Specific induction of tumor neovasculature death by modified murine PPE-1 promoter armed with HSV-TK.

BACKGROUND: One strategy to increase tissue specificity of gene therapy is to use promoters or enhancers. OBJECTIVES: (1) To enhance the selectivity of a murine preproendothelin-1 (PPE-1) promoter in tumor angiogenesis by using a positive endothelial transcription-binding element. (2) To test the specificity and efficiency of the modified PPE-1 promoter [PPE-1(3X)] in vitro and in vivo by using reporter genes, and the therapeutic gene herpes simplex virus-thymidine kinase (HSV-TK) in a mouse model of Lewis lung carcinoma (LLC). RESULTS: The modified PPE-1 promoter specifically induced expression in the tumor angiogenic vascular bed with a 35-fold higher expression compared to the normal vasculare bed of the lung. Thus, when the HSV-TK gene controlled by the modified PPE-1 promoter was used systemically, it induced tumor-specific necrosis, apoptosis and mononuclear infiltrates, leading to massive destruction of the neovasculature of the pulmonary metastasis, which suppressed metastasis development. CONCLUSIONS: These results show that an adenoviral vector armed with HSV-TK controlled by the endothelial-selective murine PPE-1(3X) promoter is efficient and safe to target tumor neovasculature.

12/15-Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor-deficient mice.

BACKGROUND: Human 15-lipoxygenase (LO) and its murine analogue 12/15-LO are capable of directly oxidizing esterified fatty acids in lipoproteins and phospholipids. Because these oxidized products possess atherogenic properties, it was suggested that LOs may be involved in enhancing atherogenesis. Previous in vivo tests of the role of LOs in atherogenesis animal models, however, have yielded conflicting results. METHODS AND RESULTS: Aiming to study the role of the 12/15-LO in murine atherogenesis, we crossed LDL-receptor-deficient mice (LDL-R(-/-)) with 12/15-LO-knockout mice and evaluated plaque formation 3 to 18 weeks after initiation of a high-fat diet. Atherosclerotic lesions were considerably reduced in the LDL-R/12/15-LO-double-knockout mice compared with LDL-R(-/-) mice at 3, 9, 12, and 18 weeks, at the aortic root as well as throughout the aorta. The cellular composition of plaques from mice deficient in 12/15-LO did not differ with respect to macrophage and T-lymphocyte content compared with plaques from 12/15-LO littermates. CONCLUSIONS: 12/15-LO plays a dominant role in promoting atherogenesis in LDL-R(-/-) mice.

Effect of active limb movements on symptoms in patients with low back pain.

STUDY DESIGN: A descriptive, correlational study of patients with mechanical low back pain (LBP). OBJECTIVES: To assess the effect of active limb movements on symptoms in patients with LBP and to examine the relationship between symptoms with limb movements and select patient characteristics. BACKGROUND: Limb movements result in forces applied to the spine and, thus, may be important in the examination and treatment of patients with LBP. METHODS AND MEASURES: A total of 188 people with LBP, 84 men and 104 women, participated in a standardized examination. Six of the items required patients to move their limbs and note LBP symptoms as increased, remained the same, or decreased. The prevalence of various symptom responses with each limb movement test was calculated. Relationships between patient characteristics and reports of increased symptoms were examined with Cochran's linear trend statistic and the Spearman and Pearson correlation coefficients. Differences in characteristics of patients with and without increased symptoms were examined with chi2 test, Mann-Whitney U test, or Student's t test for independent groups. RESULTS: An increase in symptoms was reported by 149 patients with at least 1 of the limb movement tests, and 3 of the patients reported a decrease in symptoms. Across the patient sample, the mean number of limb movement tests for which symptoms were reported as increased was 2.30 +/- 1.64. Patients with an increase in symptoms reported higher average pain intensity the week prior to the examination (median = 2; range: 1-5) and higher functional disability (mean = 0.25; SD = 0.15) than those without a change in symptoms (pain intensity: median = 1; range: 0-2 and functional disability: mean = 0.16; SD = 0.12). The correlation between the number of increased symptoms and the person's average pain intensity was r = 0.23; the correlation with the functional disability score was r = 0.36. Patients with a history of LBP tended to report an increase in symptoms with more of the limb movement tests (mean = 3.5; SD = 1.40) than those without a previous history of LBP (mean = 2.0; SD = 1.11). CONCLUSIONS: Active limb movements performed during the examination primarily resulted in increased LBP symptoms. The presence and number of increased symptoms with the active limb movements was related to the patient's report of average pain intensity and functional disability. Tests of symptoms with active limb movements may provide insight into factors contributing to a LBP problem, as well as information to guide the treatment of patients with LBP.

