Gaia as Solaris: An Alternative Default Evolutionary Trajectory.

Now that we know that Earth-like planets are ubiquitous in the universe, as well as that most of them are much older than the Earth, it is justified to ask to what extent evolutionary outcomes on other such planets are similar, or indeed commensurable, to the outcomes we perceive around us. In order to assess the degree of specialty or mediocrity of our trajectory of biospheric evolution, we need to take into account recent advances in theoretical astrobiology, in particular (i) establishing the history of habitable planets' formation in the Galaxy, and (ii) understanding the crucial importance of "Gaian" feedback loops and temporal windows for the interaction of early life with its physical environment. Hereby we consider an alternative macroevolutionary pathway that may result in tight functional integration of all sub-planetary ecosystems, eventually giving rise to a true superorganism at the biospheric level. The blueprint for a possible outcome of this scenario has been masterfully provided by the great Polish novelist Stanislaw Lem in his 1961 novel Solaris. In fact, Solaris offers such a persuasive and powerful case for an "extremely strong" Gaia hypothesis that it is, arguably, high time to investigate it in a discursive astrobiological and philosophical context. In addition to novel predictions in the domain of potentially detectable biosignatures, some additional cognitive and heuristic benefits of studying such extreme cases of functional integration are briefly discussed.

Lipopolysaccharide can modify differentiation and immunomodulatory potential of periodontal ligament stem cells via ERK1,2 signaling.

Lipopolysaccharide (LPS) is a pertinent deleterious factor in oral microenvironment for cells which are carriers of regenerative processes. The aim of this study was to investigate the emerging in vitro effects of LPS (Escherichia coli) on human periodontal ligament stem cell (PDLSC) functions and associated signaling pathways. We demonstrated that LPS did not affect immunophenotype, proliferation, viability, and cell cycle of PDLSCs. However, LPS modified lineage commitment of PDLSCs inhibiting osteogenesis by downregulating Runx2, ALP, and Ocn mRNA expression, while stimulating chondrogenesis and adipogenesis by upregulating Sox9 and PPARγ mRNA expression. LPS promoted myofibroblast-like phenotype of PDLSCs, since it significantly enhanced PDLSC contractility, as well as protein and/or gene expression of TGF-ß, fibronectin (FN), α-SMA, and NG2. LPS also increased protein and gene expression levels of anti-inflammatory COX-2 and pro-inflammatory IL-6 molecules in PDLSCs. Inhibition of peripheral blood mononuclear cells (MNCs) transendothelial migration in presence of LPS-treated PDLSCs was accompanied by the reduction of CD29 expression within MNCs. However, LPS treatment did not change the inhibitory effect of PDLSCs on mitogen-stimulated proliferation of CD4+ and the ratio of CD4+ CD25high /CD4+ CD25low lymphocytes. LPS-treated PDLSCs did not change the frequency of CD34+ and CD45+ cells, but decreased the frequency of CD33+ and CD14+ myeloid cells within MNCs. Moreover, LPS treatment attenuated the stimulatory effect of PDLSCs on CFC activity of MNCs, predominantly the CFU-GM number. The results indicated that LPS-activated ERK1,2 was at least partly involved in the observed effects on PDLSC differentiation capacity, acquisition of myofibroblastic attributes, and changes of their immunomodulatory features.

Parallel targeted next generation sequencing of childhood and adult acute myeloid leukemia patients reveals uniform genomic profile of the disease.

The age-specific differences in the genetic mechanisms of myeloid leukemogenesis have been observed and studied previously. However, NGS technology has provided a possibility to obtain a large amount of mutation data. We analyzed DNA samples from 20 childhood (cAML) and 20 adult AML (aAML) patients, using NGS targeted sequencing. The average coverage of high-quality sequences was 2981 × per amplicon. A total of 412 (207 cAML, 205 aAML) variants in the coding regions were detected; out of which, only 122 (62 cAML and 60 aAML) were potentially protein-changing. Our results confirmed that AML contains small number of genetic alterations (median 3 mutations/patient in both groups). The prevalence of the most frequent single gene AML associated mutations differed in cAML and aAML patient cohorts: IDH1 (0 % cAML, 5 % aAML), IDH2 (0 % cAML, 10 % aAML), NPM1 (10 % cAML, 35 % aAML). Additionally, potentially protein-changing variants were found in tyrosine kinase genes or genes encoding tyrosine kinase associated proteins (JAK3, ABL1, GNAQ, and EGFR) in cAML, while among aAML, the prevalence is directed towards variants in the methylation and histone modifying genes (IDH1, IDH2, and SMARCB1). Besides uniform genomic profile of AML, specific genetic characteristic was exclusively detected in cAML and aAML.

