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)

TLR4 is the receptor for the Gram-negative bacterial cell wall component LPS. TLR4 signaling is controlled by both positive and negative regulators to balance optimal immune response and potential sepsis. Unchecked TLR4 activation might result in autoimmune diseases, a hypothesis that has not been formally resolved. In this study, we found that TLR4 signaling to LPS can be positively enforced by expressing gp96 on cell surfaces through the chaperone function of, but not the direct signaling by, gp96; TLR4 as well as the commensal flora are essential for the production of anti-dsDNA Ab and the immune complex-mediated glomerulonephritis in transgenic mice that express surface gp96. Moreover, a similar constellation of autoimmunity was evident in mice that encode multiple copies of tlr4 gene. Our study has revealed that increased TLR4 signaling alone without exogenous insult can break immunological tolerance. It provides a strong experimental evidence for TLR4 dysregulation as an etiology of lupus-like renal disease.
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PMID:TLR4 up-regulation at protein or gene level is pathogenic for lupus-like autoimmune disease. 1708 2

Two recent trials concluded that the use of oral contraceptives (OC) did not induce flares in lupus patients. We record our experience with OC in patients with stable lupus. Eight patients were enrolled in an open trial. Six received a combined contraceptive pill and two were allocated to the control arm. During a 12 month follow-up, 3 patients in the active arm experienced 4 major flares. One patient died as a result of uncontrolled disease complicated by sepsis. At this point, we abandoned the trial. The 2 patients in the control arm experienced no disease exacerbation during the 7 months of observation. We would urge that patients who are placed on OC be closely monitored.
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PMID:Major flares in women with SLE on combined oral contraception. 1748 47

Perinatal thrombosis in infants born to mothers with antiphospholipid antibodies (aPL) is a rare event, but with risk of death or severe sequelae. We analysed 16 infants with such perinatal thrombosis reported in the literature in the last 20 years. Thromboses were arterial (13/16), mostly strokes (8/16). Hydrops fetalis with left renal vein thrombosis was associated to a lupus anticoagulant (LA) present only in the child. Risk factors additional to aPL: either prenatal (preeclampsia and/or intra-uterine growth retardation) or perinatal (asphyxia, sepsis, arterial or venous catheter and congenital thrombophilia) were present (one to four of them) in nine out of the 14 evaluable babies. aPL were the only risk factor found in five full term babies who suffered from stroke in four cases and from renal thrombosis in another. Eleven of these infants with aPL in their serum presented a neonatal APS with the same antibody (LA or aCL IgG) found in neonates and their mothers, while the other infants had thrombosis with aPL only in their mother's blood. aCL IgM was only found in one neonate who suffered from sepsis. Thrombosis treatments were diverse. This analysis suggests that women with aPL should be investigated for other thrombophilic risk factors and that aPL should be detected systematically at birth in the offspring of mothers with APS.
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PMID:Infant perinatal thrombosis and antiphospholipid antibodies: a review. 1771

Tumour necrosis factor (TNF) ligand members and their associated TNF receptor (TNFR) superfamilies have many diverse physiological roles. TNF is thought to play a critical role in the pathophysiology of a range of diseases including refractory asthma, sepsis, ankylosing spondylitis, lupus, type II diabetes, multiple sclerosis and psoriasis. The recent continued expansion of the novel anti-TNF therapeutic agents (etanercept and infliximab) has seen major improvements in the treatment of some inflammatory-based human diseases including notably rheumatoid arthritis and Crohn's disease, with other conditions currently being trialled using anti-TNF agents. The cellular signalling machinery used by TNFRs to achieve their many cellular responses are discussed, as is the gonadotrophin-releasing hormone (GnRH) receptor signalling mechanisms. TNF is known to have many actions throughout the body including effects on the hypothalamic-pituitary-adrenal/gonadal axes, with many anti-gonadotrophic effects including a role in the development of endometriosis. These interactions between TNF, GnRH and gonadotrophs are discussed.
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PMID:Interactions between TNF and GnRH. 1798 35

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 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.
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PMID:Pulmonary involvement of systemic lupus erythematosus: analysis of 90 necropsies. 1976 78

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


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