Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombotic disease is less frequent in children than in adults, but may result in severe morbidity and mortality. The coagulation system is balanced to provide rapid activation to stop bleeding and appropriate inhibition to prevent unwanted clot extension. It is regulated by fibrinolysis and by three major anticoagulant pathways: the protein C, antithrombin, and tissue factor pathway inhibitor systems. Acquired or inherited abnormalities of coagulation proteins or hemostatic regulatory mechanisms, particularly when combined with dehydration or the presence of indwelling catheters, may pose a high risk for thrombosis. Thrombosis in a child warrants investigation of potential underlying prothrombotic conditions. These include acquired antiphospholipid antibodies or the lupus anticoagulant as well as abnormalities of the inherited anticoagulant factors including protein C, protein S, antithrombin, and Factor V Leiden. Other abnormalities may result in heightened levels of otherwise normal coagulation proteins such as hyperprothrombinemia due to the prothrombin 20210 mutation. A large survey of children with thrombosis indicated that Factor V Leiden, protein C deficiency, and increased lipoprotein(a) were found most commonly. The most severe predisposition occurs with homozygous protein S or protein C deficiency with resultant purpura fulminans in the newborn. The risk of thrombosis in children with heterozygous deficiencies of anticoagulant proteins is not well defined, although it is clear that combined heterozygotes or a combination of an inherited and an acquired defect heightens the risk for thrombosis. Treatment of thrombosis primarily involves a rapidly acting anticoagulant such as heparin or low-molecular-weight heparin to prevent extension, and long-term anticoagulation with warfarin may be instituted to prevent recurrence. Fibrinolytic therapy is infrequently used because of the risk of serious bleeding complications and is reserved for selected cases of arterial thrombosis to initiate rapid reperfusion of ischemic tissue or used in those patients with a large venous thrombosis and pulmonary emboli causing hemodynamic compromise.
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PMID:Anticoagulant proteins in childhood venous and arterial thrombosis: a review. 1111 87

Recent studies have highlighted the close link between activation of the coagulation system and the inflammatory response in the pathophysiology of severe sepsis. The protein C anticoagulant pathway plays an integral part in modulating the coagulation and inflammatory responses to infection. In patients with sepsis, endogenous protein C levels are decreased, shifting the balance toward greater systemic inflammation, coagulation, and cell death. On the basis of a single large randomised phase 3 trial, drotrecogin alfa (activated), a recombinant form of human activated protein C, was recently approved for the treatment of adult patients with severe sepsis and a high risk of death. Since its approval, several questions have been raised regarding the appropriate use of this agent. Given the increased risk of serious bleeding and the high cost of treatment, drotrecogin alfa (activated) should be reserved at this time for the most acutely ill patients with severe sepsis who meet the criteria that were used in the phase 3 trial.
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PMID:Drotrecogin alfa (activated): a novel therapeutic strategy for severe sepsis. 1256 44