Tissue-specific gene therapy directed to tumor angiogenesis.

Gene therapy directed specifically to the vascular wall, particularly to angiogenic endothelial cells is a prerequisite in vascular disease treatment. Angiogenesis is a major feature in many pathological conditions including wound healing, solid tumors, developing metastases, ischemic heart diseases and diabetic retinopathy. In the present study we developed a tissue-specific gene therapy to the angiogenic blood vessels of tumor metastasis using an adeno-based vector containing the murine preproendothelin-1 (PPE-1) promoter. Genes activated by the PPE-1 promoter were highly expressed in bovine aortic endothelial cells in vitro. Systemic injection of the adenoviral vectors AdPPE-1-luciferase and AdCMV-luciferase to normal C57BL/6 mice, resulted in higher activity of PPE-1 promoter compared with CMV promoter in the aorta and vascularized tissues such as heart, kidney, lung and pancreas. Systemic administration of the adenoviral vector, in mice bearing Lewis lung carcinoma, resulted in high and specific activity of PPE-1 in the new vasculature of primary tumors and lung metastasis. Cellular distribution of the delivered gene revealed highest expression of GFP in angiogenic endothelial cells of the metastasis. We expect that this approach of 'vascular-directed' gene therapy will be applicable to both vascular diseases and cancer.

Cytotoxic T lymphocytes are activated following myocardial infarction and can recognize and kill healthy myocytes in vitro.

The damage of myocardial infarction (MI) is often progressive. A possible mechanism for subsequent myocardial damage and heart failure after MI is immune response against cardiac self-antigens. The purpose of our study was to test the hypothesis that cytotoxic T lymphocytes are activated following acute MI and may have a role in producing further myocardial damage. Rats were allocated into three experimental groups: acute MI, Sham MI and non-operated control. One, two and three weeks after surgery, lymphocytes were obtained from rat spleens and incubated with neonatal cardiac myocytes. Lymphocyte proliferation was assessed by a thymidine incorporation assay and calculated as proliferation index (PI). Myocyte destruction was measured by a crystal-violet staining assay and expressed as percentage of cell destruction. Proliferation index was significantly higher among lymphocytes obtained from MI animals (44. 3+/-5.8 and 44.9+/-5.1, at 2 and 3 weeks after MI, respectively) than sham MI (29.3+/-5.3, 27.1+/-4.7) (P<0.05) or control animals (17.1+/-2.5, 16.2+/-2.8) (P=0.03). Cytotoxic activity of the MI lymphocytes against the cultured cardiomyocytes was significantly higher 2 and 3 weeks after MI, (36.4+/-7.3%, 69.3+/-4.9%) compared to sham MI (17.9+/-3.14%, 36.6+/-5.3%) (P<0.001) and control animals respectively (13.3+/-5.4%, 17.4+/-6.1%) (P<0.001). The cytotoxic activity against healthy cardiomyocytes was myocyte-specific, induced by CD8 lymphocytes and major-histocompatibility complex (MHC) restricted. Cytotoxic T lymphocytes (CD8) are activated following MI and can recognize and kill normal cardiomyocytes in vitro. The newly described pathophysiological insights may provide novel oportunities to prevent death of non-ischemic cardiomyocytes and heart failure following myocardial infarction.

Potential effects of forest fire and storm flow on total mercury and methylmercury in sediments of an arid-lands reservoir.

