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Biomedical subjects

K M Anderson

Publications and source records attributed to K M Anderson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Widespread countervailing genomic responses induced by chemotherapy or radiation as a cause of therapeutic failure.

If chemotherapy or ionizing radiation induce widespread genomic responses tending to circumvent or antagonize their ability to kill malignant cells, an additional cause for therapeutic failure would be suggested. There is evidence that some agents evoke extensive countervailing genomic activity, the nature and extent of which can be assessed with the use of 'gene chips'.

Antineoplastic Agents↗
PubMed2000

Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway.

Dendritic cells (DC) are key components of innate and adaptive immune responses. The identity of endogenous signals that activate DC is a crucial and unresolved question. We report here that heat shock proteins (HSP), the most abundant and conserved mammalian molecules, constitute such an internal signal. Necrotic but not apoptotic cell death leads to release of HSP gp96, calreticulin, hsp90 and hsp70. HSP stimulate macrophages to secrete cytokines, and induce expression of antigen-presenting and co-stimulatory molecules on the DC. The HSP gp96 and hsp70 act differentially, and each induces some but not all molecules. HSP interact with these antigen-presenting cells through the highly conserved NF-kappa B pathway. As HSP are intracellular, abundant and soluble, their presence in the extra-cellular milieu and the consequent activation of antigen-presenting cells (APC) constitutes an excellent mechanism for response to cell death. As HSP are conserved from bacteria to mammals, the ability of HSP to activate APC provides a unified mechanism for response to internal and external stimuli.

Animals↗
PubMed2000

Modulation of human monocyte activities by tranilast, SB 252218, a compound demonstrating efficacy in restenosis.

Tranilast (SB 252218) is a compound initially identified as an anti-atopic agent. Recently the compound has demonstrated clear beneficial effects in animal models of restenosis. Here we confirm tranilast has broad and profound effects on human monocytes, which could contribute to the vascular antifibrotic activity. Tranilast exhibited significant immunomodulatory activity inhibiting endotoxin-induced prostaglandin E(2) (PGE(2); IC(50) = approximately 1-20 microM), thromboxane B(2) (IC(50) = approximately 10-50 microM), transforming growth factor-beta1 (TGF-beta1; IC(50) = approximately 100-200 microM), and interleukin-8 (IC(50) = approximately 100 microM) formation, but had no effect on tumor necrosis factor-alpha. Interleukin-12 and -18-induced interferon-gamma formation by monocytes was also attenuated by tranilast. A23187-induced monocyte leukotriene C(4) or PGE(2) formation was inhibited by tranilast at IC(50) values of 10-40 microM and 2-20 microM, respectively, incubated with or without exogenous arachidonic acid. Interestingly, tranilast (up to 1000 microM) had no direct effects on cyclooxygenase I or II activity, nor did it have significant effects on human type IIA 14 kDa or type IV 85 kDa phospholipase A(2) activity. Furthermore, tranilast had no effect on endotoxin-induced cyclooxygenase II protein expression, suggesting tranilast modulates eicosanoid production and release by an as yet unidentified mechanism. Alternatively, the expression of TGF-beta1 was inhibited by tranilast but found to be due in part to inhibition of PGE(2) because exogenous PGE(2) could abrogate tranilast-mediated inhibition of TGF-beta1. Taken together, although a reported direct inhibitor of fibroblast proliferation, we show tranilast also attenuates the proinflammatory activity of human monocytes, adding to its potential efficacy as a therapeutic agent in restenosis.

Arachidonic Acid↗
PubMed1999

Identification and characterization of cvHsp. A novel human small stress protein selectively expressed in cardiovascular and insulin-sensitive tissues.