Unlike other types of cancer, there are several options for screening for colorectal cancer (CRC). The most extensively examined method, faecal occult blood testing (FOBT), has been shown, in three large randomized trials, to reduce mortality from CRC by up to 20% if offered biennally and possibly more if offered every year. Recently published data from the US trial suggest that CRC incidence rates are also reduced by up to 20%, but only after 18 years. In this study, the number of positive slides was associated with the positive predictive value both for CRC and adenomas larger than 1 cm, suggesting that the reduction in CRC incidence was caused by the identification and removal of large adenomas. In this respect, this study supports the concept that removing adenomas prevents CRC. More efficient methods of detecting adenomas include the use of colonoscopy or flexible sigmoidoscopy (FS). Considerable evidence exists from case-control and uncontrolled cohort studies to suggest that endoscopic screening by sigmoidoscopy reduces incidence of distal colorectal cancer. However, in the absence of evidence from a randomized trial, several countries have been reluctant to introduce endoscopic screening. Three trialsare currently in progress (in the UK, Italy and the US) to address this issue. Two of these trials are examining the hypothesis that a single FS screen at around age 55-64 might be a cost-effective and acceptable method for reducing CRC incidence rates. Recruitment and screening are now complete in both studies and the first analysis of results on incidence rates is expected in 2004. Colonoscopy screening at 10-year intervals has recently been endorsed in the US on the basis that the reductions in incidence observed with distal CRC screening can be extrapolated to the proximal colon. However, data are lacking and a pilot study for a trial of the acceptability and efficacy of colonoscopy screening is in progress in the US. It has also been suggested that FOBT testing should be used to detect proximal CRC missed by sigmoidoscopy screening, but the small amount of published data suggest that supplementing FS with FOBT offers very little advantage over FS alone. Other forms of CRC screening are under investigation and represent exciting options for the future. Extraction of DNA from stool is now feasible and a number of research groups have shown high sensitivity for CRC using a panel of DNA markers including mutations in k-ras, APC, p53 and BAT26. Data so far indicate that, with the exception of k-ras, these markers are highly specific and therefore represent a significant improvement over FOBT. Whether these tests will replace or supplement existing methods of screening has yet to be determined. It has been suggested that BAT26, which is a marker of microsatellite instability, a feature of proximal sporadic CRC, might be a useful adjunct to sigmoidoscopy screening. Others have suggested that a test for occult blood should be included with the DNA markers to further increase sensitivity. It is not yet known how sensitive these markers are for adenomas--it is only by detecting adenomas that CRC incidence rates can be reduced. A final exciting new option for screening is virtual colonoscopy (VC), which by screening out people without neoplasia allows colonoscopy to be reserved for patients requiring a therapeutic intervention. The sensitivity of VC for large adenomas and CRC appears to be high, although results vary by centre and there is a steep learning curve. Sensitivity for small adenomas is low, but perhaps it is less essential to find such lesions. Some groups have suggested that virtual colonoscopy might be a useful option for investigating patients who test positive with stool-based screening tests. Whichever CRC screening method is finally chosen (and there is no reason why several methods should not ultimately be available), high quality endoscopy resources will always be required to investigate and treat neoplastic lesions detected.
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PMID:Options for screening for colorectal cancer. 1279 74

Critically ill patients still commonly die of the effects of sepsis, despite numerous interventions. Earlier trials investigated mostly anti-inflammatory strategies, based on the prevailing theory that sepsis represents an uncontrolled inflammatory response. We now know that sepsis represents a biphasic response to infection, and the initial pro-inflammatory response that we have targeted thus far is invariably followed by a prolonged period of immune suppression. Indeed, a patient may oscillate between a pro- and anti-inflammatory state repeatedly. The use of steroids remains controversial, and should probably be reserved for a select subset of patients. The coagulation cascade has a powerful effect on inflammation, and manipulation by means of Activated Protein C has been beneficial. It appears tremendously advantageous to resuscitate the critically ill patient early and aggressively to maintain normal oxidative metabolism. This, coupled with the rigorous maintenance of a physiologically neutral milieu (particularly blood glucose levels) seems to be the most powerful weapon we have to manage the critically ill patient with sepsis.
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PMID:New concepts in treatment of sepsis. 1544 42

To evaluate the utilization of thrombophilia screening at a large urban academic tertiary care center, we retrospectively examined the indications, appropriateness, and results of 200 consecutive thrombophilia panels. Of the panels, 103 (51.5%) were ordered for venous thromboembolism; 124 (62.0%) were ordered during acute thrombotic episodes, and at least 40 (20.0%) had abnormal protein C and S results, of which 25 (63%) were attributable to anticoagulation and the remainder to pregnancy. Of the 200 panels, 46 (23.0%) had a significant abnormality; the most common abnormal result was a lupus anticoagulant, occurring in 23 cases (11.3%). Thrombophilia screening seems to be overutilized in our population, especially considering that the majority of tests are ordered during suboptimal conditions, eg, acute thrombosis, pregnancy, or anticoagulation. At present, outside the research setting, thrombophilia panels should be reserved for special circumstances, targeted to factors for which there would be a specific clinical impact, and performed in the absence of confounding clinical variables.
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PMID:An evaluation of thrombophilia screening in an urban tertiary care medical center: A "real world" experience. 1675 92

