Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Azathioprine (AZA) is a commonly used immunosuppressant for systemic lupus erythematosus (SLE). Myelosuppression is a serious adverse reaction due to AZA and its metabolites. Thiopurine S-methyltransferase (TPMT) is the rate-limiting enzyme. Variations of TPMT enzyme activity may be responsible for myelosuppression. However, a correlation between certain mutant alleles of low TPMT enzyme activity and myelotoxicity has also been suggested as a factor. We describe herein a case of AZA-induced severe myelosuppression associated with TPMT*3C heterozygous mutant allele in a SLE patient. The patient presented with pancytopenia, sepsis, typhlitis and disseminated intravascular coagulopathy after a short period of AZA therapy. The patient had low TPMT activity and TPMT*3C genotype. Measurement of TPMT activity and determination of TPMT variant allele may identify patients at risk for AZA-induced myelosuppression.
Lupus 2008 Feb
PMID:Azathioprine-induced fatal myelosuppression in systemic lupus erythematosus patient carrying TPMT*3C polymorphism. 1825 Jan 37

Systemic erythematosus lupus (SLE) is a disease with wide range of clinical manifestations, signs and symptoms. Disease outcome depends mostly on the affection of kidneys and central nervous system by the disease. Very important cause of death in patients with SLE is infection. Infections are very common among these patients due to aggressive immunosuppressive treatment that is needed for the disease inflammatory activity control. In this case report we have presented a patient with SLE who initially had severe renal affection, but also complications of immunosuppressive therapy that was administered. Even though the disease was accidentally diagnosed, it had a severe clinical progress. Because of lupus nephropathy, in the early phase of the disease we administered aggressive immunosuppressive therapy (combined parenteral therapy of glucocorticoides and cyclophosphamide). As an outcome of the combined effect of disease and immunosuppressive agents used in the treatment of the disease, the patient had increased infective diathesis (repeated infections caused by S. enteritidis--urinary infections and sepsis). During one of the disease flares the patient was hospitalized an opportunistic infection developed. It was meningitis caused by C. neoformans. This opportunistic mycosis infection presented with clinically totally nonspecific signs and symptoms of CNS affection. Therefore, we suspected affection of CNS with SLE. Even though all diagnostic procedures were made on time and that adequate antifungal and supportive agents were applied very early after the infection onset, the outcome was fatal. Because of infective diathesis in patients with SLE, which present with common and opportunistic infections, and due to high mortality rates caused by these infections, we have tried to emphasise the importance of taking adequate specimens early after infection outcome for these rare infective agents like C. neophormans. In recent medical literature are dominant cases reported in Asia. Reports from Europe are very rare, and this case is the one of that kind in Croatia.
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PMID:[Cryptococcal meningitis as a diagnostic problem in a patient with SLE--case report]. 1879 61

The activated partial thromboplastin time (APTT) is the most common coagulation test procedure performed in routine laboratories, apart from the prothrombin time. The test is traditionally used for identifying quantitative and qualitative abnormalities in the intrinsic and common pathways of coagulation, monitoring anticoagulant therapy with unfractionated heparin, and detecting inhibitors of blood coagulation, the most common of which is the lupus anticoagulant. Whereas short APTT values have been mostly overlooked in the past, recent evidence suggests that these might be associated with hypercoagulability. Although clinical relevance is yet to be clearly defined, hypercoagulability detected by a shortened APTT appears to be significantly associated with a major risk of venous thromboembolism independently from other variables such as blood group, the presence of inherited thrombophilia, and factor VIII levels. This novel finding suggests that this traditional, simple, and inexpensive test might have renewed utility along with traditional thrombophilic tests in the evaluation of venous thromboembolic risk. In addition, APTT waveform analysis is also providing mounting evidence of added utility, in particular for identifying sepsis and disseminated intravascular coagulation in critically ill patients (particularly where this might worsen the prognosis), for monitoring therapy in patients with inhibitors, and as a diagnostic aid to identify patients with antiphospholipid antibodies. In total, such emerging evidence suggests that the APTT is either an old dogma displaying new tricks or else might describe a new dogma for an old laboratory trick.
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PMID:Activated partial thromboplastin time: new tricks for an old dogma. 1908 61

The role of autoantibodies in the pathogenesis of systemic lupus erythematosus (SLE) has not been completely defined. From more than a hundred autoantibodies described in SLE, relatively few have been associated with clinical manifestations. The glycan-binding proteins of the galectin family can modulate the immune system. Anti-galectin autoantibodies thus could have functional and/or pathogenic implications in inflammatory processes and autoimmunity. We previously reported function-blocking autoantibodies against galectin-8 (Gal-8) in SLE. Here we tested these autoantibodies against a series of other human galectins and demonstrated their specificity for Gal-8, being detectable in 23% of 78 SLE patients. Remarkably, they associated with lymphopenia (50% of 18 anti-Gal-8-positive versus 18% of 60 anti-Gal-8-negative cases, Fisher's Exact test two-tailed: P < 0.012). Lymphopenia is a common clinical manifestation in SLE, yet of unknown mechanism. In addition, six of eight patients with both lymphopenia and malar rash had anti-Gal-8 in their sera. Occurrence of these autoantibodies was not confined to SLE as we also found them in sera of patients with rheumatoid arthritis (16%) and septicemia (20%). This study thus establishes occurrence of specific anti-Gal-8 autoantibodies in autoimmune rheumatic diseases and in acute inflammation, with an apparent association to a clinical subset in SLE.
Lupus 2009 May
PMID:Autoantibodies against galectin-8: their specificity, association with lymphopenia in systemic lupus erythematosus and detection in rheumatoid arthritis and acute inflammation. 1939 56

