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Biomedical subjects

F J Miller

Publications and source records attributed to F J Miller.

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

Refractory abdominal-cutaneous fistulas or leaks: percutaneous management with a collagen plug.

BACKGROUND: We report the results of abdominal-cutaneous fistula tract occlusion with a collagen plug in a series of patients with fistulas or leaks refractory to conservative therapy. STUDY DESIGN: Seven patients were found to have persistent fistula or leak after percutaneous drainage of abdominal pelvic fluid collections. All patients but one were refractory to surgical or percutaneous drainage. Under fluoroscopic guidance, modified Vasoseal (Datascope Inc, Montvale, NJ) collagen plugs were deployed into the fistulas using catheter-directed techniques. The plugs were split longitudinally to fit into an 8F or 9F peel-away sheath, placed into the fistula, and deployed. Results were tabulated and patients were followed up. RESULTS: Six of seven patients undergoing fluoroscopically guided, catheter-directed tract occlusion had resolution of the fistula, with no evidence of fistula or abscess recurrence from 30 to 180 days after closure. There were no procedural complications. The technique was unsuccessful in dosing a gastrocutaneous fistula after removal of a large-bore gastrostomy tube; this failure was believed to be secondary to the short length and large caliber of the tract in a patient with hypercortisolemia. CONCLUSIONS: Closure of abdominal-cutaneous fistula tracts by occlusion with a modified Vasoseal collagen plug shows promise in the management of fistulas refractory to catheter drainage.

Abdomen↗
PubMed2000

Respiratory tract pathology and cytokine imbalance in clinically healthy children chronically and sequentially exposed to air pollutants.

Chronic exposure of children to a complex mixture of air pollutants leads to recurrent episodes of upper and lower respiratory tract injury. An altered nasal mucociliary apparatus leaves the distal acinar airways more vulnerable to reactive gases and particulate matter (PM). The heterogeneity of structure in the human lung can impart significant variability in the distribution of ozone dose and particle deposition; this, in turn, influences the extent of epithelial injury and repair in chronically exposed children. Cytokines are low-molecular-weight proteins that act as intercellular mediators of inflammatory reactions, including lung injury of various etiologies. Cytokines are involved in generating inflammatory responses that contribute to injury at the lung epithelial and endothelial barriers. Mexico City is a 20-million-person megacity with severe air pollution problems. Southwest Metropolitan Mexico City (SWMMC) atmosphere is characterized by a complex mixture of air pollutants, including ozone, PM, and aldehydes. There is radiological evidence that significant lower respiratory tract damage is taking place in clinically healthy children chronically and sequentially exposed to air pollutants while growing up in SWMMC. We hypothesize that there is an imbalanced and dysregulated cytokine network in SWMMC children with overproduction of proinflammatory cytokines and cytokines involved in lung tissue repair and fibrosis. The nature of the sustained imbalance among the different cytokines ultimately determines the final lung histopathology, which would include subchronic inflammation, emphysema, and fibrosis. Cytokines likely would reach the systemic circulation and produce systemic effects. Individuals with an underlying respiratory or cardiovascular disease are less able to maintain equilibrium of the precarious cytokine networks.

Air Pollutants↗
PubMed2000

The effect of heterogeneity of lung structure on particle deposition in the rat lung.

