Biomedical subjects

M J Post

Publications and source records attributed to M J Post.

At least 19 recordsLinked to original sources

PubMed2003

Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) affects about 1 in 20 individuals with the acquired immunodeficiency syndrome (AIDS) and has been associated with poor survival. This report describes the results of a phase II clinical trial using the drug topotecan, a semisynthetic analogue of camptothecan, administered to a cohort of subjects with AIDS-related PML. Data were evaluated on 11 of 12 subjects enrolled in the study. Three responded to therapy. Additionally, one patient was treated off-protocol and showed a response to treatment. Progression occurred after the first course; however, a partial response was noted after five courses. One study patient died from accidental overdose of topotecan. Overall, responders had higher pretreatment Karnofsky and lower Kurtzke expanded disability status scale scores than nonresponders. The most frequent toxicities were hematologic (anemia, neutropenia, and thrombocytopenia). Five patients had dose delays; all delays were due to hematologic adverse events. This study demonstrates that topotecan treatment may be associated with decreased lesion size and prolonged survival from the infection. Because of the small number of subjects in the study, further studies are required to evaluate the efficacy of topotecan in treating this disease.

Acquired Immunodeficiency Syndrome↗

PubMed2003

The rational phase of therapeutic angiogenesis.

Largely disappointing results from early clinical trials have settled down the initial unrealistic hope that fueled therapeutic angiogenesis. Now that this research has reached a rational phase, every concept in the theory of neo-vascularization needs to be re-evaluated. Neo-vascularization in adult tissues has been described as the result of either arteriogenesis, angiogenesis or vasculogenesis. The contribution of these mechanisms to neo-vascularization in vivo can likely not be separated experimentally. All currently known growth factors are pleiotropic and induce the secondary release of other growth factors. A complete analysis of the efficacy of growth factors therefore should include parameters of arteriogenesis, angiogenesis and vasculogenesis. Current clinical studies have likely suffered from drug regimens with short exposure of a single growth factor. Although combinations of growth factors may be theoretically appealing to create robust sustained neo-vessels, preclinical and clinical study designs may become too complex. Instead, there is some evidence that prolonged exposure to a single growth factor might result in vessels that are resistant to regression. With the vast and rapidly growing body of data that is being obtained on growth factors and pro-angiogenic strategies, approaches will emerge that are more effective than the ones presently tested in the clinic. It remains imperative however, that these approaches are rationally based on fundamental and preclinical data.

Genes, Switch↗

PubMed2001

Shear-stress and wall-stress regulation of vascular remodeling after balloon angioplasty: effect of matrix metalloproteinase inhibition.

BACKGROUND: Constrictive vascular remodeling (VR) is the most significant component of restenosis after balloon angioplasty (PTA). Whereas in physiological conditions VR is associated with normalization of shear stress (SS) and wall stress (WS), after PTA the role of SS and WS in VR is unknown. Furthermore, whereas matrix metalloproteinase inhibition (MMPI) has been shown to modulate VR after PTA, its effect on the SS and WS control mechanisms after PTA is unknown. METHODS AND RESULTS: PTA was performed in external iliac arteries of 12 atherosclerotic Yucatan pigs, of which 6 pigs (7 vessels) received the MMPI batimastat and 6 pigs (10 vessels) served as controls. Before and after the intervention and at 6-week follow-up, intravascular ultrasound pullback was performed, allowing 3D reconstruction of the treated segment and computational fluid dynamics to calculate the media-bounded area and SS. WS was derived from the Laplace formula. Immediately after PTA, media-bounded area, WS, and SS changed by 20%, 16%, and -49%, respectively, in both groups. VR was predicted by SS and WS. In the control group, SS and WS had been normalized at follow-up with respect to the reference segment. In contrast, for the batimastat group, the SS had been normalized, but not the WS. The latter is attributed to an increase in wall area at follow-up. CONCLUSIONS: Vascular remodeling after PTA is controlled by both SS and WS. MMPI inhibited the WS control system.

Angioplasty, Balloon↗

PubMed2001

Therapeutic angiogenesis in cardiology using protein formulations.

