Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0028754 (obesity)
124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerotic lesions usually occur in the proximal and middle portion of the coronary arteries. Multiple obstructive lesions appearing only in the peripheral branches without lesions in the proximal or distal portion have not been reported. We encountered a patient with ischemic heart disease showing multiple obstruction in the peripheral branches of the right and left coronary arteries without significant stenotic lesions in the proximal or middle portion. This 49-year-old male was admitted to Yamada Red Cross Hospital due to angina pectoris. Coronary risk factors for him included hypertension, abnormal glucose tolerance, smoking habit, and obesity. Laboratory studies showed a complete blood count and normal blood chemistries, as well as thromboplastin and prothrombin times. Coronary angiography showed multiple obstruction or marked stenosis in the distal portion and peripheral branches; there was no stenosis in the proximal and middle portions. Left ventriculography showed severe hypokinesis in the diaphragmatic segment. Biopsy of the left ventricular endocardium showed interstitial fibrosis but showed no abnormalities in the myocardial fibers or cell infiltration to perivascular areas and vascular walls. Coronary angiography after two months showed multiple lesions, as previously observed. Although ischemic heart disease is caused by various types of vasculitis, embolism, coronary spasm, and fibromuscular dysplasia, in this patient, there were no findings suggestive of causes other than atherosclerosis. This case is interesting in terms of rare angiographic findings and its cause.
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PMID:Ischemic heart disease showing unusual angiographic findings. 834 Oct 3

The rapidity with which heparin anticoagulation is achieved is essential to a positive clinical outcome in patients with deep venous thrombosis or pulmonary embolus. However, adequate anticoagulation is frequently not achieved, either as a result of dosing regimens that do not take heparin kinetics into account or because of clinicians' wariness of possible hemorrhagic complications associated with elevated activated activated partial thromboplastin times. Obese patients are at particularly greater risk for subtherapeutic heparin dosing because their pharmacokinetic volumes of distribution differ from those in nonobese patients. Traditional empiric heparin dosing schemes may have pitfalls; methods that take into account the patient's weight are more likely to allow rapid anticoagulation. A nomogram that uses pharmacokinetic and volume of distribution principles to predict therapeutic levels of anticoagulation is presented.
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PMID:Rapid heparin anticoagulation: use of a weight-based nomogram. 896 50

Altered expression of proteins of the fibrinolytic and coagulation cascades in obesity may contribute to the cardiovascular risk associated with this condition. We previously reported that plasminogen activator inhibitor 1 (PAI-1) is dramatically up-regulated in the plasma and adipose tissues of genetically obese mice. This change may disturb normal hemostatic balance and create a severe hypofibrinolytic state. Here we show that tissue factor (TF) gene expression also is significantly elevated in the epididymal and subcutaneous fat pads from ob/ob mice compared with their lean counterparts, and that its level of expression in obese mice increases with age and the degree of obesity. Cell fractionation and in situ hybridization analysis of adipose tissues indicate that TF mRNA is increased in adipocytes and in unidentified stromal vascular cells. Transforming growth factor beta (TGF-beta) is known to be elevated in the adipose tissue of obese mice, and administration of TGF-beta increased TF mRNA expression in adipocytes in vivo and in vitro. These observations raise the possibility that TF and TGF-beta may contribute to the increased cardiovascular disease that accompanies obesity and related non-insulin-dependent diabetes mellitus, and that the adipocyte plays a key role in this process. The recent demonstration that TF also influences angiogenesis, cell adhesion, and signaling suggests that its exact role in adipose tissue physiology/pathology, may be complex.
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PMID:Tissue factor gene expression in the adipose tissues of obese mice. 963 94