A study was conducted from July 1995 to June 1996 to examine the spatial and temporal changes of mercury concentrations in sediments of an arid-lands reservoir. Prior to the first sample collection in July, a forest fire burned 2930 ha of mixed conifer and ponderosa pine in the watershed of Caballo Reservoir in south-central New Mexico. The fire was eventually extinguished by summer rains and storm runoff resulting in the mobilization and transport of charred vegetative material into an intermittent tributary (Palomas Creek) that drains the watershed into Caballo Reservoir. Concentrations of total mercury (THg), monomethlymercury (MMHg), and total organic carbon (TOC) in surficial sediments revealed fire, followed by storm runoff, enhanced the transport of mercury and organic matter to the reservoir. Concentrations of THg in sediments increased from 7.5 etag/g in July to 46.1 etag/g by November 1995 at one site (Palomas) nearest the outflow of Palomas Creek. No other spatial or temporal trends were observed for THg at other sites throughout the remainder of the study. Concentrations of MMHg in sediments at the Palomas site increased from 0.428 etag/g in July to 12.46 etag/g by October 1995 compared to concentrations in sediments at the remaining sites which ranged from 0.11 to 1.50 etag/g throughout the study. The ratio of MMHg to THg (a gross index of methylation activity) was greatest in sediments from the Palomas site (5.4-33.8%) compared to the remaining sites (0.01-3.60%). The ratio was mirrored by elevated TOC in sediments at the Palomas site (2.5-11.8%) that remained elevated throughout the study. Fire and subsequent late-summer rains may have had a twofold effect on mercury concentrations in Caballo Reservoir. The storm-driven runoff following the forest fire carried mercury complexed to organic matter which resulted in elevated levels of mercury as well as providing a carbon source for microbial methylation processes in sediment.

Discharge of methylmercury-enriched hypolimnetic water from a stratified reservoir.

A study conducted from July 1995 to June 1996 examining spatial and temporal distribution of mercury (Hg) at the Caballo Reservoir, New Mexico, revealed that the highest levels of methylmercury (MMHg) occurred in both the inlet and the Rio Grande upstream of the reservoir. As a result, a second study was designed to identify possible sources of the elevated levels of MMHg, and to determine if water discharged from the Elephant Butte Reservoir upstream could be a primary source. In July 1996, as anoxia began to develop in the hypolimnion of the Elephant Butte Reservoir, surface water MMHg concentrations were below the MDL of 0.018 ng/l while water discharged into the tailrace was 0.149 ng/l MMHg. By September 1996, when the anoxic hypolimnion spanned 60% of the total reservoir depth, surface water MMHg was still below the MDL, while discharge water had increased to 1.144 ng/l MMHg. Following reservoir turnover in November 1996, surface water increased to 0.264 ng/l MMHg while discharge water decreased to 0.420 ng/l MMHg. By January 1997, MMHg in the tailrace decreased to pre-stratification levels, and both surface water and discharge water reached similar MMHg levels until the onset of summer stratification in July 1997. This trend was repeated the following year when MMHg concentrations in the tailrace increased from 0.190 ng/l in August 1997 to 1.240 ng/l in September 1997. In addition, vertical profile sampling of the reservoir from August 1997 to September 1997 showed a buildup of MMHg in the anoxic hypolimnion which coincided with increasing levels of MMHg discharged into the tailrace. During the course of this study the single largest contribution of MMHg to the river below the reservoir was from water released through the dam during the fall months of the year.

Analysis and stability of mercury speciation in petroleum hydrocarbons.