Starting with computational tools that search for tissue-selective expression of assembled expressed sequenced tags, we have identified by focusing on heart libraries a novel small stress protein of 170 amino acids that we named cvHsp. cvHsp was found as being computationally selectively and highly (0.3% of the total RNA) expressed in human heart. The cvHsp gene mapped to 1p36.23-p34.3 between markers D1S434 and D1S507. The expression of cvHsp was analyzed with RNA dot, Northern blots, or reverse transcription-polymerase chain reaction: expression was high in heart, medium in skeletal muscle, and low in aorta or adipose tissues. In the heart of rat models of cardiac pathologies, cvHsp mRNA expression was either unchanged (spontaneous hypertension), up-regulated (right ventricular hypertrophy induced by monocrotaline treatment), or down-regulated (left ventricular hypertrophy following aortic banding). In obese Zucker rats, cvHsp mRNA was increased in skeletal muscle, brown, and white adipose tissues but remained unchanged in the heart. Western blot analysis using antipeptide polyclonal antibodies revealed two specific bands at 23 and 25 kDa for cvHsp in human heart. cvHsp interacted in both yeast two-hybrid and immunoprecipitation experiments with alpha-filamin or actin-binding protein 280. Within cvHsp, amino acid residues 56-119 were shown to be important for its specific interaction with the C-terminal tail of alpha-filamin.

Amino Acid Sequence↗
PubMed1999

Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting.

BACKGROUND: We assessed in a randomised trial the long-term outcomes for potent adjunctive antiplatelet therapy given at the time of coronary stenting. METHODS: In 63 hospitals in the USA and Canada, 2399 patients were randomly assigned stenting with abciximab, stenting with placebo, or balloon angioplasty with abciximab. Standard adjunctive therapy with aspirin, ticlopidine, and heparin was used. The major outcomes of death and myocardial infarction were assessed at 1-year follow-up by intention to treat. We also investigated the 1-year cost-effectiveness of combined stenting and abciximab therapy. FINDINGS: At 1-year follow-up, eight (1.0%) of 794 patients in the stent plus abciximab group had died, compared with 19 (2.4%) of 809 in the stent plus placebo group (hazard ratio 0.43 [95% CI 0.19-0.97], p=0.037). The combined endpoint of death or large myocardial infarction occurred in 42 (5.3%) and 89 (11.0%), respectively (0.46 [0.32-0.67], p<0.001). By multivariate modelling, the factors independently associated with improved survival were assignment to stenting with abciximab (p=0.027) and greater preprocedural stenosis (p=0.002); those associated with worse survival were age greater than 70 years (p<0.001), previous heart failure (p=0.001), diabetes treated with insulin (p=0.02), and postprocedural occlusion (p<0.001). Relative to stenting plus placebo and balloon angioplasty plus abciximab, the incremental 1-year costs of stenting plus abciximab were US$581 and $932. The corresponding cost-effectiveness ratios were US$5291 and $6213 per added life-year. INTERPRETATION: Coronary stenting with abciximab, compared with stenting alone or balloon angioplasty with abciximab, is associated with improved survival and is an economically attractive therapy by conventional standards.

Abciximab↗
PubMed1999

Sustained suppression of ischemic complications of coronary intervention by platelet GP IIb/IIIa blockade with abciximab: one-year outcome in the EPILOG trial. Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade.

BACKGROUND: Blockade of the platelet glycoprotein IIb/IIIa receptor with the monoclonal antibody fragment abciximab was shown in a placebo-controlled randomized trial to reduce the incidence of acute ischemic complications within 30 days among a broad spectrum of patients undergoing percutaneous coronary revascularization. The durability of clinical benefit in this setting has not been established. METHODS AND RESULTS: A total of 2792 patients enrolled in the Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG) trial were followed with maintenance of double-blinding for 1 year. Patients had been assigned at the time of their index coronary interventional procedure to receive placebo with standard-dose, weight-adjusted heparin (100 U/kg initial bolus), abciximab with standard-dose, weight-adjusted heparin, or abciximab with low-dose, weight-adjusted heparin (70 U/kg initial bolus). The primary outcome was the composite of death, myocardial infarction, or urgent repeat revascularization by 30 days; this composite end point and its individual components were also assessed at 6 months and 1 year. Rates of any repeat revascularization (urgent or elective), target vessel revascularization, and a composite of death, myocardial infarction, or any repeat revascularization were also reported. Follow-up at 1 year was 99% complete for survival status and 97% complete for other end points. By 1 year, the incidence of the primary composite end point was 16.1% in the placebo group, 9.6% in the abciximab with low-dose heparin group (P<0.001), and 9.5% in the abciximab with standard-dose heparin group (P<0.001). Each of the components of this composite end point was reduced to a similar extent. Nonurgent or target vessel repeat revascularization rates were not significantly decreased by abciximab therapy. Mortality rates over 1 year increased with increasing levels of periprocedural creatine kinase MB fraction elevation. CONCLUSIONS: Acute reductions in ischemic events after percutaneous coronary intervention by abciximab are sustained over follow-up to at least 1 year. Early periprocedural myocardial infarctions suppressed by this therapy are associated with long-term mortality rates.

