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Clinical and genetic risk factors for new-onset diabetes mellitus after transplantation (NODAT) in major transplant centres in Malaysia.

BACKGROUND: New-onset diabetes after transplantation (NODAT) is associated with reduced patient and graft survival. This study examined the clinical and selected genetic factors associated with NODAT among renal-transplanted Malaysian patients. METHODS: This study included 168 non-diabetic patients (58% males, 69% of Chinese ethnicity) who received renal transplantation between 1st January 1994 to 31st December 2014, and were followed up in two major renal transplant centres in Malaysia. Fasting blood glucose levels were used to diagnose NODAT in patients who received renal transplantation wi

Stable bronchiectasis is associated with low serum L-ficolin concentrations.

BACKGROUND AND AIMS: Bronchiectasis is a common chronic respiratory condition with recurrent cough and sputum production and recurrent chest infections. It is characterised by pathological dilatation of the bronchi thought to result from infection and inflammation. It was hypothesised that impaired innate immunity might influence susceptibility to this disease process. The aim of the present study was to look for an association between bronchiectasis and insufficiency of either mannan-binding lectin (MBL) or L-ficolin. MATERIALS AND METHODS: MBL and L-ficolin were measured by Enzyme-linked Im

Aspergillus fumigatus conidial metalloprotease Mep1p cleaves host complement proteins.

Innate immunity in animals including humans encompasses the complement system, which is considered an important host defense mechanism against Aspergillus fumigatus, one of the most ubiquitous opportunistic human fungal pathogens. Previously, it has been shown that the alkaline protease Alp1p secreted from A. fumigatus mycelia degrades the complement components C3, C4, and C5. However, it remains unclear how the fungal spores (i.e. conidia) defend themselves against the activities of the complement system immediately after inhalation into the lung. Here, we show that A. fumigatus conidia conta

Expression and localization of collectins in feto-maternal tissues of human first trimester spontaneous abortion and abortion prone mouse model.

Dysregulation of immune response at the feto-maternal interface during first trimester of pregnancy is one of the leading causes of spontaneous abortion. Previously, we reported differential expression of collectins, soluble pattern recognition molecules involved in immunoregulation, in placental and decidual tissues during spontaneous labor. In the present pilot study, the expression of collectins was analyzed in the inflamed human gestational tissues of spontaneous abortion ('SA') and in 13.5 dpc placental tissues from resorption survived embryos of murine model (CBA/J X DBA/2J). Transcripts

Mislocalization of large ARF-GEFs as a potential mechanism for BFA resistance in COG-deficient cells.

Defects in subunits of the conserved oligomeric Golgi (COG) complex represent a growing subset of congenital disorders of glycosylation (CDGs). In addition to altered protein glycosylation and vesicular trafficking, Cog-deficient patient fibroblasts exhibit a striking delay in the Golgi-disrupting effects of brefeldin A (BFA). Despite the diagnostic value of this BFA resistance, the molecular basis of this response is not known. To investigate potential mechanisms of resistance, we analyzed the localization of the large ARF-GEF, GBF1, in several Cog-deficient cell lines. Our results revealed m

Investigation of TNF-alpha, TGF-beta 1, IL-10, IL-6, IFN-gamma, MBL, GPIA, and IL1A gene polymorphisms in patients with idiopathic thrombocytopenic purpura.

Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by the presence of autoantibodies developing against thrombocyte membrane glycoproteins (GPs), such as GPIIa/IIIa and GPIb/IX. Single nucleotide polymorphisms (SNPs) of inflammatory cytokine genes were investigated in 71 patients with chronic ITP and 71 healthy controls, and they were compared with the clinical parameters. The polymorphisms in the SNPs were investigated with the polymerase chain reaction, polymerase chain reaction with sequence specific primer, and polymerase chain reaction-restriction fragment length

Immunohistochemical detection of sepsis-induced lung injury in human autopsy material.

This review addresses our present-day knowledge on the role of different cellular adhesion molecules, cytokines and glycoproteins for the detection of sepsis-induced injury in the microvasculature of the human lung using immunohistochemistry. Through the induction and modulation of endothelial cell adhesion molecules, such as E-selectin (CD 62E), the vascular endothelium controls leukocyte extravasation into tissue. E-Selectin, not expressed by unstimulated endothelium, is activated by cytokines and initiates neutrophil recruitment in sepsis-induced lung injury. Since E-selectin is strongly ex

Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene that produces wide disease phenotypic variability. The lack of ample genotype-phenotype correlation hinders translational study development aimed at improving disease prognosis. In response to this need, an induced pluripotent stem cell (iPSC) disease model has been used to test patient-specific cells by a proteomic approach. This model has the potential to risk stratify patients to make clinical decisions, including timing for surgical treatment. The regional propensity for aneurysm formation in MFS may

Complement activation pathways in murine immune complex-induced arthritis and in C3a and C5a generation in vitro.