Raw petroleum and natural gas often contain high concentrations of mercury, which can be damaging to the metal components of production facilities, as well as to the environment. Various Hg species have different properties in terms of mobility, reactivity and bioavailability. Thus, for cost-effective decisions regarding plant design, Hg extraction, and pollution control, speciation information must be available at the production facility. In this paper, a simple, wet chemical speciation method, which provides data on Hg(o), dissolved and particulate total Hg, Hg(II), and methyl Hg is presented. The method incorporates species-specific extraction and separation procedures, followed by cold vapor atomic fluorescence spectrometry (CVAFS). For each species, detection limits of approximately 0.1 ng/g were obtained. Storage experiments in various containers showed that organo-mercury species were stable for at least 30 days in all containers except those made of polyethylene; and Hg(o) was stable in all containers except those made of stainless steel or polyethylene. Hg(II) was rapidly lost from all containers except those made of aluminum, which rapidly converted it to Hg(o), which was stable. In general, most of the total Hg in petroleum products was particulate Hg, followed by dissolved Hg(II) and Hg(o). Sub-ng/g concentrations of methyl-Hg were observed in most samples.

Trace metals in ancient hair from the Karluk Archaeological Site, Kodiak, Alaska.

Considerable interest exists in characterizing the extent of changes in methylmercury exposures from preindustrial to modern-day times. Hair is often preserved over centuries and has been useful in determining the extent of dietary trace metal exposures, particularly methylmercury. We examined 16 human hair samples taken from human hair bundles buried in the soil of the Karluk One Archaeological site located near the current Karluk village on the Kodiak Archipelago of Alaska. Hair samples were analyzed for total mercury, methylmercury, selenium, and cadmium. The mean total mercury level was 1.33 ppm (SD = 1.09). The mean methylmercury level, however, was considerably lower than the total mercury concentration: the mean methylmercury level was 0.03 ppm (SD = 0.02). The mean cadmium level was 0.15 ppm (SD = 0.14) and the mean selenium level was 5.22 ppm (SD = 5.73). While the concentration of total mercury in the Karluk hair samples is comparable to those observed in ancient hair from other locations, direct methylmercury quantization demonstrated that methylmercury levels were less than 2% of the total mercury in these hair samples. Because the hair was subjected to a variety of environmental influences over the centuries, the possibility of degradation of methylmercury in the hair over the last 400 to 800 years cannot be ruled out. The use of hair from remains found in more protected frozen or dry environments may provide the best evidence for the extent of preindustrial exposures to methylmercury and other trace metals.

Basic fibroblast growth factor induces myocardial hypertrophy following acute infarction in rats.

Basic fibroblast growth factor (bFGF) is a potent mitogen which induces growth of collateral vessels in ischaemic and infarcted myocardium. The effect of systemically administered bFGF on left ventricular (LV) function, myocardial hypertrophy and LV remodelling following acute myocardial infarction (MI) have not yet been fully investigated. Thirty Sprague-Dawley male rats were randomized to receive bFGF (0.5 mg) or rat albumin intraperitoneally for 1 week, beginning immediately after the induction of MI. Five animals served as controls and did not undergo any operation. Animals were killed 6 weeks after surgery and the hearts were perfused and fixed at physiological pressure. Transverse cross-sections from infarcted areas were stained with antibodies against proliferating cell nuclear antigen (PCNA) and Masson-trichrome and analysed with a coloured-image analyser for LV area (mm2), LV cavity diameter (mm), infarcted area (%), and wall thickness (mm) in infarcted and non-infarcted regions. LV area was similar in MI rats and in controls (41.7 +/- 6.9 and 43.0 +/- 1.5 mm2, respectively) and was significantly larger in MI bFGF-treated (MI/bFGF) animals (47.6 +/- 7.1 mm2) (P = 0.023). LV cavity diameter was significantly larger in the MI group than in MI/bFGF and control animals (6.0 +/- 0.8, 4.9 +/- 1.4, and 4.4 +/- 0.8 mm, respectively, P = 0.018). Wall thickness in the non-infarcted region was significantly smaller in MI animals (1.4 +/- 0.3 mm) than in MI/bFGF animals (1.6 +/- 0.4 mm) and the control group (1.6 +/- 0.1 mm) (P = 0.015). The ratio between LV cavity diameter/non-MI wall thickness was higher in MI than in control and MI/bFGF groups (4.8 +/- 1.6, 2.7 +/- 0.6 and 3.3 +/- 1.8, respectively, P = 0.03). Proliferating endothelial cells were significantly more abundant in infarcted than in normal areas in both MI and MI/bFGF groups, but with no significant differences between the groups. Intraperitoneal administration of bFGF did not cause any untoward extracardiac effects. Thus, systemic bFGF administration following acute MI in rats prevents dilatation of the LV, induces hypertrophy of the non-infarcted myocardium and exerts no untoward effects on extracardiac organs.