Evolvability Is an Evolved Ability: The Coding Concept as the Arch-Unit of Natural Selection.

Physical processes that characterize living matter are qualitatively distinct in that they involve encoding and transfer of specific types of information. Such information plays an active part in the control of events that are ultimately linked to the capacity of the system to persist and multiply. This algorithmicity of life is a key prerequisite for its Darwinian evolution, driven by natural selection acting upon stochastically arising variations of the encoded information. The concept of evolvability attempts to define the total capacity of a system to evolve new encoded traits under appropriate conditions, i.e., the accessible section of total morphological space. Since this is dependent on previously evolved regulatory networks that govern information flow in the system, evolvability itself may be regarded as an evolved ability. The way information is physically written, read and modified in living cells (the "coding concept") has not changed substantially during the whole history of the Earth's biosphere. This biosphere, be it alone or one of many, is, accordingly, itself a product of natural selection, since the overall evolvability conferred by its coding concept (nucleic acids as information carriers with the "rulebook of meanings" provided by codons, as well as all the subsystems that regulate various conditional information-reading modes) certainly played a key role in enabling this biosphere to survive up to the present, through alterations of planetary conditions, including at least five catastrophic events linked to major mass extinctions. We submit that, whatever the actual prebiotic physical and chemical processes may have been on our home planet, or may, in principle, occur at some time and place in the Universe, a particular coding concept, with its respective potential to give rise to a biosphere, or class of biospheres, of a certain evolvability, may itself be regarded as a unit (indeed the arch-unit) of natural selection.

Immunomodulation by heavy metals as a contributing factor to inflammatory diseases and autoimmune reactions: Cadmium as an example.

Cadmium (Cd) represents a unique hazard because of the long biological half-life in humans (20-30 years). This metal accumulates in organs causing a continuum of responses, with organ disease/failure as extreme outcome. Some of the cellular and molecular alterations in target tissues can be related to immune-modulating potential of Cd. This metal may cause adverse responses in which components of the immune system function as both mediators and effectors of Cd tissue toxicity, which, in combination with Cd-induced alterations in homeostatic reparative activities may contribute to tissue dysfunction. In this work, current knowledge concerning inflammatory/autoimmune disease manifestations found to be related with cadmium exposure are summarized. Along with epidemiological evidence, animal and in vitro data are presented, with focus on cellular and molecular immune mechanisms potentially relevant for the disease susceptibility, disease promotion, or facilitating development of pre-existing pathologies.

Gender differences in acute cadmium-induced systemic inflammation in rats.

OBJECTIVE: To examine the presence of gender differences in pro-inflammatory potential of cadmium in rats by comparing systemic inflammatory response to acute cadmium intoxication in animals of the two sexes. METHODS: Basic aspects of this response were evaluated, including plasma levels of inflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) and of major rat acute phase protein alpha 2-macroglobulin (alpha2-M), as soluble indicators of inflammation, and the number and activity of peripheral blood leukocytes, as cellular indicators of inflammation. RESULTS: Differential increases of IL-6 and alpha2-M (higher in males than in females) in peripheral blood cell counts and types (leukocytosis and shift in the ratio of granulocytes to lymphocytes more pronounced in males vs females) and in levels of neutrophil priming (higher in males vs females) were noted. CONCLUSION: The data document a more intense inflammatory response to cadmium administration in males. The sex differences in inflammatory effects of cadmium might be taken into consideration in studying the toxicity of this heavy metal.

Lymphoblastic lymphomas in children ­ A single-center experience from Serbia.

Introduction: Intensive treatment protocols used for non-Hodgkin lymphoma in children lead to eventfree survival rates ranging from 80% to 90%. However, the results are less successful in developing countries. Lymphoblastic lymphoma (LBL) is the second most frequent type of lymphoma in children, contributing with about one third to all non-Hodgkin lymphoma in childhood. Objective: The aim of the study was to evaluate the results of LBL treatment in University Children's Hospital (UCH), Belgrade. Methods: A retrospective analysis of patient records at UCH from 1997 to 2015 was carried out in patients aged 0­18 years, in whom the diagnosis of LBL had been established. Twenty-two children were included in the analysis. Results: Mean age at diagnosis was 10 years, with preponderance of male patients. All patients were treated according to Berlin-Frankfurt-Münster-based chemotherapy protocols. With median follow-up of 91.5 months, five-year probability of event-free survival was 79.5% for all patients, while overall survival was 81.8%. Conclusion: Our results, although slightly inferior to those of leading international groups, reflect a good treatment outcome in our patients.