Abciximab↗
PubMed1999

Anti-human RP105 sera induces lymphocyte proliferation.

Cellular environment dictates whether antigen binding to the B lymphocyte receptor together with co-stimulatory molecules will result in proliferation, anergy, or apoptosis. Murine RP105 is a member of the leucine-rich repeat family of proteins, which is specifically expressed on mature B cells. Monoclonal antibodies to the murine RP105 induce proliferation and protect B cells from apoptosis, suggesting an important regulatory role in murine B lymphocyte function. We identified a human RP105 homolog and mapped the gene to chromosome 5q12.3-13.1. Tissue distribution analysis shows that the transcript is found predominately in lymphoid tissues including spleen, tonsils, appendix, and peripheral blood leukocytes. Polymerase chain reaction analysis of isolated primary human cell populations confirms that mRNA exists in spleen B lymphocytes and monocytes but not T lymphocytes. Western blot analysis demonstrates specific expression of human RP105 in human B lymphocytes. Murine anti-human RP105 sera was generated using DNA immunization. The antisera contained antibodies that recognized and bound to human B lymphocytes from both spleen and peripheral blood as assessed by flow cytometry. Assessment of biological function showed that human peripheral blood leukocytes incubated with anti-RP105 sera were induced to proliferate as measured by tritiated thymidine incorporation. Moreover, anti-CD40 and interleukin-4-treated cells but not those exposed to anti-RP105 sera produced soluble CD23, suggesting distinct functional roles. This is the first demonstration of both the existence of RP105 protein on human B lymphocytes and its role in the regulation of B lymphocyte activation.

Animals↗
PubMed1999

cDNA sequence and characterization of the gene that encodes human myotrophin/V-1 protein, a mediator of cardiac hypertrophy.

The predominant response of the heart to sustained increased work load is development of ventricular hypertrophy, principally as a result of hypertrophy of cardiomyocytes. The molecular mechanisms and factors involved in cardiomyocyte hypertrophy are poorly understood. Myotrophin is a novel 12-kilodalton protein recently implicated as a factor associated with and able to induce cardiac hypertrophy. Cloning of rat myotrophin revealed that this protein is identical to the functionally undefined rat, murine and chicken V-1 proteins. Although human myotrophin has been purified to homogeneity, its gene has not been characterized. In this report we describe the cloning, expression, purification and characterization of the human homolog of myotrophin/V-1 protein. Sequence analysis indicators high homology (>90%) between all species at both the nucleotide and amino acid levels, and Southern blot analysis of genomic DNA from diverse species verifies that myotrophin/V-1 is a highly conserved gene. Northern analysis indicates wide-spread expression of a single human transcript, and examination of mRNA distribution in 50 human tissues by dot blot analysis indicates ubiquitous expression with relatively high expressioon in adult and fetal heart. We verify that recombinant human myotrophin produces cardiomyocyte hypertrophy, and we demonstrate for the first time that elevated levels of myotrophin/V-1 protein mRNA are expressed in human dilated cardiomyopathic hearts. We report the novel findings that myotrophin expression is elevated in ischemic hearts, and that myotrophin expression correlates positively with ventricular mass in a hypoxic rat model of induced right ventricular hypertrophy.

Amino Acid Sequence↗
PubMed1999

Risk factors and outcomes following revascularization for chronic mesenteric ischemia.