Objectives: To investigate a possible relationship between hypertriglyceridemia and the coagulation system, a Cardiovascular Risk Factor Two-township Study was conducted in Taiwan. Design: A case-control study. This longitudinal, prospective study focused on the evolution of cardiovascular disease risk factors with emphasis on haemostatic factors. Subjects: Hypertriglyceridemic subjects (triglyceride <2.26 mmoll+1, n = 327) and age-matched normal controls from a population screening program. Main outcome measures: Haemostatic parameters measured in this study included prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors VIIc and VIIIc, and antithrombin-III and plasminogen levels. Results: In our male hypertriglyceridemic subjects, aPTT was not significantly reduced, while significant elevations of factor VIIIc, factor VIIc, and plasminogen and antithrombin-III levels were noted. In the female hypertriglyceridemic subjects, the elevation of factor VIIc, factor VIIIc, and plasminogen and antithrombin-III levels was highly-significant, whereas aPTT was not significantly reduced. Unexpectedly, the levels of the established coronary risk factor, fibrinogen, did not show a statistically different change. Similar to previous data, our hypertriglyceridemic subjects also presented with hyperinsulinemia, glucose intolerance, upper body obesity, and elevated blood pressure. Conclusions: Despite the fact that in population studies, triglycerides do not consistently appear to be an independent risk factor for coronary heart disease, our data suggest that a pronounced increase in triglycerides warrants aggressive therapy, because this increase may be associated with a hypercoagulable state. This phenomenon contributes another perspective to the study of higher cardiovascular mortality in hypertriglyceridemic subjects.
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PMID:Thrombophilia in Patients with Hypertriglyceridemia. 1063 47

Altered expression of proteins of the fibrinolytic and coagulation cascades in obesity may contribute to the cardiovascular risk associated with this condition. In spite of this, the zymogenic nature of some of the molecules and the presence of variable amounts of activators, inhibitors, and cofactors that alter their activity have made it difficult to accurately monitor changes in the activities of these proteins in tissues where they are synthesized. Thus, as a first approach to determine whether tissue factor (TF) expression is altered in obesity, this study examined changes in TF mRNA in various tissues from lean and obese (ob/ob and db/db) mice. TF gene expression was elevated in the brain, lung, kidney, heart, liver, and adipose tissues of both ob/ob and db/db mice compared with their lean counterparts. In situ hybridization analysis indicated that TF mRNA was elevated in bronchial epithelial cells in the lung, in myocytes in the heart, and in adventitial cells lining the arteries including the aortic wall. Obesity is associated with insulin resistance and hyperinsulinemia, and administration of insulin to lean mice induced TF mRNA in the kidney, brain, lung, and adipose tissue. These observations suggest that the hyperinsulinemia associated with insulin-resistant states, such as obesity and noninsulin-dependent diabetes mellitus, may induce local TF gene expression in multiple tissues. The elevated TF may contribute to the increased risk of atherothrombotic disease that accompanies these conditions.
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PMID:Regulation of tissue factor gene expression in obesity. 1171 74

ISIS 104838 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that binds tumor necrosis factor-alpha (TNF-alpha) mRNA. It carries a 2'-methoxyethyl modification on the five 3' and 5' nucleotide sugars, with 10 central unmodified deoxynucleotides. ISIS 104838 was identified from a 264 ASO screen in phorbol myristate acetate-activated keratinocytes, and the dose response was assessed in lipopolysaccharide (LPS)-activated monocytes. Healthy males received multiple intravenous (i.v.) ISIS 104838 infusions in a placebo-controlled dose escalation trial (0.1-6 mg/kg). Additional volunteers received single or multiple subcutaneous (s.c.) injections. ISIS 104838 suppressed TNF-alpha protein by 85% in stimulated keratinocytes. The IC50 for TNF-alpha mRNA inhibition in stimulated monocytes was <1 microM. For i.v., C(max) occurred at the end of infusion. The effective plasma half-life was 15 to 45 min at 0.1 to 0.5 mg/kg and 1 to 1.8 h for higher doses. The apparent terminal plasma elimination half-life approximated 25 days. Obese subjects had higher plasma levels following equivalent mg/kg doses. For s.c. injections, C(max) occurred at 2 to 4 h and was lower than with equivalent i.v. dosing. Plasma bioavailability compared with i.v. was 82% following a 200 mg/ml s.c. injection. Transient activated partial thromboplastin time prolongation occurred after i.v. infusions and minimally after s.c. injections. Two subjects experienced rash, one a reversible platelet decrease, and mild injection site tenderness was noted. TNF-alpha production by peripheral blood leukocytes, induced ex vivo by LPS, was decreased by ISIS 104838 (p < 0.01). ISIS 104838, a second-generation antisense oligonucleotide, was generally well tolerated intravenously and subcutaneously. The pharmacokinetics support an infrequent dosing interval. Inhibition of TNF-alpha production ex vivo was demonstrated.
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PMID:Phase I trial of ISIS 104838, a 2'-methoxyethyl modified antisense oligonucleotide targeting tumor necrosis factor-alpha. 1243 59