Extreme Hypertriglyceridemia in an Infant with Hemophagocytic Lymphohistiocytosis and Hydroxycobalamin Deficiency.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition characterized by fever, cytopenias, hepatosplenomegaly and hemophagocytosis. HLH may be primary or secondary to infection, autoimmune disease or malignancy. Hypertriglyceridemia is a common abnormality in HLH and one of the HLH-2004 diagnostic criteria. CASE OUTLINE: We present an infant with severe hypotonia and hypoproteinemic edema who also had extreme hypertriglyceridemia (21 mmol/l) and was diagnosed with HLH based on six of eight HLH-2004 criteria (fever, hepatosplenomegaly, bicytopenia, hypertriglyceridemia with hypofibrinogenemia, slL-2R > 2400 IU/ml, hemophagocytosis). The presence of IgM antibodies to Epstein-Barr virus and cytomegalovirus indicated a probable infectious trigger. The child was cured by the HLH-2004 protocol for secondary HLH (consisting of dexamethasone and cyclosporine). He was also found to have low serum hydroxycobalamin levels, promptly corrected upon hydroxycobalamin administration. CONCLUSION: The presented case history underlines the need to ascertain the presence or absence of each of the eight HLH-2004 criteria in any patient suspected to suffer from HLH.

Hemophagocytic lymphohistiocytosis arising in a child with Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is characterized by the proliferation of clonal dendritic cells, while hemophagocytic lymphohistiocytosis (HLH) is an extreme inflammatory process sustained by the uncontrolled activation of macrophages. HLH can be primary or secondary, the latter arising in infectious, autoimmune or neoplastic disorders. We hereby present a young girl who developed secondary HLH while being treated for relapsed multisystem LCH under the LCH III Protocol. She fulfilled 5 of 8 HLH-2004 criteria (fever, splenomegaly, pancytopenia, ferritin level >500 µ/l and sIL-2R >2400 IU/ml) and was successfully treated by the HLH-2004 Protocol for secondary HLH. She remains in good health, apart from insipid diabetes she developed as a complication of LCH. Considering that the occurrence of HLH in LCH patients has been reported before, the case history presented here yields additional support for the hypothesis that the pathogenesis of the two histiocytoses--LCH and HLH--may indeed overlap to a considerable extent.

[Clinical characteristics and disease course in children with haemophagocytic lymphohistiocytosis treated at the University Children's Hospital in Belgrade].

INTRODUCTION: Haemophagocytic lymphohistiocytosis (HLH) is a disorder characterised by long-standing fever, splenomegaly and bicytopoenia or pancytopoenia. Lymphadenopathy, jaundice and neurological symptoms mayalsooccur. HLH may ensue in various forms of innate or acquired immunodeficiency with impaired cytotoxic lymphocyte function resulting in excessive macrophage activation. OBJECTIVE: To describe and analyse clinical characteristics of patients treated for HLH at the University Children's Hospital of Belgrade from August 2000 to August 2010. METHODS: Retrospective analysis of medical records. RESULTS: Diagnosis of HLH was established in 13 children (five boys and eight girls) aged from one month to 14 years. In six children HLH was secondary (to visceral leishmaniasis in two, Ebstein-Barr virus infection in one, Langerhans' cell histiocytosis in one and systemic juvenile rheumatoid arthritis in two). Of the remaining seven patients, genes for perforin and syntaxin 11 were examined in two and no mutations were found. Of the remaining seven patients, genes encoding perforin and syntaxin 11 were analyzed in two, but no mutations were found. All children had fever, splenomegaly, cytopoenias, hyperferritinaemia and hypertriglyceridaemia, but haemophagocytosis was seen in only six (46.1%). Six children were cured (four with secondary HLH and two with primary HLH).Two children are undergoing treatment, while five succumbed (three before treatment could be administered and two due to complications). In four of the six cured children, HLH arose in the first year of life. Cure rate in those who underwent haematopoietic stem cell transplantation was 2/3. CONCLUSION: Results underscore the importance of timely diagnosis and treatment of HLH, warranting that in all children with fever, splenomegaly and/or cytopoenias, with or without haemophagocytosis, HLH be actively sought.

Immediate allergic reaction to methylprednisolone with tolerance of other corticosteroids.

