Using literature-based discovery to identify disease candidate genes

We present BITOLA, an interactive literature-based biomedical discovery support system. The goal of this system is to discover new, potentially meaningful relations between a given starting concept of interest and other concepts, by mining the bibliographic database MEDLINE. To make the system more suitable for disease candidate gene discovery and to decrease the number of candidate relations, we integrate background knowledge about the chromosomal location of the starting disease as well as the chromosomal location of the candidate genes from resources such as LocusLink and Human Genome Organization (HUGO). BITOLA can also be used as an alternative way of searching the MEDLINE database. The system is available at http://www.mf.uni-lj.si/bitola/.     

CTLA-4 exon 1 polymorphism in patients with autoimmune blood disorders

CTLA-4 is a CD28 homologue that plays an important role in negative regulation of T-cell responses. Its transient expression on the surface of activated T cells antagonizes the activating signals and terminates the T-cell response. An A to G polymorphism at position 49 of the CTLA-4 first exon has recently been associated with several autoimmune disorders. In the present study we have examined the prevalence of the A and G alleles of the CTLA-4 gene in 50 patients with autoimmune hemolytic anemia (AIHA), of which 20 had idiopathic AIHA and 30 had AIHA and chronic lymphocytic leukemia (CLL), and in 60 patients with immune thrombocytopenic purpura (ITP). Control subjects were 100 healthy individuals and 100 CLL patients without clinical evidence for an autoimmune disease. The G allele was present at a significantly higher frequency among the patients with AIHA (P = 0.003), whereas no difference was observed between patients with ITP and controls. The G allele frequency was highest among CLL patients who had developed AIHA. The obtained data indicate that the G allele of CTLA-4 predisposes to the development of AIHA, particularly among patients with CLL.     

Inflammatory, abscess-forming foreign body reaction mimics a thrombus formation on an atrial septal defect closure device: A commented case report.

We are presenting a case of floating left and right atrial formations on an atrial septal defect occluder system (23mm StarFLEX)-Occluder) initially supposed to be thrombotic appositions in a 57-year-old man. The closure was performed on the background of left hemispheric stroke and atrial septal aneurysm (ASA) with patent foramen ovale (PFO). The suspect structures were detected in the 6-month follow-up by transesophageal echocardiography (TEE). The patient underwent a successful surgical explantation of the closure device and closure of the patent foramen ovale (PFO) using a pericardial patch. The pathological evaluation of the biatrial device associated appositions revealed hytrophic heart muscle tissue with perifocal scarring and purulent abscess-forming, granulating and foam-cell including inflammatory foreign body reaction instead of the expected thrombus formation.     

Affinity of C-reactive protein toward FcgammaRI is strongly enhanced by the gamma-chain

C-reactive protein (CRP), the prototype human acute phase protein, is widely regarded as a key player in cardiovascular disease, but the identity of its cellular receptor is still under debate. By using ultrasensitive confocal imaging analysis, we have studied CRP binding to transfected COS-7 cells expressing the high-affinity IgG receptor FcgammaRI. Here we show that CRP binds to FcgammaRI on intact cells, with a kd of 10+/-3 micromol/L. Transfection of COS-7 cells with a plasmid coding for both FcgammaRI and its functional counterpart, the gamma-chain, markedly increases CRP affinity to FcgammaRI, resulting in a kd of 0.35+/-0.10 micromol/L. The affinity increase results from an approximately 30-fold enhanced association rate coefficient. The pronounced enhancement of affinity by the gamma-chain suggests its crucial involvement in the CRP receptor interaction, possibly by mediating interactions between the transmembrane moieties of the receptors. Dissociation of CRP from the cell surfaces cannot be detected throughout the time course of several hours and is thus extremely slow. Considering the pentameric structure of CRP, this result indicates that multivalent binding and receptor clustering are crucially involved in the interaction of CRP with nucleated cells.     

Monoclonal gammopathy and serum immunoglobulin levels as prognostic factors in chronic lymphocytic leukaemia

The relationship between chronic lymphocytic leukaemia (CLL) and qualitative/quantitative gammaglobulin abnormalities is well established. Nevertheless, in order to better understand this kind of connection, we examined 1505 patients with CLL and divided them into four subgroups on the basis of immunoglobulin (Ig) aberrations at diagnosis. A total of 73 (4·8%), 149 (10%), 200 (13·2%) and 1083 (72%) patients were identified with IgM monoclonal gammopathy (IgM/CLL), IgG monoclonal gammopathy (IgG/CLL), hypogammaglobulinaemia (hypo-γ) and normal Ig levels (γ-normal) respectively. IgM paraprotein was significantly associated with a more advanced Binet/Rai stage and del(17p)/TP53 mutation, while IgG abnormalities correlated with a higher occurrence of trisomy 12. Patients with any type of Ig abnormality had shorter treatment-free survival (TFS) but no significant impact affecting overall survival (OS) compared to those with normal Ig levels.     