Therapeutic angiogenesis in cardiovascular disease aims at improving myocardial function by increasing blood flow to ischemic myocardium that is not amenable to traditional forms of revascularization. Preclinical data have provided proof of the concept that angiogenic growth factors such as fibroblast growth factor 2 (FGF-2) and vascular endothelium growth factor (VEGF) may indeed improve myocardial flow and function when administered in ways that ensure prolonged tissue exposure to these short-lived molecules. Although other cytokines have been shown to enhance angiogenesis in vivo, FGF-2 and VEGF have been most widely studied and may serve as prototype proangiogenic drugs. Currently, several delivery techniques that are clinically applicable are being studied with respect to tissue distribution and retention as well as angiogenic efficacy of FGF-2 and VEGF. Although tissue distribution and retention of FGF-2 after intramyocardial injection compares favorably with other routes of administration, efficacy studies are not yet conclusive. At the same time, different protein- and gene-based formulations are being investigated. Arguments for and against protein and gene therapy are presented, showing that protein-based therapy seems to have advantages over gene therapy at the present time, although continuous efforts should be made to increase the tissue exposure time after a single administration of protein. While delivery systems and growth factor formulations are being improved, double-blind, placebo-controlled trials designed with existing animal data in mind, are needed to firmly establish the utility of therapeutic angiogenesis in cardiovascular disease.

Animals↗

PubMed2001

Intramyocardial delivery of FGF2 in combination with radio frequency transmyocardial revascularization.

Therapeutic angiogenesis and percutaneous transmyocardial revascularization (PMR) are potentially synergistic modalities to improve myocardial perfusion. To evaluate the efficiency of FGF2 delivery into an area that has been radio frequency (RF) ablated, we studied two catheter-based delivery methods, a direct injection system (Stiletto) and a combined RF ablation-delivery system (RF-PMR). Four groups (n = 3/group) of pigs received six transendocardial injections of (125)I-FGF2/fluorescent microspheres with either the Stiletto or the RF-PMR catheter. RF-PMR injections were preceded by a 0.6 sec RF ablation step. After either 1 or 24 hr, hearts and other tissues were harvested. Intramyocardial deposition sites were located with UV light and isolated. Specific activity per site was expressed as a percentage of total activity injected per site corrected for quenching. Injection site recovery was high for both catheter systems (average = 88%) and systemic uptake was low (< 6% in the liver). FGF2 retention was significantly higher with the Stiletto than the RF-PMR catheter (Stiletto 1 hr 41% +/- 17%, 24 hr 26% +/- 10%, RF-PMR 1 hr 21% +/- 14%, 24 hr 13% +/- 8%; P < 0.001), principally explained by the differences in catheter design. The Stiletto has a retractable needle and is optimized for intramyocardial delivery, whereas infusion from the RF-PMR device occurs at the endocardial surface and relies on channels created during RF ablation. Overall, FGF2 retention after transendocardial intramyocardial delivery by the Stiletto or the RF-PMR system is significantly higher than previously observed for intracoronary, intravenous and intrapericardial delivery. In conclusion, the combination of RF ablation and growth factor delivery using the RF-PMR system is feasible and efficient. Cathet Cardiovasc Intervent 2001;53:429-434.

Animals↗

PubMed2001

Efficacy of intracoronary or intravenous VEGF165 in a pig model of chronic myocardial ischemia.

OBJECTIVES: We sought to optimize vascular endothelial growth factor (VEGF) treatment for therapeutic angiogenesis in myocardial ischemia, we explored the efficacy of five different regimens. BACKGROUND: Although VEGF165 is one of the most potent pro-angiogenic growth factors, VEGF165 treatment for myocardial ischemia has been hampered by low efficacy and dose-limiting hypotension after systemic or intracoronary delivery. METHODS: This study evaluated the effect of intravenous or intracoronary rhVEGF165 in the presence or absence of nitric oxide (NO) synthase inhibition in a porcine model of chronic myocardial ischemia. Forty-two Yorkshire pigs with chronically occluded left circumflex coronary arteries were randomly assigned to receive 10 microg/kg of VEGF165: 1) rapid (40 min) intravenous VEGF165 0.25 microg/kg/min, 2) slow (200 min) intravenous VEGF165 0.05 microg/kg/min, 3) rapid intracoronary VEGF165 0.25 microg/kg/min, 4) rapid intracoronary VEGF165 0.25 microg/kg/min + nitro-L-arginine methyl ester hydrochloride (L-NAME) or 5) rapid vehicle infusion. RESULTS: Intracoronary and intravenous VEGF165 induced hypotension. Intracoronary VEGF-induced hypotension was blocked by L-NAME. Coronary angiography three weeks after treatment showed improvement in collateral index in both intracoronary groups but not the intravenous VEGF165 groups. Likewise, myocardial blood flow and microvascular function in the ischemic territory improved in both intracoronary groups but not in the intravenous groups. Global and regional myocardial function showed no significant improvements in any groups. CONCLUSIONS: Intracoronary infusion of VEGF165 significantly improves blood flow to the ischemic myocardium. Concomitant administration of L-NAME inhibits VEGF-induced hypotension while most likely preserving VEGF-induced angiogenesis. Intravenous infusion of VEGF165 was not effective in augmenting either myocardial flow or function in this model.