INTRODUCTION: In spite of the wide usage of corticosteroids for the treatment of a plethora of diseases, sometimes they can induce immediate hypersensitivity reactions, which are however uncommon. CASE OUTLINE: We report a case of immediate allergic reaction induced by intravenous methylprednisolone given before operation for surgical repair of an arm contracture as a sequel of burns, which the child had tolerated a month before. Six weeks later the patient repeated the anaphylactic reaction during skin testing to methylprednisolone. In addition, basophile activation test with methylprednisolone (BAT) was positive. CONCLUSION: This case report describes a patient who experienced intraoperative anaphylaxis and anaphylactic reaction induced by skin testing. This is the first report on induction of both anaphylactic reactions by methylprednisolone in the same child. Clinical findings, positive BAT and positive skin tests with methylprednisolone imply that the child developed type-I hypersensitivity. The lack of crossreactivity with other corticosteroids emphasizes that the reactions were caused by the steroid molecule.

[Hyper-IgM syndrome in a boy with recurrent pneumonia and hepatosplenomegaly].

INTRODUCTION: We present a boy diagnosed at age 14 years with hyper-immunoglobulin (Ig) M syndrome, a congenital immunodeficiency characterized by reduced plasma concentrations of IgA, IgE and IgG, with normal or elevated concentrations of IgM. This syndrome is caused by a defect of CD40 ligand (CD40L) on T-helper lymphocytes, impeding the "second signal" during activation of B lymphocytes and interactions of T cells with dendritic cells and macrophages, resulting in the absence of secondary immune response (class switching, affinity maturation, immune memory), as well as responses to T-dependent antigens, with an impairment of cellular immunity. CASE OUTLINE: The history of the presented patient was dominated by frequent lower respiratory infections and failure to thrive. Physical examination demonstrated severe hepatosplenomegaly. The suspicion of hyper-IgM syndrome was raised by low plasma IgA (0.36 g/l) with high plasma IgM (35.5 g/l), while the concentration of IgG was within the normal range (12.1 g/l). The diagnosis was confirmed by flow cytometry, which demonstrated the absence of expression of CD40L on lymphocytes following stimulation by phorbolmyristylacetate and calcium ionophore. Since the time of diagnosis, intravenous immunoglobulin therapy has led to catch-up growth, recession of hepatosplenomegaly and reduction in the frequency of respiratory infections. CONCLUSION: Our report emphasizes the importance for the primary healthcare paediatrician to be well informed about the clinical presentation and pathogenesis of hyper-IgM syndrome, in order to provide early detection and increase the likelihood of success in treating this rare immunodeficiency. To the best of our knowledge, this is the first case of hyper-IgM syndrome reported in the Republic of Serbia.

[IPEX syndrome--case report].

INTRODUCTION: IPEX syndrome, namely, a hereditary (X-linked) immunodysregulation with autoimmune polyendocrinopathy and enteropathy, as the basic manifestations, presents a rare and exceptionally severe disease. It develops due to gene mutation responsible for the synthesis of a specific protein (FOXP3), which, by differentiation and activation of regular T-lymphocytic CD4+CD25+, has the key role in the induction and maintenance of the peripheral tolerance of one's own tissue. CASE OUTLINE: We present a male infant with classic clinical features of IPEX syndrome, which manifested by the end of the first month after birth, first with type 1 diabetes mellitus and chronic diarrhoea followed by dehydration and disordered development, and then with facial eczema and laboratory signs of thyroiditis without thyroid dysfunction (antithyreoglobulin antibodies 1:5500, antimicrosomal antibodies 1:40). In addition, plasma IgE level was high (517 IU/l), while antibodies to tissue transglutaminase were mildly increased (IgA 7.5 U/ml), and anti-smooth muscle and anti-DNA antibodies were absent. Based on the typical clinical features, as well as the laboratory findings, IPEX syndrome was diagnosed, which was further confirmed by proved IVS7+5G>A mutations in the FOXP3 gene. Therapy with insulin and Pronison, combined with parenteral and semielementary nutrition resulted in the patient's clinical improvement. At the age of 9 months, despite Pronison and hypoallergenic nutrition, the child had a relapse of severe and persistent diarrhoeal disorder followed by dehydration, weight loss and deterioration of general condition. Beside the complete parenteral nutrition, as well as other measures, azathioprine was introduced into the treatment, but without the desired effect. At the age of 12.5 months, due to bacteraemia and disseminated intravascular coagulation as complications, the patient ended lethally. CONCLUSION: IPEX syndrome should be kept in mind in all the cases of associated type 1 diabetes mellitus and chronic diarrhoea in male neonates or infants. Although treatment results have still been modest, it is quite certain they will be far better in the near future.