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)

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine released from T-cells and macrophages, and is a key molecule in inflammation. Although a detailed understanding of the biological functions of MIF has not yet been found, it is known that MIF catalyzes the tautomerization of phenylpyruvate and a non-physiological molecule, D-dopachrome. A potent tautomerase inhibitor would be expected, as a validation tool, to shed light on role of MIF activity and the relationship between its biological and enzymatic activity. Such tautomerase inhibitors would be useful in the treatment of MIF-related diseases, such as sepsis, acute respiratory distress syndrome (ARDS), asthma, atopic dermatitis, rheumatoid arthritis (RA), nephropathy and tumors. In this review, we have focused on (1) the biological and enzymatic activities of MIF, (2) the discovery of novel, drug-like tautomerase inhibitors of MIF using a structure-based computer-assisted search, and (3) a crystallographic and molecular modeling study of the MIF-tautomerase inhibitor complexes (A review with 133 references).
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PMID:Macrophage migration inhibitory factor and the discovery of tautomerase inhibitors. 1205 20

Researchers have sought therapeutic applications for monoclonal antibodies since their development in 1975. However, murine-derived monoclonal antibodies may cause an immunogenic response in human patients, reducing their therapeutic efficacy. Chimeric and humanized antibodies have been developed that are less likely to provoke an immune reaction in human patients than are murine-derived antibodies. Antibody fragments, bispecific antibodies, and antibodies produced through the use of phage display systems and genetically modified plants and animals may aid researchers in developing new uses for monoclonal antibodies in the treatment of disease. Monoclonal antibodies may have a number of promising potential therapeutic applications in the treatment of asthma, autoimmune diseases, cancer, poisoning, septicemia, substance abuse, viral infections, and other diseases.
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PMID:Therapeutic applications of monoclonal antibodies. 1212 Aug 21

Between May 1990 and January 1999, 100 patients (68 adult, 32 pediatric) with severe respiratory or cardiac instability were successfully transported to the University of Michigan Medical Center on extracorporeal life support. Diagnoses included adult respiratory distress syndrome (n = 78), cardiac failure (n = 7), sepsis (n = 7), asthma (n = 5), respiratory distress syndrome (of newborn) (n = 2), and airway compromise (n = 1). Of the patients, 53 were supported with venovenous bypass and 47 with venoarterial bypass. Patients were transported by ground ambulance (n = 80), helicopter (n = 15), or fixed-wing aircraft (n = 5). The median transport distance was 44 miles (range 2-790 miles), and the median transport time was 5 hours and 30 minutes (range: 1 h 33 min to 16 h 6 min). Sixty-six patients (66%) survived to discharge. One death occurred during cannulation, and two patients died before cannulation began. Complications that occurred during transport included 10 cases of electrical failure, 3 cases of circuit tubing leakage, and 1 case each of circuit rupture, membrane lung thrombosis, and membrane lung leakage. None of the complications occurring during transport had an adverse effect on outcome. We conclude that the long distance transport of patients on extracorporeal life support can be safely accomplished and is an effective option for the unstable patient with severe respiratory or cardiac failure.
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PMID:A review of 100 patients transported on extracorporeal life support. 1245 71

The necessity to optimise the management of atopic dermatitis of infants needs knowledge of three components: increase of prevalence, extreme frequency of food allergy and increase in the frequency of the syndrome of multiple allergies, that frequently develops into asthmatic disease. Management of DA in infancy (first year of life) is based on the global strategy of understanding the physiological Th2 polarisation at birth, that does not allow a re-equilibration of the Th1-Th2 balance that progresses in the first six months of life (in normal infants) making in this period a window of opportunity for sensitizations. Prevention in high-risk children (familial history of atopy) covers the non-exposure to in door pollutants (tobacco and volatile organic compounds), breast-feeding or a hypoallergenic formula for a hydrolysate of pork and soya proteins or better an extensive hydrolysate of casein. Four situations require moving to an amino acid substitute: failure to thrive, severe atopic dermatitis, a syndrome of multiple food allergies, allergy to hydrolysates. Reintroduction of foods should be considered with the least delay so as to induce digestive tolerance. It should take into account the clinical development, the intensity of the sensitisation and eventually depend on a realistic test of introduction. Management of DA searches for recovery of generalized eczema, failure to immediate improvement of quality of life prevention of immediate complications (local sepsis) acceleration of return to food tolerance. Prevention of ulterior development of asthma by immediately introducing measures to diminish respiratory exposure to allergens and tobacco is hoped for.
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PMID:Optimal management of atopic dermatitis in infancy. 1251 91