Venous thromboembolism is a common and potentially fatal disease. If properly used, anticoagulation therapy is effective in preventing recurrence of venous thromboembolism and in improving survival. Symptomatic patients with an objective diagnosis of acute deep vein thrombosis (DVT) or pulmonary embolism (PE) should receive immediate systemic heparin anticoagulation at dosages sufficient to rapidly prolong the activated partial thromboplastin time into the laboratory-specific therapeutic range; this range corresponds to a plasma heparin concentration of 0.2 to 0.4 IU/ml (as measured by protamine sulfate titration), or 0.3 to 0.7 anti-Xa IU/ml. An oral vitamin K antagonist (e.g. warfarin) should be started within 24 hours after starting heparin; the starting dose should be the estimated patient-specific daily dose with no loading dose. Heparin and warfarin anticoagulation should be overlapped for at least 4 to 5 days and until the international normalized ratio (INR) is within the therapeutic range (2.0 to 3.0) on 2 measurements made at least 24 hours apart. The duration of warfarin anticoagulation should be individualized based on the respective risks of venous thromboembolism recurrence and anticoagulant-related bleeding. In general, warfarin should be continued for at least 3 months, and longer for patients with recurrent or idiopathic venous thromboembolism, malignant neoplasm, neurologic disease with extremity paresis, obesity, or laboratory evidence of a lupus anticoagulant/anticardiolipin antibody, homozygous carrier or combined heterozygous carrier for the factor V R506Q (Leiden) and prothrombin G20210A mutations, and possibly deficiency of either antithrombin, protein C, or protein S. Low molecular weight heparin (LMWH) is effective and well tolerated as acute therapy for patients with DVT or stable PE, and does not require laboratory monitoring or dose adjustment. Outpatient LMWH therapy is also well tolerated and cost effective for most patients with DVT, and possibly for selected patients with PE.
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PMID:Current management of acute symptomatic deep vein thrombosis. 1472 51

This article about unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) is part of the Seventh American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a pentasaccharide, catalyzing the inactivation of thrombin and other clotting factors. UFH also binds endothelial cells, platelet factor 4, and platelets, leading to rather unpredictable pharmacokinetic and pharmacodynamic properties. Variability in activated partial thromboplastin time (aPTT) reagents necessitates site-specific validation of the aPTT therapeutic range in order to properly monitor UFH therapy. Lack of validation has been an oversight in many clinical trials comparing UFH to LMWH. In patients with apparent heparin resistance, anti-factor Xa monitoring may be superior to measurement of aPTT. LMWHs lack the nonspecific binding affinities of UFH, and, as a result, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties. LMWHs have replaced UFH for most clinical indications for the following reasons: (1) these properties allow LMWHs to be administered subcutaneously, once daily without laboratory monitoring; and (2) the evidence from clinical trials that LMWH is as least as effective as and is safer than UFH. Several clinical issues regarding the use of LMWHs remain unanswered. These relate to the need for monitoring with an anti-factor Xa assay in patients with severe obesity or renal insufficiency. The therapeutic range for anti-factor Xa activity depends on the dosing interval. Anti-factor Xa monitoring is prudent when administering weight-based doses of LMWH to patients who weigh > 150 kg. It has been determined that UFH infusion is preferable to LMWH injection in patients with creatinine clearance of < 25 mL/min, until further data on therapeutic dosing of LMWHs in renal failure have been published. However, when administered in low doses prophylactically, LMWH is safe for therapy in patients with renal failure. Protamine may help to reverse bleeding related to LWMH, although anti-factor Xa activity is not fully normalized by protamine. The synthetic pentasaccharide fondaparinux is a promising new antithrombotic agent for the prevention and treatment of venous thromboembolism.
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PMID:Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. 1538 72