Functional conservation of suppressors of cytokine signaling proteins between teleosts and mammals: Atlantic salmon SOCS1 binds to JAK/STAT family members and suppresses type I and II IFN signaling

Suppressor of cytokine signaling (SOCS) proteins are crucially involved in the control of inflammatory responses through their impact on various signaling pathways including the JAK/STAT pathway. Although all SOCS protein family members are identified in teleost fish, their functional properties in non-mammalian vertebrates have not been extensively studied. To gain further insight into SOCS functions in bony fish, we have identified and characterized the Atlantic salmon (Salmo salar) SOCS1, SOCS2 and CISH genes. These genes exhibited sequence conservation with their mammalian counterparts and they were ubiquitously expressed. SOCS1 in mammalian species has been recognized as a key negative regulator of interferon (IFN) signaling and recent data for the two model fish Tetraodon (Tetraodon nigroviridis) and zebrafish (Danio rerio) suggest that these functions are conserved from teleost to mammals. In agreement with this we here demonstrate a strong negative regulatory activity of salmon SOCS1 on type I and type II IFN signaling, while SOCS2a and b and CISH only moderately affected IFN responses. SOCS1 also inhibited IFNγ-induced nuclear localization of STAT1 and a direct interaction between SOCS1 and STAT1 and between SOCS1 and the Tyk2 kinase was found. Using SOCS1 mutants lacking either the KIR domain or the ESS, SH2 and SOCS box domains showed that all domains affected the ability of SOCS1 to inhibit IFN-mediated signaling. These results are the first to demonstrate that SOCS1 is a potent inhibitor of IFN-mediated JAK-STAT signaling in teleost fish.     

Liver dysfunction as a cytokine storm manifestation and prognostic factor for severe COVID-19

Liver damage in severe acute respiratory coronavirus 2 infection occurs in patients with or without preexisting liver disorders, posing a significant complication and mortality risk. During coronavirus disease 2019 (COVID-19), abnormal liver function is typically observed. However, liver injury may occur because of the treatment as well. Ischemia, cytokine storm, and hypoxia were identified as the three major factors contributing to liver damage during COVID-19. Indeed, raised liver enzymes during hospitalizations may be attributed to medications used, as well as sepsis and shock. As a result, the proportion of hospitalized patients afflicted with COVID-19 and pathological liver biomarkers varies from 14% to 53%. Aminotransferases and bilirubin are found most often elevated. Usually, increased gamma-glutamyltransferase, alkaline phosphatase, and decreased serum albumin levels are demonstrated. Additionally, although there is no specific treatment for COVID-19, many of the drugs used to treat the infection are hepatotoxic. In this mini-review, we focus on how liver dysfunction can be one of the features associated with the COVID-19 cytokine storm. Furthermore, data show that liver injury can be an independent predictor of severe COVID-19, the need for hospitalization, and death.     

Renal and cardiovascular effects of renal denervation in conscious rats after adenosine administration and nitric oxide synthase inhibition

The role of renal nerves on renal and cardiovascular responses to adenosine administration and/or acute NO synthase inhibition was investigated. Conscious male Wistar rats with implanted catheters in femoral artery for blood pressure registration, femoral vein for drug infusion and bladder for urine collection were used. Adenosine was applied i.v. (1.0 mg/kg BW bolus) followed by infusion of 0.1 mg/kg.min, and/or nitric oxide synthase inhibition (NOSI) was performed by i.v. administration of 10 mg/kg BW N-Omega-nitro-L-arginine methyl ester (L-NAME) before and 1 week after bilateral renal denervation (BRD). NOSI decreased HR and increased SAP, MAP and DAP both in intact and BRD rats. Baroreflex sensitivity increased in intact and BRD rats. Adenosine did not change HR, blood pressure or baroreflex sensitivity in intact as well as BRD rats. NOSI increased V, VU(Na) and VU(CI) in intact rats but decreased V and did not alter VU(Na) and VU(CI) in BRD rats. Adenosine increased V, VU(CI) and C(cr) in intact rats but did not change renal excretory function in BRD rats. Combined application of adenosine and L-NAME led to a dramatic increase of V, VU(Na), VU(Cl) and C(cr) in intact rats. However, VU(Na) and VU(CI) in BRD rats were lower as compared to intact rats. Therefore, changes in renal excretory function seen after NOSI are not exclusively the result of pressure diuresis and natriuresis but in some way are dependent on renal nerves. Renal denervation attenuates the renal excretory response to adenosine. Sympathetic nervous system is important in mediating the effects of adenosine and/or NO on renal excretory function. Renal denervation did not change the pattern of baroreflex sensitivity after adenosine and/or L-NAME administration.