The platelet-activating factor-acetylhydrolase (PAF-AH) is an enzyme which catalyzes the hydrolysis of acetyl ester at the sn-2 position of PAF. The family of PAF-AHs consists of two intracellular isoforms (Ib and II), and one secreted isoform (plasma). These PAF-AHs show different biochemical characteristics and molecular structures. Plasma PAF-AH and intracellular isoform, II degrade not only PAF but also oxidatively fragmented phospholipids with potent biological activities. Among these PAF-AHs, plasma PAF-AH has been the target of many clinical studies in inflammatory diseases, such as asthma, sepsis, and vascular diseases, because the plasma PAF-AH activity in the patients with these diseases is altered when compared with normal individuals. Finding a genetic deficiency in the plasma PAF-AH opened the gate in elucidating the protecting role of this enzyme in inflammatory diseases. The most common loss-of-function mutation, V279F, is found in more than 30% of Japanese subjects (4% homozygous, 27% heterozygous). This single nucleotide polymorphism in plasma PAF-AH and the resulting enzymatic deficiency is thought to be a genetic risk factor in various inflammatory diseases in Japanese subjects. Administration of recombinant plasma PAF-AH or transfer of the plasma PAF-AH gene improves pathology in animal models. Therefore, substitution of plasma PAF-AH would be an effective in the treatment of the patients with the inflammatory diseases and a novel clinical approach. In addition, the detection of polymorphisms in the plasma PAF-AH gene and abnormalities in enzyme activity would be beneficial in the diagnosis of the inflammatory diseases.
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PMID:Plasma platelet activating factor-acetylhydrolase (PAF-AH). 1254 53

Roles for Toll-like receptors (TLRs) are emerging in conditions such as sepsis syndrome, systemic lupus erythromatosis, rheumatoid arthritis and asthma, suggesting that the selective targeting of TLRs might be useful therapeutically. TLRs are defined by the presence of extracellular leucine-rich repeats and an intracellular Toll/interleukin-1 receptor domain, and play a role in host defence and inflammation. Signalling pathways activated by TLRs show remarkable similarity to those activated by the pro-inflammatory cytokine interleukin-1 (the receptor for which also has a Toll/interleukin-1 receptor domain), although adaptor proteins specific for certain TLRs are starting to emerge (e.g. Mal and Trif). The common signalling pathways used by all members of the TLR superfamily are being targeted, with drugs that block nuclear factor-kappaB and p38 mitogen-activated protein kinase in clinical development for diseases such as rheumatoid arthritis and psoriasis. As we learn more about TLR signal transduction, more options are presenting themselves for pharmacological targeting.
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PMID:Therapeutic targeting of Toll-like receptors for inflammatory and infectious diseases. 1290 49

The aim of the present study was to study the epidemiological and clinical profile of patients attending an exclusive pediatric Emergency Department (ED). Data was retrieved from records of the patients seen over a 6-year period from 1995 to 2000. Descriptive analysis was done to define demographic and clinical details, and monthly admission rates and diagnoses. A total of 43800 patients were seen during the study period. Of these 42.1 per cent were admitted after initial evaluation. The ratio of boys to girls was 3:1; 47 per cent were infants under 1 year of age. The common reasons for attending the emergency department were gastrointestinal and respiratory illnesses (23 per cent each), neurological emergencies (16 per cent), and neonatal problems (15.6 per cent). Poisonings were seen in 0.6 per cent of patients. Eight illnesses, i.e. acute diarrhea, upper respiratory infection, pneumonia, acute asthma, seizures, meningitis, and neonatal sepsis and jaundice, comprised nearly half of all the emergency visits. Acute diarrhoeal diseases, pneumonia, asthma, and encephalitis showed a distinct seasonal trend. Our data implies that planning of staff training and triage and efficient resource utilization in the pediatric ED in a developing country such as ours should take into consideration the preponderance of infants, seasonal trends, and the most common emergencies (acute diarrhea, pneumonia, acute asthma, seizures and neonatal infection) as priorities.
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PMID:Pediatric emergencies at a tertiary care hospital in India. 1292 80