Differences in particle deposition patterns between human and rat lungs may be attributed primarily to their differences in breathing patterns and airway morphology. Heterogeneity of lung structure is expected to impact acinar particle deposition in the rat. Two different morphometric models of the rat lung were used to compute particle deposition in the acinar airways: the multiple-path lung (MPL) model (Anjilvel and Asgharian, 1995, Fundam. Appl. Toxicol. 28, 41-50) with a fixed airway geometry, and the stochastic lung (SL) model (Koblinger and Hofmann, 1988, Anat. Rec. 221, 533-539) with a randomly selected branching structure. In the MPL model, identical acini with a symmetric subtree (Yeh et aL, 1979, Anat. Rec. 195, 483-492) were attached to each terminal bronchiole, while the respiratory airways in the SL model are represented by an asymmetric stochastic subtree derived from morphometric data on the Sprague-Dawley rat (Koblinger et al., 1995, J. Aerosol. Med. 8, 7-19). In addition to the original MPL and SL models, a hybrid lung model was also used, based on the MPL bronchial tree and the SL acinar structure. Total and regional deposition was calculated for a wide range of particle sizes under quiet and heavy breathing conditions. While mean total bronchial and acinar deposition fractions were similar for the three models, the SL and hybrid models predicted a substantial variation in particle deposition among different acini. The variances of acinar deposition in the MPL model were consistently much smaller than those for the SL and the hybrid lung model. The similarity of acinar deposition variations in the two latter models and their independence on the breathing pattern suggests that the heterogeneity of the acinar airway structure is primarily responsible for the heterogeneity of acinar particle deposition.

Administration, Inhalation↗
PubMed2000

Enhanced H(2)O(2)-induced cytotoxicity in "epithelioid" smooth muscle cells: implications for neointimal regression.

Vascular smooth muscle cells (SMCs) are phenotypically diverse. Although most medial SMCs can be classified as "fusiform," others are of the "epithelioid" phenotype. Proliferation and apoptosis of epithelioid SMCs may contribute importantly to neointimal formation and regression, respectively. Because reactive oxygen species (ROS) are increased in vascular injury and can induce apoptosis of SMCs, we compared the effects of ROS on epithelioid and fusiform SMCs. Epithelioid and fusiform SMC lines were clonally isolated from rat aortic media and studied under similar conditions and passage numbers. H(2)O(2) produced dose- and time-dependent cytotoxicity that was enhanced in epithelioid compared with fusiform cells. After 24-hour exposure to 50 micromol/L H(2)O(2), epithelioid cell numbers were reduced by 34+/-5% versus a 3+/-5% (P<0.05) reduction in fusiform cell numbers. Similar results were obtained whether H(2)O(2) was administered to growth-arrested or growing cells or when epithelioid and fusiform cells were exposed to extracellular O(2)(.-). To investigate whether apoptosis contributed to enhanced ROS-induced cytotoxicity in epithelioid SMCs, terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick-end labeling (TUNEL) staining was performed. The incidence of TUNEL positivity was 5-fold increased in epithelioid versus fusiform SMCs after treatment with 50 micromol/L H(2)O(2) (19+/-1% epithelioid versus 5+/-1% fusiform, P<0.05). Enhanced H(2)O(2)-induced apoptosis in epithelioid SMCs was confirmed by DNA laddering. Furthermore, when balloon-injured aortas were exposed to H(2)O(2) ex vivo, enhanced apoptosis was observed in neointimal compared with medial SMCs. These results suggest that epithelioid SMCs exhibit enhanced sensitivity to ROS-induced apoptosis, which may play an important role in neointimal regression.

Animals↗
PubMed2000

Gene transfer of endothelial nitric oxide synthase reduces angiotensin II-induced endothelial dysfunction.