The aim of this paper is retrospective analysis of data from patients in whom the indication for cyclophosphamide (CF) pulse therapy was established in our department. Indications for CF pulse treatment were lupus nephritis (LN) alone or associated with central nervous system lupus. CF was administred in the dose of 500-1000 mg/m2 intravenously once monthly for the 6 months and once every 3 months thereafter. Patients were treated with adequate dose of glucocorticoids and other symptomatic therapy. The effect of applied therapy has been analysed by monitoring proteinuria, serum creatinine concentration, creatinine clearance, ESR, ANF titer and total complement hemolytic activity. Initial therapeutic procedure has been completed in 25/30 patients. The reasons for discontinuation in 5/30 patients were as follows: end-stage renal failure in spite of therapy (1), psychosis and lost of compliance (1), recurrent pancytopenia and subsequent sepsis (1), death non related to SLE (1) and failure to show at follow-up (1). Significant improvement of all control parameters was observed in the majority of patients in whom the therapy was completely conducted. 16/25 patients continued therapy for the next 18 months and in only 1/16 patients therapy was discontinued because of end-stage renal failure. In other 15/16 patients further improvement of control parameters was observed, although not so expressed as in the first 6 months. The most frequent complications were infections (16 infections were microbiologically proved and there were probably more infections). Alopecia (2), haematuria (1) and amenorrhoea (1) were also observed. Relatively low incidence of complications may be explained by careful patient monitoring. Considering that therapeutic success is defined not only by the improvement of renal function, but by stopping of further progression of renal failure, it can be concluded that intermittent CF pulse therapy showed good effect on LN in patients with clear indication.
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PMID:[Intermittent intravenous cyclophosphamide application in patients with systemic lupus erythematosus]. 1965 69

Pleuropulmonary manifestations of systemic lupus erythematosus (SLE) have been reported to be of variable prevalence, depending on the diagnostic methods used. The objective of this study was to determine the anatomopathological prevalence and the nature of lung involvement associated with SLE and to define if there were differences in the grade and type of pulmonary involvement in patients who had died at different time periods, before or after 1996. Complete autopsy studies of 90 patients with SLE diagnosis carried out between 1958 and 2006 and their clinical records were studied. All patients fulfilled the American College of Rheumathology (ACR) diagnostic criteria for SLE. Two groups of patients were analyzed: patients who had died before 1996 and those deceased in 1996-2006. Some pleuropulmonary involvement was detected in 97.8% of the autopsies. The most frequent findings were pleuritis (77.8%), bacterial infections (57.8%), primary and secondary alveolar haemorrhages (25.6%), followed by distal airway alterations (21.1%), opportunistic infections (14.4%) and pulmonary thromboembolism (7.8%), both acute and chronic. No cases of acute or chronic lupus pneumonitis were found. Opportunistic lung infections were invasive aspergillosis, disseminated strongyloidiasis, mucormicosis and Pneumocystis carinii. Only three of 23 patients with alveolar haemorrhage showed capillaritis. The four patients with primary pulmonary hypertension (PHT) had plexiform lesions. Deceased patients' age at death (46.09 +/- 11.01 vs 30.3 +/- 11.5 years, P < 0.0001) as well as survival time from diagnosis date (11.8 +/- 11.2 vs 4.4 +/- 4.9 years, P < 0.0001) in the second time period evaluated were significantly higher. However, there were no statistically significant differences in the prevalence of any of the pulmonary manifestations. Sepsis was considered the major cause of death without significant differences in both groups. Our results show that pulmonary manifestations directly caused by systemic lupus erythematosus are very uncommon and that their prevalence has not changed in the past 10 years. Pulmonary infection is still the most frequent affection, and it is an important cause of death in patients with lupus.
Lupus 2009 Oct
PMID:Pulmonary involvement of systemic lupus erythematosus: analysis of 90 necropsies. 1976 78

Gigantomastia is a rare breast condition characterised by diffuse, rapid, and excessive breast hypertrophy that can result in symptoms ranging from pain to necrosis and sepsis. It typically occurs in the setting of marked hormonal changes such as puberty and pregnancy. Rarely, gigantomastia has been reported to develop in the setting of an autoimmune illness. We present a case of gigantomastia developing in a patient with systemic lupus erythematosus, who was treated with methotrexate and bilateral mammoplasty.
Lupus 2009 Oct
PMID:Gigantomastia and autoimmunity: a case report. 1976 5

