecular masses. The FN-fibrin bands of about 750 kDa, 1000 kDa, 1300 kDa, 1600 kDa, and 1900 kDa appeared more frequently and in significantly higher relative amounts in the pathological samples (P < 0.000) than in relatively healthy individuals. The revealing of high-molecular FN-fibrin complexes by SDS-agarose FN immunobloting might have the potential to become a laboratory biomarker of some diseases in which the coagulation system is triggered.

EDA-containing fibronectin levels in the cerebrospinal fluid of children with meningitis.

Fibronectin containing an alternatively spliced extra domain A (EDA-FN) participates in diverse biological cell functions, being also directly or indirectly engaged during an inflammatory response to brain injury and/or neuron regeneration. We analyzed FN and EDA-FN isoform levels by ELISA in 85 cerebrospinal fluid samples and 67 plasma samples obtained from children suffering from bacterial or viral meningitis and non-meningitis peripheral inflammation. We have found that the cerebrospinal level of EDA-FN was significantly lower in the bacterial meningitis group than in the viral- and non-meningitis groups. In the patients' plasma, EDA-FN was almost undetectable. The determination of fibronectin containing the EDA segment might be considered as an additional diagnostic marker of bacterial meningitis in children.

Alterations in molecular status of plasma fibronectin associated with aging of normal human individuals.

OBJECTIVES: Senescence, progressive deterioration of many bodily functions might be associated with age-dependent alterations of plasma fibronectin (FN) molecular status (i.e., domain, glycotope, and molecular form expressions). DESIGN AND METHODS: FN molecular status was analyzed in 127 plasma samples of healthy individuals in groups of newborns, and subjects aged 3-14, 15-39, 41-59, and 60-82 years by FN-ELISA, lectin-FN-ELISA, and immunoblotting using a set of domain-specific monoclonal antibodies, specific lectins, and monoclonal antibody to FN, respectively. RESULTS: During the first four decades of human life the levels of cell-binding-, carboxyl-terminal-, collagen-, heparin-, and fibrin-domains of plasma FN gradually increased. In subjects aged up to 82 years the cell-binding and carboxyl-terminal FN domain concentrations did not change, while the heparin, fibrin, and collagen domains significantly increased. The relative reactivity of plasma FN with Maackia amurensis lectin, specific to α2,3-linked sialic acid, significantly decreased after birth, reaching a stable level in the subsequent life period, whereas with Sambucus nigra lectin, specific to α2,6-linked sialic acid, it significantly decreased in the 60-82 year old group. Moreover, the appearance of 280-kDa and 320-kDa FN bands, absent in young and mature healthy individuals, was found in the groups of 41-59 and 60-82 year olds. CONCLUSIONS: The alterations of FN molecular status throughout growth, maturation and senescence might be associated not only with disturbances in the balance of FN production rate and degradation, but concomitantly with conformational rearrangements of FN and its engagement in age-related vascular remodeling processes.

Human plasma and cerebrospinal fibronectins differ in the accessibility of the epitopes on the N-terminal domains.

Three monoclonal antibodies specific to the central cell-binding and the C- and N-terminal domains of fibronectin (FN) were used to test antigenic epitope accessibility on human plasma and cerebrospinal fibronectins. In the plasma group, the mean N-terminal FN domain immunoreactivity was about one fourth that of the cell-binding and C-terminal domains, whereas in cerebrospinal fluid they were nearly equal. In the presence of 0.5-6 M urea N-terminal domain immunoreactivity in the plasma increased 3-6-fold, but it decreased 0.7-3-fold in the cerebrospinal fluid. Analysis of fibronectin domain immunoreactivities of the cell-binding and N-terminal domains by a panel of specific monoclonal antibodies may reveal N-terminal fibronectin domain accessibility for reaction with biological partner ligand(s) and/or processes in which FN could be implicated. Such determinations may have important clinical implications.

Presence of high-molecular-weight forms and domain alterations of fibronectin in pleural effusion of patients with lung cancer.