Angiotensin II stimulates vascular NADPH oxidase to produce superoxide, which can react with nitric oxide and impair vasomotor function. We tested the hypothesis that the overexpression of endothelial nitric oxide synthase (eNOS) or superoxide dismutase (SOD) would correct angiotensin II-induced endothelial dysfunction. We examined the effects of the gene transfer of eNOS or 2 isoforms of SOD to the aorta in angiotensin II-treated rabbits on vasomotor function. New Zealand White rabbits were treated for 1 week with angiotensin II (100 ng. kg(-1). min(-1)) or saline by osmotic minipumps. In angiotensin II-treated rabbits, mean blood pressure was 107+/-8 mm Hg; it was 67+/-5 mm Hg in saline-infused rabbits (P<0.05). In aortas from angiotensin II-treated rabbits, lucigenin-enhanced chemiluminescence demonstrated a 2.5-fold increase in superoxide levels, and the oxidative fluorescent probe hydroethidine indicated increased superoxide levels throughout the vascular wall, especially in the endothelium and adventitia. Maximal relaxation to acetylcholine was less in aortas from rabbits treated with angiotensin II (72+/-5% versus 87+/-4% in saline-treated rabbits; P<0.01), but responses to sodium nitroprusside were similar. Segments of the thoracic aorta were incubated in vitro with an adenoviral vector that expressed eNOS, copper zinc SOD (CuZnSOD), extracellular SOD (ECSOD), or beta-galactosidase. beta-Gal treatment with adenovirus containing the gene for eNOS (AdeNOS) but not adenovirus containing the gene for beta-gal (Adbeta-gal) (control virus) restored responses to acetylcholine (82+/-3% after AdeNOS and 67+/-4% after Adbeta-gal). Gene transfer of CuZnSOD or ECSOD did not improve the endothelium-dependent relaxation of the aorta in rabbits that received angiotensin II. Thus, gene transfer of eNOS, but not SOD, effectively restores vasomotor function in angiotensin II-infused rabbits.

Angiotensin II↗
PubMed1999

Overexpression of human catalase inhibits proliferation and promotes apoptosis in vascular smooth muscle cells.

The role of reactive oxygen species, such as superoxide anions (O(2). (-)) and hydrogen peroxide (H(2)O(2)), in modulating vascular smooth muscle cell proliferation and viability is controversial. To investigate the role of endogenously produced H(2)O(2), rat aortic smooth muscle cells were infected with adenoviral vectors containing cDNA for human catalase (AdCat) or a control gene, beta-galactosidase (AdLacZ). Infection with AdCat resulted in dose-dependent increases in intracellular catalase protein, which was predominantly localized to peroxisomes. After infection with 100 multiplicity of infection (MOI) of AdCat, cellular catalase activity was increased by 50- to 100-fold, and intracellular H(2)O(2) concentration was reduced, as compared with control. Infection with AdCat reduced [(3)H]thymidine uptake, an index of DNA synthesis, in cells maintained in medium supplemented with 2% serum (0.37+/-0.09 disintegrations per minute per cell [AdLacZ] versus 0.22+/-0.08 disintegrations per minute per cell [AdCat], P<0.05). Five days after infection with 100 MOI of AdCat, cell numbers were reduced as compared with noninfected or AdLacZ-infected cells (157 780+/-8413 [AdCat], P<0.05 versus 233 700+/-3032 [noninfected] or 222 410+/-5332 [AdLacZ]). Furthermore, the number of apoptotic cells was increased 5-fold after infection with 100 MOI of AdCat as compared with control. Infection with AdCat resulted in induction of cyclooxygenase (COX)-2, and treatment with a COX-2 inhibitor overcame the AdCat-induced reduction in cell numbers. These findings indicate that overexpression of catalase inhibited smooth muscle proliferation while increasing the rate of apoptosis, possibly through a COX-2-dependent mechanism. Our results suggest that endogenously produced H(2)O(2) importantly modulates survival and proliferation of vascular smooth muscle cells.

Animals↗
PubMed1999

Clinical outcomes of patients after a negative spiral CT pulmonary arteriogram in the evaluation of acute pulmonary embolism.