The alternative pathway (AP) of complement alone is capable of mediating immune complex-induced arthritis in the collagen antibody-induced arthritis (CAIA) model in mice. Whether the classical pathway (CP) or lectin pathway (LP) alone can mediate CAIA is not known. Using mice genetically deficient in different complement components, our results reported herein establish that the CP and LP alone are each incapable of mediating CAIA. A lower level or absence of C3 and/or C5 activation by the CP may be possible explanations for the importance of the AP in CAIA and in many murine models of disease

Genetic factors in the pathogenesis of primary biliary cirrhosis.

Current knowledge of the genetic basis of PBC is at best incomplete and at worst poor. Studies so far may be used as a guide to the pitfalls that await unwary investigators and also in deciding where to look and which genes or systems are most likely to yield informative results. The Human Genome Project has revealed a vast array of polymorphism that is too much to contemplate even with the best of current techniques. The crucial processes are the selection of candidates and study design. The strong genetic associations so far in PBC are with chromosomes 6p21.3 and 2q and include; HLA DRBI*08

A defective lysophosphatidic acid-autophagy axis increases miscarriage risk by restricting decidual macrophage residence.

Massive infiltrated and enriched decidual macrophages (dMφ) have been widely regarded as important regulators of maternal-fetal immune tolerance and trophoblast invasion, contributing to normal pregnancy. However, the characteristics of metabolic profile and the underlying mechanism of dMφ residence remain largely unknown. Here, we observe that dMφ display an active glycerophospholipid metabolism. The activation of ENPP2-lysophosphatidic acid (LPA) facilitates the adhesion and retention, and M2 differentiation of dMφ during normal pregnancy. Mechanistically, this process is mediated through ac

Levels of Complement Components in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome.

IMPORTANCE: Multisystem inflammatory syndrome in children (MIS-C) is a severe and unrestrained inflammatory response with multiorgan involve … C3 (318.2 [70.7] ng/mL vs 237.7 [61.8] ng/mL), C5a (2614 [336.2] ng/mL vs 1826 [541.0] ng/mL), and mannose-binding lectin (79.4 [12.4] ng/mL vs 69.6 [14.7] ng/mL) in comparison to children with acute COVID-19. Levels of some of these analytes at admission (ie, pretreatment) were more elevated in children with MIS-C who needed pediatric intensive care unit (PICU) suppor …

Genetic polymorphisms and risk of recurrent wheezing in pediatric age.

BACKGROUND: Wheezing during early life is a very common disorder, but the reasons underlying the different wheezing phenotypes are still unclear. The aims of this study were to analyse the potential correlations between the risk of developing recurrent wheezing and the presence of specific polymorphisms of some genes regulating immune system function, and to study the relative importance of the associations of different viruses and genetic polymorphisms in causing recurrent episodes. METHODS: The study involved 119 otherwise healthy infants admitted to hospital for a first episode of wheezing

Macrophage Activation Markers, CD163 and CD206, in Acute-on-Chronic Liver Failure.

Macrophages facilitate essential homeostatic functions e.g., endocytosis, phagocytosis, and signaling during inflammation, and express a variety of scavenger receptors including CD163 and CD206, which are upregulated in response to inflammation. In healthy individuals, soluble forms of CD163 and CD206 are constitutively shed from macrophages, however, during inflammation pathogen- and damage-associated stimuli induce this shedding. Activation of resident liver macrophages viz. Kupffer cells is part of the inflammatory cascade occurring in acute and chronic liver diseases. We here review the ex

Novel Treatment Paradigms: Primary IgA Nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Approximately 30% to 45% of patients progress to kidney failure (KF) within 20 to 25 years of diagnosis, and there has long been a lack of effective treatments. The therapeutic landscape in IgAN is rapidly evolving, driven in large part by the acceptance of the surrogate clinical trial end point of proteinuria reduction by regulatory authorities for the accelerated approval of new therapies. Two drugs, targeted release formulation (TRF)-budesonide (nefecon) and sparsentan, have recently been approved under this sch

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… Gd-IgA1, galactose deficient-IgA1; IgAN, IgA nephropathy; MASP1, mannose-binding lectin serine protease 1; MASP2, mannose-binding lectin serine protease 2. … Lectin Pathway Inhibition Glomerular deposition of lectin pathway components, including mannose-binding lectin serine protease 1 and 2 (MASP1/2) and C4d, are detected in 30% to 40% of IgAN cases, and their presence correlates with a worse outcome. 34 Narsoplimab, a monoclonal antibody against mannose-binding …

Associations of Ficolins With Hematological Malignancies in Patients Receiving High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantations.