OBJECTIVES: Appearance of fibronectin (FN) molecular forms and alterations of domain expositions can be associated with lung cancer. DESIGN AND METHODS: The presence of the FN molecular forms and epitopes in its cell-binding, carboxyl-, and amino-terminal domains was determined in the plasma and pleural effusion of patients suffering from small- and non-small-cell lung cancer, and lung inflammation by immunoblotting and FN-ELISA. RESULTS: The 320-kDa and 280-kDa FN forms as well as FN fragments appeared in the pleural effusion and plasma of patients suffering from lung inflammation or cancer in significantly higher relative amounts in both lung cancer groups than in the inflammation. The domain concentrations were higher in the cancer and inflammatory plasma groups than those in the control group. The higher N-terminal epitope expression in pleural effusion than in plasma indicates different epitope accessibility for the monoclonal antibody. CONCLUSIONS: The molecular status of FN probably reflects the dynamic changes which occur in cancer and inflammatory tissue.

Antibacterial potential of saliva in children with leukemia.

OBJECTIVES: The objectives of this study were to evaluate the local oral defense mechanisms during the course of leukemia, and to define the correlation between the activity of salivary antibacterial factors and the oral clinical findings. STUDY DESIGN: A total of 44 children with newly diagnosed acute leukemia participated in the study. The control group consisted of 23 healthy children. The examination took place at the time of the diagnosis, and during and at the end of the chemotherapy treatment course. During the collection of resting mixed saliva samples the salivary flow rate was measured. In the saliva's supernatant the following parameters were determined: total protein, peroxidase, myeloperoxidase, lysozyme, lactoferrin, and secretory immunoglobulin A. RESULTS: The introduction of chemotherapy caused a slight decrease of salivary secretion rate (P < .05), as well as the decrease of S-IgA concentration (P < .01), which remained at the same level after the end of chemotherapy (P < .001). Patients with aplasia had decreased levels of peroxidase (P = .014) and myeloperoxidase (P = .013). Patients with oral mucositis presented with lower myeloperoxidase (P = .026) and peroxidase (P = .003) activity levels as well as the drop of S-IgA (P = .000) concentration compared with subjects with no mucositis. CONCLUSIONS: Antileukemic treatment contributes to the compromise of salivary defense mechanisms, therefore it is reasonable to support pharmacologically the saliva's antibacterial potential of leukemic patients to impede the development of local infection.

Time-dependent observations of secretion marker levels in nasal secretion after histamine and methacholine provocations.

Nasal provocation tests with histamine and methacholine were carried out on 25 healthy men in an effort to assess the dynamic changes of albumin, total IgA, secretory IgA and lactoferrin concentrations in the nasal secretion. The trials were performed with 0.5, 1, and 4 mg of histamine and 8, 16, and 32 mg of methacholine. Each dose of histamine or methacholine was sprayed into the nose every 2nd day, with two days' interval between the two provoking agents. Nasal secretions were collected after saline spraying only, forming the baseline group, after 3, 10 and 15 min of administration of the challenge agent. The baseline levels presented the following values: for albumin 257 +/- 230 microg/ml, secretory IgA 608 +/- 379 microg/ml, total IgA 1025 +/- 423 micog/ml, and lactoferrin 213 +/- 156 microg/ml. The increase in albumin level after nasal provocation, particularly significant after histamine administration (to 3713 +/- 2311 microg/ml), indicates incessant protein plasma leakage from the blood circulation to the nasal secretion. After administration of both provocating agents, there was a significant gradual decrease in secretory IgA level, even below the baseline value. After the 2nd and 3rd doses of methacholine and histamine spray, the concentration of secretory IgA decreased by 2-3 times and was found to be 200-300 microg/ml, respectively. Also, lactoferrin concentration values decreased gradually after the 2nd and 3rd doses of methacholine and histamine to levels close the baseline value. These observations suggest a time- and dose-dependent, non-specific dysfunction of local immunity response after nasal provocations.