PURPOSE: To examine 6-month clinical outcomes of patients after acquisition of a spiral computed tomography (CT) pulmonary arteriogram interpreted as negative for acute pulmonary embolism (PE). MATERIALS AND METHODS: A retrospective review was performed on a consecutive series of 143 patients who underwent spiral CT pulmonary arteriography for possible acute PE during a 19-month period. All studies were performed on a HiSpeed Scanner with use of 3-mm collimation with a pitch between 1.3 and 2.0, depending on patient size. All imaging was performed during dynamic contrast material injection at rates between 3.0 and 4.0 mL/sec, timed to peak pulmonary arterial enhancement. For the studies interpreted as negative for PE through the segmental (fourth order) pulmonary arteries, follow-up data were collected by telephone interviews with patients or surviving relatives, and by medical record reviews. RESULTS: Among 143 patients, 22 studies (15%) were positive for PE, eight (6%) were suboptimal to exclude PE to the segmental artery level, and 113 (79%) were interpreted as negative for acute PE. Among the 113 negative studies, 13 patients were lost to follow-up, leaving a study population of 100 patients. Eighty-one patients were alive a minimum of 6 months after acquisition of a negative spiral CT pulmonary arteriogram (mean, 9 months; range, 6-24 months) and were without interim diagnosis of PE. Nineteen patients died within the follow-up period after a negative spiral CT pulmonary arteriogram (mean, 3 months; range, 0-8 months); however, in none of these cases was acute pulmonary embolus reported as the cause of death. No documented PE was identified by subsequent imaging studies or autopsy within the study population. CONCLUSION: A series of 100 patients with a negative spiral CT pulmonary arteriogram did not experience significant morbidity and mortality as a result of pulmonary embolic disease within a 6-month follow-up period.

Adult↗
PubMed1999

Nucleo-cytoplasmic interactions that control nuclear envelope breakdown and entry into mitosis in the sea urchin zygote.

In sea urchin zygotes and mammalian cells nuclear envelope breakdown (NEB) is not driven simply by a rise in cytoplasmic cyclin dependent kinase 1-cyclin B (Cdk1-B) activity; the checkpoint monitoring DNA synthesis can prevent NEB in the face of mitotic levels of Cdk1-B. Using sea urchin zygotes we investigated whether this checkpoint prevents NEB by restricting import of regulatory proteins into the nucleus. We find that cyclin B1-GFP accumulates in nuclei that cannot complete DNA synthesis and do not break down. Thus, this checkpoint limits NEB downstream of both the cytoplasmic activation and nuclear accumulation of Cdk1-B1. In separate experiments we fertilize sea urchin eggs with sperm whose DNA has been covalently cross-linked to inhibit replication. When the pronuclei fuse, the resulting zygote nucleus does not break down for >180 minutes (equivalent to three cell cycles), even though Cdk1-B activity rises to greater than mitotic levels. If pronuclear fusion is prevented, then the female pronucleus breaks down at the normal time (average 68 minutes) and the male pronucleus with cross-linked DNA breaks down 16 minutes later. This male pronucleus has a functional checkpoint because it does not break down for >120 minutes if the female pronucleus is removed just prior to NEB. These results reveal the existence of an activity released by the female pronucleus upon its breakdown, that overrides the checkpoint in the male pronucleus and induces NEB. Microinjecting wheat germ agglutinin into binucleate zygotes reveals that this activity involves molecules that must be actively translocated into the male pronucleus.

Animals↗
PubMed1998

Superoxide production in vascular smooth muscle contributes to oxidative stress and impaired relaxation in atherosclerosis.

The endothelium is a source of reactive oxygen species in short-term models of hypercholesterolemia and atherosclerosis. We examined a chronic model of atherosclerosis for increased vascular production of superoxide (O2-.) and determined whether endothelial overexpression of superoxide dismutase (SOD) would improve endothelium-dependent relaxation. Superoxide generation was 3 times higher in isolated aortas from Watanabe heritable hyperlipidemic (WHHL) rabbits (2 to 4 years old) compared with aortas from New Zealand White (NZ) rabbits (43+/-10 versus 14+/-2 relative light units x min(-1) x mm(-2), n=9, P<0.05). After in vitro transduction with adenovirus containing the gene for CuZn-SOD (AdCMVCuZn-SOD) or extracellular SOD (AdCMVEC-SOD), endothelial O2-. levels in WHHL aortas were significantly reduced. Gene transfer of SOD to WHHL aortas, however, failed to improve the impaired relaxation to acetylcholine or calcium ionophore. By use of the oxidative fluorescent dye hydroethidine, an in situ assay indicated markedly increased generation of O2-. throughout the wall of WHHL aorta, especially within layers of smooth muscle. This finding was confirmed by demonstrating increased O2-. levels in smooth muscle cells cultured from WHHL aorta. We conclude that elevated O2-. levels in atherosclerotic vessels are not confined to the endothelium but occur throughout the vascular wall, including smooth muscle cells. Reduction in endothelial O2-. levels is not sufficient to improve endothelium-dependent relaxation. Generation of reactive oxygen species within the media may contribute to vasomotor dysfunction in atherosclerosis.