The blood-brain barrier (BBB) is a crucial anatomic location in the brain. Its dysfunction complicates many neurodegenerative diseases, from acute conditions, such as sepsis, to chronic diseases, such as systemic lupus erythematosus (SLE). Several studies suggest an altered BBB in lupus, but the underlying mechanism remains unknown. In the current study, we observed a definite loss of BBB integrity in MRL/MpJ-Tnfrsf6(lpr) (MRL/lpr) lupus mice by IgG infiltration into brain parenchyma. In line with this result, we examined the role of complement activation, a key event in this setting, in maintenance of BBB integrity. Complement activation generates C5a, a molecule with multiple functions. Because the expression of the C5a receptor (C5aR) is significantly increased in brain endothelial cells treated with lupus serum, the study focused on the role of C5a signaling through its G-protein-coupled receptor C5aR in brain endothelial cells, in a lupus setting. Reactive oxygen species production increased significantly in endothelial cells, in both primary cells and the bEnd3 cell line treated with lupus serum from MRL/lpr mice, compared with those treated with control serum from MRL(+/+) mice. In addition, increased permeability monitored by changes in transendothelial electrical resistance, cytoskeletal remodeling caused by actin fiber rearrangement, and increased iNOS mRNA expression were observed in bEnd3 cells. These disruptive effects were alleviated by pretreating cells with a C5a receptor antagonist (C5aRant) or a C5a antibody. Furthermore, the structural integrity of the vasculature in MRL/lpr brain was maintained by C5aR inhibition. These results demonstrate the regulation of BBB integrity by the complement system in a neuroinflammatory setting. For the first time, a novel role of C5a in the maintenance of BBB integrity is identified and the potential of C5a/C5aR blockade highlighted as a promising therapeutic strategy in SLE and other neurodegenerative diseases.
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PMID:C5a alters blood-brain barrier integrity in experimental lupus. 2006 6

Double-stranded (ds) DNA, DNA- or RNA-associated nucleoproteins are the primary autoimmune targets in SLE, yet their relative inability to trigger similar autoimmune responses in experimental animals has fascinated scientists for decades. While many cellular proteins bind non-specifically negatively charged nucleic acids, it was discovered only recently that several intracellular proteins are involved directly in innate recognition of exogenous DNA or RNA, or cytosol-residing DNA or RNA viruses. Thus, endosomal Toll-like receptors (TLR) mediate responses to double-stranded RNA (TLR-3), single-stranded RNA (TLR-7/8) or unmethylated bacterial cytosine (phosphodiester) guanine (CpG)-DNA (TLR-9), while DNA-dependent activator of IRFs/Z-DNA binding protein 1 (DAI/ZBP1), haematopoietic IFN-inducible nuclear protein-200 (p202), absent in melanoma 2 (AIM2), RNA polymerase III, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) mediate responses to cytosolic dsDNA or dsRNA, respectively. TLR-induced responses are more robust than those induced by cytosolic DNA- or RNA- sensors, the later usually being limited to interferon regulatory factor 3 (IRF3)-dependent type I interferon (IFN) induction and nuclear factor (NF)-kappaB activation. Interestingly, AIM2 is not capable of inducing type I IFN, but rather plays a role in caspase I activation. DNA- or RNA-like synthetic inhibitory oligonucleotides (INH-ODN) have been developed that antagonize TLR-7- and/or TLR-9-induced activation in autoimmune B cells and in type I IFN-producing dendritic cells at low nanomolar concentrations. It is not known whether these INH-ODNs have any agonistic or antagonistic effects on cytosolic DNA or RNA sensors. While this remains to be determined in the future, in vivo studies have already shown their potential for preventing spontaneous lupus in various animal models of lupus. Several groups are exploring the possibility of translating these INH-ODNs into human therapeutics for treating SLE and bacterial DNA-induced sepsis.
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PMID:Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus. 2045 14

Our immune defense depends on two specialized armed forces. The innate force acts as an alarm mechanism that senses changes in the microenvironment through the recognition of common microbial patterns by Toll-like receptors (TLR) and NOD proteins. It rapidly generates an inflammatory response aimed at neutralizing the intruder at the mucosal checkpoint. The innate arm also communicates this message with more specialized adaptive forces represented by pathogen-specific B cells and T cells. Interestingly, B cells also express some innate sensors, like TLR7 and TLR9, and may respond to bacterial hypomethylated CpG motifs and single-stranded RNA viruses. Intracellular nucleic acid sensing TLRs play an important role in the pathogenesis of Systemic Lupus Erythematosus (SLE). In this review, we describe recent achievements in the development of oligonucleotide-(ODN)-based inhibitors of TLR9 and/or TLR7 signaling. We categorize these novel therapeutics into Classes G, R, and B based on their cellular and molecular targets. Several short ODNs have already shown promise as pathway-specific therapeutics for animal lupus. We envision their future use in human SLE, microbial DNA-dependent sepsis, and in other autoinflammatory diseases.
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PMID:Classification, mechanisms of action, and therapeutic applications of inhibitory oligonucleotides for Toll-like receptors (TLR) 7 and 9. 2049 Feb 86


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