Animals↗

PubMed2001

PR-39 and PR-11 peptides inhibit ischemia-reperfusion injury by blocking proteasome-mediated I kappa B alpha degradation.

PR-39 inhibits proteasome-mediated I kappa B alpha degradation and might protect against ischemia-reperfusion injury. We studied PR-39, its truncated form PR-11, and a mutant PR-11AAA, which lacks the ability to prevent I kappa B alpha degradation, in a rat heart ischemia-reperfusion model. After 30 min of ischemia and 24 h of reperfusion, cardiac function, infarct size, neutrophil infiltration, and myeloperoxidase activity were measured. Intramyocardial injection of 10 nmol/kg PR-39 or PR-11 at the time of reperfusion reduced infarct size by 65% and 57%, respectively, which improved blood pressure, left ventricular systolic pressure, and relaxation and contractility (+/-dP/dt) compared with vehicle controls 24 h later. Neutrophil infiltration, myeloperoxidase activity, and the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule 1 were reduced. Thus PR-39 and PR-11 effectively inhibit myocardial ischemia-reperfusion injury in the rat in vivo. This effect is mediated by inhibition of I kappa B alpha degradation and subsequent inhibition of nuclear factor-kappa B-dependent adhesion molecules. The active sequence is located in the first 11 amino acids, suggesting a potential for oligopeptide therapy as an adjunct to revascularization.

Animals↗

PubMed2001

Characterization of a mouse model for thrombomodulin deficiency.

Mutations in the gene encoding thrombomodulin (TM), a thrombin regulator, are suspected risk factors for venous and arterial thrombotic disease. We have previously described the generation of TM(Pro/Pro) mice carrying a TM gene mutation that disrupts the TM-dependent activation of protein C. Here, it is shown that inbred C57BL/6J TM(Pro/Pro) mice exhibit a hypercoagulable state and an increased susceptibility to thrombosis and sepsis. Platelet thrombus growth after FeCl(3)-induced acute endothelial injury was accelerated in mutant mice. Vascular stasis after permanent ligation of the carotid artery precipitated thrombosis in mutant but not in normal mice. Mutant mice showed increased mortality after exposure to high doses of endotoxin and demonstrated altered cytokine production in response to low-dose endotoxin. The severity of the hypercoagulable state and chronic microvascular thrombosis caused by the TM(Pro) mutation is profoundly influenced by mouse strain-specific genetic differences between C57BL/6 and 129SvPas mice. These data demonstrate that in mice, TM is a physiologically relevant regulator of platelet- and coagulation-driven large-vessel thrombosis and modifies the response to endotoxin-induced inflammation. The phenotypic penetrance of the TM(Pro) mutation is determined by as-yet-uncharacterized genetic modifiers of thrombosis other than TM.

Animals↗

PubMed2001

Gene transfer to induce angiogenesis in myocardial and limb ischaemia.

Stimulation of angiogenesis/arteriogenesis by gene transfer methods offers hope for treating patients with myocardial and peripheral limb ischaemia who are not candidates for standard revascularisation procedures. Preclinical studies showed that adenoviral and plasmid vectors encoding various angiogenic cytokines were capable of inducing functionally significant angiogenesis in vitro and in animal models of chronic myocardial ischaemia. Early clinical studies using VEGF121-, FGF-4- and VEGF165-encoding vectors showed a reasonable safety profile with promising results. However, significant advances in vector technology including regulatable and longer-term expression, delivery strategies (local and organ/tissue specific), clinical trial design, and outcome measure development are needed before this investigational treatment becomes reality.