Kinins are peptide hormones that exert pathophysiological as well as pronounced beneficial physiological effects, mainly by stimulation of bradykinin (BK) B(2) receptors. Owing to the strong proinflammatory properties of kinins resulting from vasodilation, plasma extravasation, activation of mast cells, fibroblasts and macrophages, stimulation of sensory neurons, and the release of nitric oxide, prostaglandins, leukotrienes and cytokines, kinins are believed to play an important role in a variety of inflammatory diseases and pain. Beneficial effects of BK B(2) receptor antagonists in perennial rhinitis, asthma and brain edema have already been shown in clinical trials. Recently, the potential therapeutic utility of BK B(2) receptor antagonists has been extended by the discovery of orally active, nonpeptide BK B(2) receptor antagonists and the identification of novel indications for their use. On the other hand, kinins also have been identified as potent antihypertensive and organ-protective peptides. They have been shown to have vasodilatory, antihypertrophic, antiaggregatory and fibrinolytic effects due to the BK B(2) receptor-mediated release of the autacoids nitric oxide, prostacyclin and tissue plasminogen activator. A recent finding is that kinins are also involved in ischemic preconditioning. Orally active, nonpeptide BK B(2) receptor agonists as potential novel therapeutic agents in cardiovascular medicine have also been identified. In conclusion, interaction with the BK B(2) receptor by either its blockade or its stimulation offers promising therapeutic approaches. BK B(2) receptor antagonists may prove to be useful in the treatment of asthma, rhinitis, arthritis, colitis, pancreatitis, sepsis, edema, tissue injury, pain and possibly infections, hepatorenal syndrome, Alzheimer's disease and lung cancer. BK B(2) receptor agonists have potential in the treatment of cardiovascular diseases like hypertension, cardiac hypertrophy, restenosis and myocardial infarction and diabetic disorders.
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PMID:Bradykinin B2 receptor as a potential therapeutic target. 1293 26

The nuclear factor kappa B (NF-kappaB) transcription factor plays a key role in the induction of pro-inflammatory gene expression, leading to the synthesis of cytokines, adhesion molecules, chemokines, growth factors and enzymes. Results of studies in in vitro and in vivo models of inflammation and malignancy have also suggested central roles for NF-kappaB in programmed cell death, or apoptosis. NF-kappaB plays a central role in a variety of acute and chronic inflammatory diseases. In the common lung diseases associated with a significant inflammatory component such as severe sepsis, acute lung injury, acute respiratory distress syndrome, cystic fibrosis and asthma, the pathogenic roles of NF-kappaB have been extensively investigated. In COPD, activation of NF-kappaB has been implicated in disease pathogenesis but its exact role is less clearly demonstrable in this heterogeneous patient population. However, the principal risk factor for COPD, cigarette smoking, is strongly associated with NF-kappaB activation. Activation of NF-kappaB has been demonstrated in mineral dust diseases and probably plays a role in the pathogenesis of these chronic illnesses. NF-kB also plays a variety of roles in lung cancer including resistance to chemotherapy, inhibition of tumorigenesis and inducing expression of antiapoptotic genes. The complex NF-kappaB pathway offers a variety of potential molecular targets for chemotherapeutic intervention. A variety of agents aimed at modulating NF-kappaB activity are in various stages of investigation.
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PMID:The role of nuclear factor kappa B in the pathogenesis of pulmonary diseases: implications for therapy. 1472 3

The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case-control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case-control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied -308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.
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PMID:Is there a future for TNF promoter polymorphisms? 1497 48


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