The environmental geochemistry and bioaccessibility of mercury in soils and sediments: a review.

There have been many studies of mercury geochemistry in the environment and its bioconcentration/bioaccumulation through the aquatic food chain. However, there is a dearth of information regarding the bioaccessibility of mercury in human receptors exposed primarily by soil ingestion. This paper reviews the current state of knowledge of mercury bioaccessibility and speciation in soils, and the utility of speciation methods to estimate mercury bioaccessibility. We conclude that additional research is necessary to determine: (1) whether analytical measurements can adequately determine the bioaccessibility of mercury in sediments and soils; (2) the accuracy of in vitro analyses in assessing mercury bioaccessibility; (3) the ability of mercury to cross tissue membranes of the mouth, esophagus, stomach, and the small and large intestines; (4) the speciation and distribution of mercury in biological fluids; and (5) mercury bioavailability using an in vivo animal model relevant to human gastrointestinal tract conditions.

The effect of low molecular weight heparin (fragmin) on myocardial neutrophil accumulation and infarct size in a rat model of myocardial infarction.

BACKGROUND: Heparin molecules possess immunomodulating properties, which are thought to complement their established antithrombotic activity. The purpose of this study was to evaluate whether the antiinflammatory properties of low molecular weight heparin (LMWH) can attenuate polymorphonuclear neutrophil accumulation and infarct size in a rat model of myocardial infarction. METHODS: Myocardial infarction was induced by ligating the left main coronary artery. LMWH (fragmin 500 anti-FXa u/kg) or vehicle (saline) were administered subcutaneously thirty minutes prior to coronary artery occlusion. Significant anticoagulant activity was attained with LMWH for more than eight hours. Twenty-four hours later, neutrophil accumulation and infarct size were determined by measuring left ventricular free wall myeloperoxidase and residual creatine kinase activity, respectively. RESULTS: As compared with rats administered vehicle, myeloperoxidase activity was insignificantly decreased in rats treated with LMWH (1.24 +/- 0.28 u/g vs 1.66 +/- 0.15 u/g, P = 0.16. Infarct size was also not significantly different between the groups (62.48 +/- 3.5% and 50.67 +/- 7.2% of left ventricular free wall with vehicle and LMWH, respectively, P = 0.1). CONCLUSION: The authors conclude that LMWH does not significantly reduce myocardial neutrophil accumulation and infarct size twenty-four hours after myocardial infarction in the rat.

Exogenous insulin-like growth factor II enhances post-infarction regional myocardial function in swine.

OBJECTIVES: Insulin-like growth factor II (IGF-II) promotes cardiac myocyte growth and contractility in vitro. This study was designed to investigate the effect of exogenous IGF-II on regional myocardial function at the area of infarct in the pig. METHODS: Myocardial infarction was induced in 12 female anaesthetized pigs by affigel blue beads, embolizing microvessels of the left anterior descending coronary artery distribution. In the experimental group (n = 6), IGF-II (0.12 microgram.kg-1 in two animals and 0.6 microgram.kg-1 in four) was incorporated into the beads and delivered by them to the infarct area. Myocardial function was followed echocardiographically, and the excised heart was analysed immunohistochemically and histopathologically. RESULTS: Myocardial function in injured zones, inversely related to an echocardiographic segmental wall motion score (mean +/- SEM), was similar between the two groups at baseline, but at 4 weeks post-infarction was significantly (P = 0.008) reduced in the control group (0.58 +/- 0.38 vs 3.42 +/- 0.84), in contrast to nearly baseline values in the experimental group (0.58 +/- 0.33 vs 1.17 +/- 0.42, P = 0.41). Cardiac performance in injured segments was significantly better after myocardial injury in the experimental group (P = 0.04). Tissue samples from both groups (4 weeks post-infarction), stained with haematoxylin and eosin demonstrated peri-infarct myocyte hypertrophy, corresponding to regions selectively stained by an antibody for CD56, which highlights growing cardiac myocytes. By image analysis semi-quantification, staining for CD56 was significantly (P = 0.04) higher in the peri-infarct region of the experimental group, as compared with controls (106.5 +/- 2.8 vs 92 +/- 4.4 gray level units). Microvessels stained for von-Willebrand factor were similar in number in both groups (P = 0.8), as were mesenchymal cells stained for vimentin (P = 0.7). CONCLUSIONS: Exogenous IGF-II, delivered to the infarct area ameliorates regional cardiac function in the pig, perhaps by inducing peri-infarct myocyte growth.