The medical records of 54 dogs presented to the Hebrew University Veterinary Teaching Hospital and diagnosed with heat stroke were retrospectively reviewed. Data abstracted included history, clinical and clinicopathological signs at admission, treatment, disease progression, and outcome. Exertional and environmental heat stroke were present in 63% (34 of 54) and 37% (20 of 54) of the dogs, respectively, and 78% (42 of 54) were examined between June and August. The mean temperature and heat discomfort index in the particular days of heat stroke were significantly increased (P < .001, P < .001, respectively) compared with their corresponding average daily values. In 27 dogs the body temperature was > or = 41 degrees C (105.8 degrees F). Belgian Malinois (15%, odds ratio [OR] = 24, 95% confidence interval [CI95%] 8.2-64.5), Golden and Labrador Retrievers (21%, OR = 2.08, CI95% 0.95-4.2), and brachycephalic breeds (25%, OR = 1.7, CI95%], 0.81-3.21) were overrepresented, whereas small breeds (<8 kg) were underrepresented (2%, OR = 0.08, CI95%, 0.002-0.48). Thrombocytopenia (45 of 54 dogs) and prolongation of the prothrombin (PT) and activated thromboplastin (aPTT) times (27 of 47 dogs) were recorded during hospitalization. Disseminated intravascular coagulation (P = .013) and acute renal failure (P = .008), diagnosed in 28 of 54 and 18 of 54 of the cases, respectively, were risk factors for death. The overall mortality rate was 50%. Hypoglycemia (<47 mg/dL, P = .003), prolonged PT (>18 seconds, P = .05), and aPTT (>30 sec, P < .001) at admission were associated with death. Serum creatinine >1.5 mg/dL (P = .003) after 24 hours, delayed admission (>90 minutes, P = .032), seizures (P = .02), and obesity (P = .04) were also risk factors for death. Heat stroke in dogs results in serious complications and high fatality rate despite appropriate treatment.
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PMID:Heat stroke in dogs: A retrospective study of 54 cases (1999-2004) and analysis of risk factors for death. 1649 21

A 32-year-old, morbidly obese African-American woman developed bilateral pulmonary emboli 12 days after undergoing Roux-en-Y gastric bypass surgery. Three days later, after receiving heparin and warfarin, she developed heparin-induced thrombocytopenia type II (HIT-II). An argatroban 1.5-microg/kg/minute infusion was administered for approximately 2.5 days. The patient also received four doses of warfarin, totaling 37.5 mg. The argatroban infusion was discontinued early on hospital day 6, at which time the patient's international normalized ratio (INR) was 4.36 and activated partial thromboplastin time (aPTT) 85.9 seconds. Her INR and aPTT values continued to rise after the argatroban was discontinued and peaked 3 days later at 5.28 and 123.6 seconds, respectively. At this time her platelet count had improved from 139 x 10(3)/mm(3) to 543 x 10(3)/mm(3). No additional warfarin was administered before discharge. On hospital day 11, the patient was discharged home with an INR of 4.12 and an aPTT of 67.1 seconds. Her aPTT and INR values remained elevated for 19 days after receiving her last dose of warfarin and for 20 days after argatroban discontinuation. She experienced no bleeding complications from these supratherapeutic coagulation parameters. She resumed treatment with warfarin as an outpatient and completed a 6-month course of anticoagulation without further incident. Clinicians should be aware that coagulation parameters may remain elevated longer than expected after argatroban discontinuation in certain patients taking concomitant warfarin. Patients with liver dysfunction and obesity appear most likely to be affected.
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PMID:Prolonged anticoagulation after discontinuation of argatroban and warfarin therapy in an obese patient with heparin-induced thrombocytopenia. 1712 42


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