Animals↗
PubMed1998

Pharmacologic activation of the human coronary microcirculation in vitro: endothelium-dependent dilation and differential responses to acetylcholine.

OBJECTIVES: In vivo studies of the human coronary resistance circulation cannot control for indirect effects of myocardial metabolism, compression, and neurohumoral influences. This study directly examined the vasodilator responses of the human coronary microcirculation to both receptor-dependent and -independent agonists. METHODS: Atrial arterioles were dissected from human right atrial appendage (103 +/- 2 microns diameter, n = 185 vessels from 145 patients) obtained at the time of cardiopulmonary bypass and left ventricular vessels from explanted human hearts (148 +/- 10 microns diameter, n = 57 vessels from 18 patients). After dissection, vessels were mounted onto pipettes in Kreb's buffer under conditions of zero flow and at a constant distending pressure of 60 mmHg. Drugs were applied extraluminally and steady state changes in diameter measured with videomicroscopy. RESULTS: After contraction by endothelin or spontaneous tone, increasing concentrations of adenosine diphosphate (ADP) produced a similar dose-dependent dilation in vessels from atria (maximum 89 +/- 4%, n = 76) and ventricles (maximum 74 +/- 9%, n = 10). The dilation to ADP was abolished by mechanical removal of the endothelium. Similar dilator responses were found to bradykinin, substance P, arachidonic acid, and the calcium ionophore A23187 in both atria and ventricle. In contrast, acetylcholine (ACh) constricted all atrial vessels (-58 +/- 3%, n = 63) regardless of patient age or underlying disease. This constriction was attenuated by denudation, but not affected by inhibition of nitric oxide synthase or cyclo-oxygenase. Microvessels isolated from human ventricle exhibited a heterogeneous response to ACh with dilation being the predominant response. CONCLUSIONS: We conclude that isolated human coronary arterioles demonstrate endothelium-dependent dilation. However, the response to acetylcholine is unique with vasoconstriction in atrial vessels and dilation in ventricular arterioles.

Acetylcholine↗
PubMed1997

Upper respiratory tract surface areas and volumes of laboratory animals and humans: considerations for dosimetry models.

To facilitate the development of regional respiratory tract dosimetry comparisons between laboratory animal species and humans, published surface area (SA) and volume (VOL) data for the upper respiratory tract (URT) were reviewed. The review of the literature revealed that (1) different studies used different techniques to prepare specimens and make measurements, (2) different areas of the URT were measured, and (3) URT surface areas and volumes have been reported for a limited number of individual subjects within a species but for a relatively wide range of species. The published data are summarized in tables in this article. New measurements made in an F344 rat and in a female human subject are also presented. Despite the differences in experimental protocols, it was possible to fit allometric scaling equations to the data: In(SA, cm2) = -0.34 + 0.52 In(body weight, g) and In(VOL, cm3) = 1.70 + 0.78 In(body weight, g). Separate scaling equations were also fitted for rats alone. To illustrate the use of these scaling equations in quantitative human health risk assessment, two dose metrics (fractional absorption/cm2 URT SA and fractional absorption/g body weight) for predicted URT uptake in laboratory animals and humans were calculated for acrolein and epichlorohydrin. Expressed as an animal-to-human ratio, the 95% confidence interval for URT SA could change the predicted dose ratio by up to a factor of 2. Additional studies are needed to describe the entire URT (from the nares through the larynx) quantitatively and to decrease variability in scaling equation predictions as well as to develop additional species-specific scaling equations. Three-dimensional imaging techniques provide a noninvasive method to obtain URT surface areas and volumes in humans and the larger laboratory animals. Comparisons of magnetic resonance image (MRI) and computed tomography (CT) scans made as part of this study suggest that the greater clarity of the mucosal-air interface in the CT image provides better resolution for the study of anatomic features. Because there is no radiation exposure associated with MRI imaging, however, it is more safely used than CT scans in making repeated measurements in a subject to elucidate changes in URT geometry associated with normal nasal cycling or other physiological changes.