Revascularization for chronic mesenteric ischemia is an infrequent vascular procedure whose objective long-term patency results have been described in relatively few patients. We reviewed our experience with such procedures and report on the objective and symptomatic long-term results. We retrospectively reviewed a consecutive series of 42 patients who underwent mesenteric arterial reconstruction of 66 vessels during an 11-year period from 1986 to 1997. All patients were treated for symptomatic chronic mesenteric ischemia. The results support the clinical efficacy and durability of visceral artery bypass procedures for patients with symptomatic chronic mesenteric ischemia. Patency rates for females were better than for males independent of graft type.

Angioplasty↗
PubMed1999

Do lipoxygenases modulate normal or aberrant lympho-hematopoiesis?

Whether 5- (and the 12- or 15-) lipoxygenases participate in normal or malignantly transformed hematopoietic cell proliferation and differentiation, or contribute to programmed or necrotic cell death has been difficult to decide. Recent evidence concerning these questions is reviewed and some reasons for these difficulties are considered.

Animals↗
PubMed1999

Induction of type 1 programmed cell death in U937 cells by the antioxidant, butylated hydroxy-toluene or the free radical spin trap, NTBN.

Oxidative stress can initiate programmed cell death and contributes to the patho-physiology of a number of diseases. Low micromolar to millimolar concentrations of various antioxidants or free radical scavengers promote cell growth and reduce cellular suicide induced by several functionally distinct agents, including some known to produce oxidative stress. Severe anoxia or inhibitors of oxidative phosphorylation also initiate programmed cell death. These results seem paradoxical. In order to compare the response of U937 monoblastoid cells to higher concentrations of an antioxidant or a free radical-spin trap, cells were cultured with 20-80 microM concentrations of butylated hydroxy-toluene or with 5 to 60 mM concentrations of the free radical spin trap, N-tertiary butyl phenyl-nitrone. At these concentrations, both agents inhibited cellular proliferation and induced oligosomic DNA, detected by its 'laddering' after electrophoresis on agarose, confirmed by TUNEL (BHT) or flow cytometric (NTBN) evidence of hypodiploid DNA and ultrastructural evidence of a type 1 programmed cell death. The ability of hydroxy-toluenes to oxidize DNA and promote carcinogenesis and whether free radical spin traps could augment or interfere with the response of malignantly transformed cells to chemotherapy or ionizing radiation provide the raison d'etre of these studies.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1999

Deep venous thrombosis after percutaneous insertion of vena caval filters.

PURPOSE: A large multicenter study has recently questioned the overall clinical efficacy of vena caval filters, especially when inserted prophylactically, because of the subsequent development of deep venous thrombosis (DVT) at the insertion site. We examined the incidence of this complication with newer, smaller diameter percutaneous devices. METHODS: We reviewed our vascular surgery and interventional radiology clinical registries to identify patients in whom a femoral percutaneous vena caval filter had been placed from 1993 to 1998. This list was cross referenced with patients who had undergone lower extremity venous ultrasound scan examinations for the diagnosis of DVT in the vascular laboratory within a 60-day period before and after the insertion of the filter device. RESULTS: A total of 35 patients during this 5-year period had timely follow-up venous duplex scan studies performed. The indications for filter placement were DVT in 16 patients (46%), pulmonary embolus in 13 patients (37%), DVT and pulmonary embolus in three patients (9%), and prophylactically in three patients (9%) at high risk for thromboembolization. Of the patients with documented thromboembolic events, 91% (29 of 32) had contraindications to anticoagulation therapy, and the remaining 9% (3 of 32) represented failure of anticoagulation therapy. A Greenfield filter was used in 13 patients (37%), a Simon Nitinol filter was used in 11 patients (31%), and a VenaTech filter was used in nine patients (26%). The other two patients (6%) had a Bird's Nest filter inserted. At a mean follow-up period of 12 +/- 2 days (median, 6 days), there was a 40% (14 of 35) incidence of proximal DVT in venous segments without evidence of thrombus before filter insertion. The majority (71%; 10 of 14) occurred in the common femoral vein, with three located in the superficial femoral vein and one in the external iliac vein. The lowest incidence of DVT was seen with the Greenfield and Bird's Nest filters as compared with the smaller Simon Nitinol and VenaTech filters (20% vs 55%; P < .05). The highest incidence of thrombosis occurred in patients with pre-insertion pulmonary emboli (50%; 8 of 16) as compared with those patients with DVT (38%; 6 of 16) and prophylactic insertion (0%; 0 of 3). However, the subgroups were too small to attain statistical significance. CONCLUSION: There is a continuing and significant incidence of new DVT development ipsilateral to the percutaneous femoral insertion site of vena caval filters. The smaller diameter filters are not associated with a lower incidence of femoral thrombosis.