Extremities↗

PubMed2001

Initial and follow-up MR imaging findings in AIDS-related progressive multifocal leukoencephalopathy treated with highly active antiretroviral therapy.

BACKGROUND AND PURPOSE: Recent studies have shown the beneficial effect of highly active antiretroviral therapy (HAART) in AIDS-related progressive multifocal leukoencephalopathy (PML). The purpose of our study was to evaluate the initial and follow-up imaging findings and survival in patients with PML who were treated with HAART. METHODS: The clinical course and MR imaging findings on initial and follow-up MR studies in four consecutive AIDS patients with PML who were treated with HAART are described. RESULTS: Two patients were short-term survivors and died after 3 months. Two patients are still alive, with a survival time of 22 and 43 months, respectively. On initial MR studies, more extensive white matter changes were seen in the short-term survivors. Development of a mass effect and temporary enhancement (in one patient) was observed in two HAART responders on follow-up MR studies. Increased hypointensity on T1-weighted images with concomitant low signal on fluid-attenuated inversion-recovery fast spin-echo (FLAIR-FSE) images was seen in two responders, representing leukomalacia. Atrophic changes of the involved areas of the brain, consistent with burnt out PML lesions, were seen in two long-term survivors. In the short-term survivors, increased hypointensity was present on T1-weighted images with increased high signal on FLAIR-FSE images, representing progressive destructive disease. CONCLUSION: Our results suggest that a clinical and radiologic response can be seen in some patients with AIDS-associated PML on HAART while in others there may be no beneficial response. Development of a mass effect and temporary enhancement on MR images in the early phase of treatment might represent positive predictive factors for prolonged survival.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Metalloproteinase inhibition reduces constrictive arterial remodeling after balloon angioplasty: a study in the atherosclerotic Yucatan micropig.

BACKGROUND: Arterial remodeling after balloon angioplasty has been recognized as a major determinant of restenosis. Perturbation of collagen metabolism might be important. After balloon injury, matrix metalloproteinase (MMP) expression is upregulated. We investigated the effect of Batimastat, a nonspecific MMP inhibitor, on late lumen loss, arterial remodeling, and neointima formation after balloon dilation. METHODS AND RESULTS: In atherosclerotic iliac arteries of 12 Yucatan micropigs, balloon dilation was performed, with intravascular ultrasound and quantitative angiography used before and after balloon dilation and at 42-day follow-up. The animals were randomly divided into 2 groups, the Batimastat group (n=6) and the vehicle group (n=6). All animals were intraperitoneally injected with either Batimastat or a vehicle immediately after balloon dilation and at 2 weeks and 4 weeks after balloon dilation. Angiographic and echographic late lumen loss in the Batimastat group versus the vehicle group was 0.3+/-0.1 versus 0.8+/-0.1 mm (P=0.01) and 2.2+/-0.5 versus 4.9+/-0.7 mm(2) (P=0.004), respectively. Late media-bounded area loss was used as a measure of remodeling after balloon dilation and was 0.9+/-0.6 mm(2) in the Batimastat group compared with 3.8+/-0.8 mm(2) in the vehicle group (P=0.003, mixed model analysis P=0.01). Neointima formation was 1.3+/-0.3 mm(2) in the Batimastat group and 1.0+/-0.2 mm(2) in the vehicle group (P=0. 542). CONCLUSIONS: Metalloproteinase inhibition by Batimastat significantly reduced late lumen loss after balloon angioplasty by inhibition of constrictive arterial remodeling, whereas neointima formation was not inhibited by MMP inhibition.

Angiography↗

PubMed2000

MRI of infections and neoplasms of the spine and spinal cord in 55 patients with AIDS.