Cellular immune responses elicited by vaccination are complex and require polychromatic analysis to accurately characterize the phenotype and function of rare, responding cells. Technical challenges and a lack of instrument standardization between research sites have limited the application of polychromatic cytometry in multicenter clinical trials. Two previously developed six-color T cell subset immunophenotyping reagent panels deliberately designed to accommodate three additional low frequency functional measurements were compared for their reproducibility of staining across three different flow cytometers. We repeatedly measured similar T cell subset frequencies between the two reagent panels and across the three different cytometers. Spectral overlap reduced sensitivity in two of the three open measurement channels (PE [IL-2] and APC [IFN gamma]) for one reagent combination, particularly in subsets with low cytokine expression. There was no significant interassay variation for measurements across instrument platforms. Careful panel design will identify reagent combinations that minimize spectral spillover into channels reserved for cytokine measurement and comparable results can be achieved using different cytometers, however, it is important to establish standardized quality control procedures for each instrument to minimize variation between cytometers.
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PMID:Nine-color flow cytometry for accurate measurement of T cell subsets and cytokine responses. Part II: Panel performance across different instrument platforms. 1838 9

Risk characterization in a study population relies on cases of disease or death that are causally related to the exposure under study. The number of such cases, so-called "excess" cases, is not just an indicator of the impact of the risk factor in the study population, but also an important determinant of statistical power for assessing aspects of risk such as age-time trends and susceptible subgroups. In determining how large a population to study and/or how long to follow a study population to accumulate sufficient excess cases, it is necessary to predict future risk. In this study, focusing on models involving excess risk with possible effect modification, we describe a method for predicting the expected magnitude of numbers of excess cases and assess the uncertainty in those predictions. We do this by extending Bayesian APC models for rate projection to include exposure-related excess risk with possible effect modification by, e.g., age at exposure and attained age. The method is illustrated using the follow-up study of Japanese Atomic-Bomb Survivors, one of the primary bases for determining long-term health effects of radiation exposure and assessment of risk for radiation protection purposes. Using models selected by a predictive-performance measure obtained on test data reserved for cross-validation, we project excess counts due to radiation exposure and lifetime risk measures (risk of exposure-induced deaths (REID) and loss of life expectancy (LLE)) associated with cancer and noncancer disease deaths in the A-Bomb survivor cohort.
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PMID:Predicting future excess events in risk assessment. 1918 83

The diagnosis of disseminated intravascular coagulation (DIC) should encompass both clinical and laboratory information. The International Society for Thrombosis and Haemostasis (ISTH) DIC scoring system provides objective measurement of DIC. Where DIC is present the scoring system correlates with key clinical observations and outcomes. It is important to repeat the tests to monitor the dynamically changing scenario based on laboratory results and clinical observations. The cornerstone of the treatment of DIC is treatment of the underlying condition. Transfusion of platelets or plasma (components) in patients with DIC should not primarily be based on laboratory results and should in general be reserved for patients who present with bleeding. In patients with DIC and bleeding or at high risk of bleeding (e.g. postoperative patients or patients due to undergo an invasive procedure) and a platelet count of <50 x 10(9)/l transfusion of platelets should be considered. In non-bleeding patients with DIC, prophylactic platelet transfusion is not given unless it is perceived that there is a high risk of bleeding. In bleeding patients with DIC and prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT), administration of fresh frozen plasma (FFP) may be useful. It should not be instituted based on laboratory tests alone but should be considered in those with active bleeding and in those requiring an invasive procedure. There is no evidence that infusion of plasma stimulates the ongoing activation of coagulation. If transfusion of FFP is not possible in patients with bleeding because of fluid overload, consider using factor concentrates such as prothrombin complex concentrate, recognising that these will only partially correct the defect because they contain only selected factors, whereas in DIC there is a global deficiency of coagulation factors. Severe hypofibrinogenaemia (<1 g/l) that persists despite FFP replacement may be treated with fibrinogen concentrate or cryoprecipitate. In cases of DIC where thrombosis predominates, such as arterial or venous thromboembolism, severe purpura fulminans associated with acral ischemia or vascular skin infarction, therapeutic doses of heparin should be considered. In these patients where there is perceived to be a co-existing high risk of bleeding there may be benefits in using continuous infusion unfractionated heparin (UFH) due to its short half-life and reversibility. Weight adjusted doses (e.g. 10 mu/kg/h) may be used without the intention of prolonging the APTT ratio to 1.5-2.5 times the control. Monitoring the APTT in these cases may be complicated and clinical observation for signs of bleeding is important. In critically ill, non-bleeding patients with DIC, prophylaxis for venous thromboembolism with prophylactic doses of heparin or low molecular weight heparin is recommended. Consider treating patients with severe sepsis and DIC with recombinant human activated protein C (continuous infusion, 24 microg/kg/h for 4 d). Patients at high risk of bleeding should not be given recombinant human activated protein C. Current manufacturers guidance advises against using this product in patients with platelet counts of <30 x 10(9)/l. In the event of invasive procedures, administration of recombinant human activated protein C should be discontinued shortly before the intervention (elimination half-life approximately 20 min) and may be resumed a few hours later, dependent on the clinical situation. In the absence of further prospective evidence from randomised controlled trials confirming a beneficial effect of antithrombin concentrate on clinically relevant endpoints in patients with DIC and not receiving heparin, administration of antithrombin cannot be recommended. In general, patients with DIC should not be treated with antifibrinolytic agents. Patients with DIC that is characterised by a primary hyperfibrinolytic state and who present with severe bleeding could be treated with lysine analogues, such as tranexamic acid (e.g. 1 g every 8 h).
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PMID:Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. 1922 77