A prospective study of 312 patients [194 with multiple myeloma (MM) and 118 with lymphomas (LYMPH)] receiving high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) was conducted. Ficolins are innate immune defense factors, able to distinguish between "self" "abnormal self," and "non-self" and contribute to the elimination of the last two by direct opsonization and/or initiation of complement activation via the lectin pathway. Concentrations of ficolin-1, ficolin-2, and ficolin-3 in serially taken serum samples were determined as were the polymorphisms of the

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… The former is directly involved in recognition of pathogen/danger-associated molecular patterns, while the latter enables complexing with mannose-binding lectin-associated serine proteases (MASP). … The latter (involving mannose-binding lectin, MBL) is of particular importance in patients treated with hematopoietic stem cell transplantation (HSCT) ( 25 ). …

"Complimenting the Complement": Mechanistic Insights and Opportunities for Therapeutics in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of death in the US and worldwide. HCC remains a global health problem and is highly aggressive with unfavorable prognosis. Even with surgical interventions and newer medical treatment regimens, patients with HCC have poor survival rates. These limited therapeutic strategies and mechanistic understandings of HCC immunopathogenesis urgently warrant non-palliative treatment measures. Irrespective of the multitude etiologies, the liver microenvironment in HCC is intricately associated with chronic

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… Mannose Binding Lectin (MBL) Mannose-binding lectin is an important component involved in the lectin pathway of complement activation ( 235 ). … Mannose-Binding Lectin (MBL)-Associated Serine Protease-2 (MASP-2) The MBL-associated protease MASP-2 predominantly promotes activation of the lectin complement pathway. …

Novel diagnostic options for endometriosis - Based on the glycome and microbiome.

BackgroundEndometriosis is a chronic gynaecological disease whose aetiology is still unknown. Despite its prevalence among women of reproductive age, the pathology of the disease has not yet been elucidated and only symptomatic treatment is available. Endometriosis has high latency and diagnostic methods are both limited and invasive.Aim of reviewThe aim of this review is to summarise minimally invasive or non-invasive diagnostic methods for endometriosis and their diagnostic efficiencies. Furthermore, we discuss the identification and diagnostic potential of novel disease biomarkers of microb

Pertussis in high-risk groups: an overview of the past quarter-century.

Infectious diseases can impact chronic medical conditions. However, it is currently not clear how pertussis correlates with preexisting or underlying disorders. We reviewed literature from the last 25 years to describe the burden and impact of pertussis infection in specific risk groups in individuals aged ≥11 years. Our literature search returned 543 hits, of which 18 were eligible for this review. Adolescents and adults with underlying conditions, such as asthma, chronic obstructive pulmonary disease (COPD), or obesity are potentially at increased risk of pertussis infection. Immunodeficienc

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… Mannose-binding lectin (MBL) deficiency; [accessed 2019. July 16]. http://www.piduk.org/static/media/up/MBLdeficiency.pdf . 63. Dhainaut J-F, Claessens Y-E, Janes J, Nelson DR. Underlying disorders and their impact on the host response to infection. … Mannose-binding lectin (MBL) deficiency; [accessed 2019. July 16]. http://www.piduk.org/static/media/up/MBLdeficiency.pdf . Supplementary Materials Supplemental Material Click here for additional data file. …

Raised Serum Levels of Syndecan-1 (CD138), in a Case of Acute Idiopathic Systemic Capillary Leak Syndrome (SCLS) (Clarkson's Disease).

BACKGROUND Systemic capillary leak syndrome (SCLS) (Clarkson's disease) is a rare disorder of unknown etiology, characterized by transient episodes of hypotension, and the microvascular leak of fluids into the peripheral tissues, resulting in edema. Between 80-90% of patients with SCLS have a concomitant monoclonal gammopathy. Although translational in vitro studies have implicated vascular endothelial barrier dysfunction in the etiology of SCLS, the etiology and disease associations in clinical cases remain unknown. CASE REPORT We report a case of SCLS in a 49-year-old woman who initially pre

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… More extensive complement analysis performed one year later revealed lack of mannose-binding lectin (MBL), as shown in Table 2 . … Mannose-binding lectin (MBL) was low or undetectable in our patient. MBL adheres to mannose on the surface of many pathogens forming the complex, MBL-associated serine protease (MASP). …