Our purpose was to describe the range of MRI findings in infectious and neoplastic involvement of the spine and spinal cord in symptomatic patients with the acquired immunodeficiency syndrome (AIDS). MRI studies in 55 patients with AIDS and neurological signs and symptoms thought to be related to the spine or spinal cord were reviewed. We categorized the findings according to the spinal compartment involved. There were 29 patients with extradural, 11 with intradural-extramedullary and 9 with intramedullary disease. In 6 patients more than one compartment was involved simultaneously, and patients presented with multiple lesions in the same compartment. The most common causes of extradural disease were bone lesions (28); an epidural mass was seen in 14 and spondylodiscitis in 4 patients. Cytomegalovirus polyradiculitis was the most common cause of intradural-extramedullary disease (in 10 cases); herpes radiculitis was seen in two, and tuberculous infection in another two. In three cases leptomeningeal contrast enhancement was due to lymphoma. Human immunodeficiency virus (HIV) myelitis was seen in two patients, presumed vacuolar myelopathy in two, toxoplasma myelitis in four, intramedullary lymphoma in one, and herpes myelitis in one. Familiarity with the various potential pathological entities that can affect the spine and spinal cord in the AIDS population and their imaging characteristics is crucial for initiation of further diagnostic tests and appropriate medical or surgical treatment.

AIDS-Related Opportunistic Infections↗

PubMed2000

Efficacy of intracoronary versus intravenous FGF-2 in a pig model of chronic myocardial ischemia.

BACKGROUND: Therapeutic angiogenesis in ischemic myocardium has been shown to be a feasible and effective strategy to improve regional blood flow and myocardial function. However, the optimal mode of growth factor administration still needs to be established. METHODS: Using a pig model of chronic myocardial ischemia, we evaluated the efficacy of intravenous and intracoronary infusion of FGF-2 at 2 and 6 microg/kg compared with a vehicle control. Improvement in myocardial perfusion and function was assessed by angiography, colored microspheres, and function and perfusion magnetic resonance imaging. RESULTS: Intracoronary 6-microg/kg FGF-2 increased angiographic collaterals (p = 0.046) and increased regional blood flow to the ischemic area from 0.36 +/- 0.07 to 0.59 +/- 0.08 mL/min/g at stress (vs control, p = 0.032). Also, after 6 microg/kg intracoronary FGF-2, ejection fraction, regional wall motion, and thickening improved significantly by 9.9% +/- 1.9%, 126% +/- 39%, and 13.8% +/- 3.6%, respectively. Intravenous FGF-2 and intracoronary 2 microg/kg FGF-2 were ineffective. CONCLUSIONS: A single 6-microg/kg intracoronary treatment with FGF-2 resulted in significant improvement in collateralization and regional and global function of chronically ischemic myocardium. Single intravenous infusion of FGF-2 was not effective in this model.

Animals↗

PubMed2000

Inhibition of ubiquitin-proteasome pathway-mediated I kappa B alpha degradation by a naturally occurring antibacterial peptide.

Induction of NF-kappaB-dependent gene expression plays an important role in a number of biological processes including inflammation and ischemia-reperfusion injury. However, few attempts aimed at selective regulation of this transcription factor have been successful. We report here that a naturally occurring antibacterial peptide PR39 reversibly binds to the alpha 7 subunit of the 26S proteasome and blocks degradation of NF-kappa B inhibitor I kappa B alpha by the ubiquitin-proteasome pathway without affecting overall proteasome activity. I kappa B alpha phosphorylation and ubiquitination occur normally after PR39 treatment, and binding of valosin-containing proteins is not impaired. The inhibition of I kappa B alpha degradation abolishes induction of NF-kappa B-dependent gene expression in cell culture and in mouse models of acute pancreatitis and myocardial infarction, including upregulation of endothelial adhesion proteins VCAM-1 and ICAM-1. In the latter model, sustained infusion of PR39 peptide resulted in significant reduction of myocardial infarct size. PR39 and related peptides may provide novel means to regulate cellular function and to control of NF-kappa B-dependent gene expression for therapeutic purposes.

Animals↗

PubMed2000

Encephalitis, cerebritis, and brain abscess: pathophysiology and imaging findings.

This article discusses the imaging findings of encephalitis, cerebritis, and brain abscess in immunocompetent patients. MR imaging is the procedure of choice in evaluating suspected intracranial infections because of its inherent contrast resolution, multiplanar capability, improved sensitivity in the posterior fossa, sensitivity to the presence of subacute, and chronic hemorrhage, and its sensitivity to the detection of meningeal disease on postcontrast images. Discussion of pathologic conditions and imaging features of encephalitis are based on the most common causative agents of each type of disease. Imaging features and pathologic conditions of cerebritis and brain abscesses also are reviewed with emphasis on pyogenic bacteria.