Accumulating lines of evidence now demonstrate that neutrophils can participate in adaptive immune responses directly or indirectly. Even more striking is their potential to acquire phenotypic and functional properties that are typically reserved for professional APCs. These newly emerging concepts of neutrophil heterogeneity and plasticity now challenge the classic view of neutrophils as terminally differentiated leukocytes fully committed to phagocyte functionality. Here, we present a brief overview of our current understanding of neutrophil plasticity by focusing on the acquisition of DC-like properties in culture and at sites of inflammation. Human and murine neutrophils acquire surface expression of MHC II, costimulatory molecules, and other surface markers of DCs when cultured in the presence of selected cytokines. The resulting populations also exhibit potent APC activities to present various antigens to T cells. "Unusual" neutrophils expressing DC markers have been detected in inflammatory lesions in human patients and mouse disease models. These findings imply that acquisition of DC-like properties by neutrophils at the sites of inflammation may represent a key process for linking the innate and adaptive arms of immune responses.
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PMID:Neutrophil plasticity: acquisition of phenotype and functionality of antigen-presenting cell. 2563 45

Desmoid tumors develop from connective tissue, fasciae, and aponeuroses, and may occur in the context of familial adenomatous polyposis or may arise sporadically; also, they may be extra-abdominal, intra-abdominal, or located in the abdominal wall. These benign tumors have a great aggressiveness with a high rate of local recurrence. Familial adenomatous polyposis is an inherited condition with autosomal dominant transmission, and is characterized by the development of multiple colonic and rectal adenomatous polyps, as well as desmoid tumors. We present the case of a 54-year-old woman with germline APC gene mutation, who underwent a total colectomy, subsequently developing two large infiltrative solid intra-abdominal lesions consistent with desmoid tumors. Medical treatment with Cox-2 inhibitors was initiated without result. She was submitted to resection for intestinal obstruction, but developed local recurrence. The lesions were also unresponsive to tamoxifen, and chemotherapy was initiated with dacarbazine plus doxorubicin, switching to vinorelbine plus methotrexate, achieving a good response in all lesions after 12 months. The approach to these intra-abdominal lesions should be progressive, beginning with observation, then a medical approach with non-steroidal anti-inflammatory drugs or with an anti-hormonal agent. Afterwards, if progression is still evident, chemotherapy should be started. Surgery should be reserved for resistance to medical treatment, in palliative situations, or for extra-abdominal or abdominal wall desmoids tumors.
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PMID:Large desmoid tumors in familial adenomatous polyposis: a successful outcome. 3077 22


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