Noninvasive evaluation of microcirculatory hemodynamic changes during hemorrhage followed by saline or blood transfusion.

The purpose of the study was to examine the ability of a system combining laser Doppler flowmetry (LDF), photoplethysmograph (PPG), and transcutaneous oxygen tension (tc-PO2) to follow changes in the microcirculation during hemorrhage and following blood or saline return, and to test the hypothesis that such changes precede and might predict changes in the systemic blood pressure. Measurements were performed on the skin of anesthetized rabbits (n = 10) during mild (0-8%), moderate (9-24%), and severe (25-30% of blood volume) hemorrhage, and following complete volume restitution by blood or saline. We found the following: 1) hemorrhage caused typical changes in the LDF, PPG, and tc-PO2 signals that could be formulated by mathematical models, 2) these signals identified blood as being more efficient than saline for volume restitution following hemorrhage, and 3) microcirculatory changes precede and might predict systemic hemodynamic events.

Ex vivo activated memory T-lymphocytes as adoptive cellular therapy of human soft-tissue sarcoma targets with potentiation by cis-diamminedichloroplatinum(II).

Autolymphocyte therapy (ALT) is tumor-specific, adoptive cellular therapy of neoplastic disease using nonspecific ex vivo activation of autologous peripheral blood lymphocytes (PBL), which are composed primarily of memory T-cells (ALT-cells) and are active in patients with metastatic renal cell carcinoma and melanoma. Ex vivo pretreatment of tumor target cells with certain chemotherapeutic agents can enhance susceptibility to lysis by antitumor lymphocytes. To determine if cis-diamminedichloroplatinum(II) (CDDP) enhances ex vivo antitumor cytotoxicity of ALT-cells and if this lysis is mediated by T- and/or NK-cells and is human leukocyte antigen (HLA)-restricted, human soft tissue sarcoma (STS) target cells were derived from primary and metastatic surgical specimens and were incubated with and without CDDP. ALT-cells were prepared from autologous PBL obtained prior to surgery. Primary (PSTS) and metastatic (MSTS) target cells from each group were labelled with chromium 51 (51Cr) and used as targets for ALT-cells, CD45-depleted ALT-cells, CD56 (NK)-depleted ALT-cells, and PBL in a standard (4-hour) and delayed (18-hour) 51Cr release assay. Interferon-gamma (IFN-gamma) release was measured as an indication of antitumor effect and recognition by the noncytolytic lymphocytes in ALT-cells. Primary tumor target cells incubated in CDDP showed enhanced lysis as measured by the 51Cr release assay compared to non-CDDP-treated controls. Metastatic tumor target cells showed less lysis than the primary targets, although this was enhanced by pretreating metastatic tumor targets with CDDP. Lysis of all tumor targets was significantly greater when ALT-cells were used as the effector cells rather than PBL. Depletion of memory T-cells abrogated ex vivo lysis. Depletion of NK cells (CD56+) affected ex vivo lysis of autologous targets during the 4-hour but not the 18-hour assay. Ex vivo ALT-cell lysis and IFN-gamma release against only the autologous tumor targets confirmed tumor-specificity in one patient. Restriction of ALT-cell lysis and IFN-gamma release against HLA-A2+ autologous and one allogeneic HLA-A2+ STS tumor target, but not other non-STS targets, was demonstrated in another patient. These data suggest that CDDP may help render STS susceptible to tumor-specific, immune-mediated attack and that the combination of ALT and CDDP may lead to effective tumor-specific chemoimmunotherapy in patients with metastatic STS.