Brain↗

PubMed2000

MR imaging of infections of the cervical spine.

Spine infections are serious clinical conditions that carry high morbidity and mortality rates. Cervical spine infections usually require a more aggressive medical and surgical approach than infections in the rest of the spine. Often, more than one anatomic structure or compartment becomes affected. Topics discussed in this article include incidence and predisposing factors of spine infections, types of micro-organisms involved in several disease conditions, pathophysiology and clinical manifestations, and imaging findings and MR imaging features.

Bone Diseases, Infectious↗

PubMed1999

Short- and long-term histopathologic evaluation of stenting using a self-expanding nitinol stent in pig carotid and iliac arteries.

Stenting is increasingly being used to treat carotid artery disease. However, complications including distal embolization, stent thrombosis, stent collapse from external compression, the need for high-pressure inflation with increased neointimal response, or balloon rupture during stent expansion and stent loss are all potential problems and of concern. To address each of these specific concerns, a new stent was designed, which is self-expandable, made of nitinol, with temperature-dependent superelastic properties, and with high vessel wall surface coverage. Since this device has a number of novel characteristics, we aimed to assess the short- and long-term histopathologic response in pig carotid and iliac arteries. Single stents were deployed in pig carotid and iliac arteries after overstretch balloon injury. Angiograms were performed pre- and poststenting and prior to sacrifice. Intravascular ultrasound was used before implantation to determine vessel size. Vessels were examined histologically at 1 month (n = 6) and 6 months (n = 6) for morphometric analysis, hemorrhage and thrombus, endothelialization, and inflammatory and fibrotic responses. There was a 100% angiographic success rate at implantation. In one case, it was determined histologically that a single stent was implanted in a dissection plane of a pig's left iliac artery and was occluded by organized thrombus, with the true lumen being patent. At 6-month follow-up, this was the only evidence of a single stent occlusion, with flow adjacent to the stent in the true lumen. In the other vessels, the stents showed good vessel wall-stent apposition and the lumens were patent with a concentric and thin neointima. Inflammatory cells were rare and there were no mural thrombi. Coverage of the vessel wall by endothelial-like cells was complete at 1 month. The novel nitinol EndoStent appears to have favorable biocompatibility with minimal thrombus deposition or inflammatory response, and its use is feasible for clinical application in carotid and iliac arteries.

Alloys↗

PubMed1998

Saline flush during excimer laser angioplasty: short and long term effects in the rabbit femoral artery.

BACKGROUND AND OBJECTIVE: In this study, the effect of flushing saline on arterial wall damage (medial ruptures and necrosis), intimal hyperplasia, and arterial remodeling was determined. During excimer laser coronary angioplasty saline is flushed to reduce the size of explosive water vapor bubbles formed by intraluminal delivery of excimer laser pulses in blood. METHODS: In the femoral artery of the rabbit, 600 excimer laser pulses (308 nm, 50 mJ/mm2 per pulse, 20 Hz) were delivered coaxially over a length of 20 mm in 10 bursts of 3 seconds each. In 24/48 procedures, saline was flushed (0.2 ml/s) via the guidewire channel. After 2 and 56 days, microscopic and angiographic results were compared. RESULTS: At 2 days, as compared to lasing in blood, saline flush had drastically reduced the incidence of dissections (2/12 vs. 11/12, P < 0.002), but had increased the extent of medial and adventitial necrosis. The latter is attributed to direct irradiation of the arterial wall. After 56 days, in the saline group, in the middle-distal part of treated segments, medial necrosis without intimal hyperplasia was observed. However, at the edges of these lesions, intimal hyperplasia and arterial shrinkage reduced the lumen. CONCLUSION: Flushing saline during coaxial excimer laser pulse delivery significantly reduced the incidence of vessel wall ruptures, and prevented intimal hyperplasia formation in part of the lesion. The histologic findings at 56 days are attributed to the optical window which the saline flush provides for direct ultraviolet light irradiation of the arterial wall.

Angiography↗