Anticoagulants↗
PubMed1999

A national survey of practice patterns in the noninvasive diagnosis of deep venous thrombosis.

PURPOSE: Recent studies have recommended unilateral venous duplex scanning for the diagnosis of deep venous thrombosis (DVT) in patients who are unilaterally symptomatic. Vascular laboratory accreditation standards, however, imply that bilateral leg scanning should be performed. We examined whether actual practice patterns have evolved toward limited unilateral scanning in such patients. METHODS: A questionnaire was mailed to all 808 vascular laboratories in the United States that were accredited by the Intersocietal Commission for the Accreditation of Vascular Laboratories (ICAVL). To encourage candid responses, the questionnaires were numerically coded and confidentiality was assured. RESULTS: A total of 608 questionnaires (75%) were completed and returned. Most of the respondents (442; 73%) were either community-hospital or office-based laboratories, and the remaining 163 (27%) were university or affiliated-hospital laboratories. Most of the laboratories (460; 76%) had been in existence for 9 years or more, and 65% had been ICAVL-accredited in venous studies for 3 years or more. Board-certified vascular surgeons were the medical directors in 54% of the laboratories. Duplex ultrasound scanning was the diagnostic method used by 98% of the laboratories. In patients with unilateral symptoms, 75% of the laboratories did not routinely scan both legs for DVT. A large majority (75%) believe that bilateral scanning is not clinically indicated. Only 57 laboratories (14%) recalled having patients return with a DVT in the previously unscanned leg, with 93% of these laboratories reporting between one and five such patients. This observation correlated with larger volumes of venous studies performed by those laboratories (P <.05). Similarly, only 52 laboratories (12%) recalled having patients return with subsequent pulmonary emboli. Of these laboratories, only five reported proximal DVT in the previously unscanned legs of such patients. Of all these laboratories, therefore, only 1% (5 of 443) have potentially missed the diagnosis of a DVT that caused a preventable pulmonary embolus with such a policy. Among those laboratories that always perform bilateral examinations, 41% do so because of habit. Most (61%) of the laboratories that perform bilateral scanning would do unilateral scanning if it were specifically approved by ICAVL. CONCLUSION: Three quarters of the ICAVL-accredited vascular laboratories perform limited single-extremity scanning for the diagnosis of DVT in patients with unilateral symptoms. This broad clinical experience suggests that this practice is widespread in selected patients. Clinical protocols should be established to provide guidelines for local laboratory implementation.

Health Care Surveys↗
PubMed1999

Free radicals and reactive oxygen species in programmed cell death.

Oxidative stress, originating from reactive oxygen species and free radicals provides a constant challenge to eukaryotic cell survival. While implicated in a number of degenerative diseases, some associated with aging and with aging itself, the manner and extent to which oxidative stress contributes to the initiation or implementation of programmed-cell death is problematic. If oxidative stress is an important modulator of programmed-cell death, any ability intentionally to augment or inhibit it might ameliorate diseases in which the process is abnormally underactive or overactive.

Animals↗
PubMed1999

Free radical spin traps as adjuncts for the prevention and treatment of disease.

Free radical spin traps exhibit properties consistent with a role in the prevention or amelioration of diseases mediated by the formation of free radical species in excess of optimum constitutive requirements. At first view, it may be surprising that they have not found a place in clinical medicine. Some studies of diseases in which free radicals and oxidative stress are aberrantly over- or underabundant and which might be ameliorated by inhibiting or augmenting their formation have been reported. A number of pathophysiologic categories in which such agents have been or might be employed are briefly summarized.

Animals↗