A septic hip complicated by a ruptured appendix in an intravenous drug user.

This paper reports on a case of hip joint sepsis complicated by a ruptured appendix in an intravenous drug user. A 41-year-old woman underwent open irrigation and débridement of her right hip joint for a methicillin-sensitive Staphylococcus aureus infection. Five days later the patient developed an intraperitoneal mass, requiring laparotomy and débridement of a periappendiceal abscess. The organisms infecting the abscess were different from those infecting the patient's hip. The patient recovered satisfactorily after 6 weeks of intravenous antibiotic therapy.

Fracture of the iliac crest following bone grafting: a case report and literature review.

Fracture of the anterior iliac crest following bone grafting is an extremely rare occurrence. Five cases have been reported in the literature, none of which were internally stabilized. We are reporting a sixth case. Of the six cases, our harvest site is the furthest posterior from the anterior superior iliac spine. The fracture resulted in a large displaced anterior fragment that required open reduction and internal fixation with plates and screws. Osteoporosis increases the risk of anterior iliac crest fractures following bone grafting, but preventive procedures can be performed.

A closed-chest pig model of sustained ventricular tachycardia.

The goal of this study was to develop and explore a closed-chest animal model of sustained VT. Seven of 11 domestic pigs had successful induction of myocardial infarction by injection of agarose gel microbeads into the left anterior descending coronary artery through an inflated balloon angioplasty catheter. Four of the first five pigs died and seem to represent a "learning experience." During a 3- to 50-day follow-up period, each pig underwent 1-3 electrophysiological studies. Sustained, monomorphic VT was induced 1-4 times in 5 of the 7 pigs (a total of 19 episodes), was reproducible during the same study in all pigs, and could be repetitively induced during successive studies in some. Ventricular fibrillation was induced less frequently (nine episodes) and was successfully terminated by DC shock in eight episodes. We conclude that a closed-chest pig model of VT is feasible and is associated with a relatively high induction rate of sustained, monomorphic, and reproducible VT and a relatively low mortality rate.

Failure of captopril to attenuate myocardial damage, neutrophil accumulation, and mortality following coronary artery occlusion and reperfusion in rat.

Captopril, a sulfhydryl-containing angiotensin-converting enzyme inhibitor, has been suggested as possessing antiischemic and antiinflammatory properties. To test the hypothesis that captopril may prevent neutrophil-induced myocardial injury during acute myocardial infarction (AMI), the authors subjected rats to coronary occlusion for thirty minutes and reperfusion for twenty-four hours (MI) or to sham operation (sham MI). Oral captopril (100 mg/kg) or vehicle was administered thirty minutes before coronary occlusion. The effect of captopril on mean arterial blood pressure was assessed in separate group of animals (n = 8). Infarct size and neutrophil accumulation in myocardium were determined by measuring creatine phosphokinase depletion and myeloperoxidase (MPO) activity, respectively, in the left ventricular free wall (LVFW). Animals treated with 100 mg/kg of captopril exhibited significant reduction in mean arterial blood pressure compared with vehicle-treated animals (P < 0.01). Compared with vehicle-treated animals, administration of 100 mg/kg of captopril to MI animals attenuated neither twenty-four-hour mortality (56% vs 52%, respectively), nor infarct size (36 +/- 7% vs 34% +/- 7% respectively), nor MPO activity (1.0 +/- 0.17 vs 1.26 +/- 0.19). Thus, in the present experiment captopril did not reduce neutrophil-induced myocardial damage following coronary occlusion and reperfusion. These findings may be partly explained by the negative effect of captopril on arterial blood pressure during AMI.