Acrolein↗
PubMed1997

Myogenic constriction of human coronary arterioles.

Myogenic constriction is an important mechanism of blood flow regulation; however, it has never been demonstrated in the human coronary circulation. We examined responses of human coronary resistance vessels in vitro to changes in intraluminal pressure and evaluated the role of protein kinase C (PKC). Microvessels (passive diameter 44-227 microns) were dissected from atrial appendages obtained during cardiac surgery and studied under conditions of zero flow. In response to stepped increases in pressure, there was a graded response such that at 100 mmHg, vessels constricted to 55 +/- 4% of their passive diameter. There was an inverse relationship between vessel diameter and myogenic responsiveness. Basal tone was attenuated by inhibition of voltage-dependent calcium channels (VDCC) with diltiazem and by inhibition of PKC with calphostin C. Activation of PKC with phorbol 12-myristate 13-acetate (PMA) enhanced basal tone. Active myogenic constriction was also impaired by calphostin C and augmented by PMA. Arterioles from patients with hypertension demonstrated enhanced myogenic constriction compared with vessels from normotensive patients (0.55 +/- 0.04 vs. 0.74 +/- 0.03; P < 0.01). These results demonstrate myogenic constriction in the human coronary microcirculation. Regulation of extracellular calcium by VDCC and intracellular calcium by PKC are important in mediating the magnitude of basal tone and myogenic responsiveness of these vessels.

Adolescent↗
PubMed1997

The checkpoint control for anaphase onset does not monitor excess numbers of spindle poles or bipolar spindle symmetry.

Exit from mitosis in animal cells is substantially delayed when spindle assembly is inhibited, spindle bipolarity is disrupted, or when a monopolar spindle is formed. These observations have led to the proposal that animal cells have a 'spindle assembly' checkpoint for the metaphase-anaphase transition that monitors bipolar spindle organization. However, the existence of such a checkpoint is uncertain because perturbations in spindle organization can produce unattached kinetochores, which by themselves are known to delay anaphase onset. In this study we have tested if cells monitor bipolar spindle organization, independent of kinetochore attachment, by analyzing the duration of mitosis in sea urchin zygotes and vertebrate somatic cells containing multipolar spindles in which all kinetochores are attached to spindle poles. We found that sea urchin zygotes containing tripolar or tetrapolar spindles progressed from nuclear envelope breakdown to anaphase onset with normal timing. We also found that the presence of supernumerary, unpaired spindle poles did not greatly prolong mitosis. Observation of untreated PtK1 cells that formed tripolar or tetrapolar spindles revealed that they progressed through mitosis, on average, at the normal rate. More importantly, the interval between the bipolar attachment of the last monooriented chromosome and anaphase onset was normal. Thus, neither of these cell types can detect the presence of gross aberrations in spindle architecture that inevitably lead to aneuploidy. We conclude that animal cells do not have a checkpoint for the metaphase-anaphase transition that monitors defects in spindle architecture independent of the checkpoint that monitors kinetochore attachment to the spindle. For dividing cells in which spindle microtubule assembly is not experimentally compromised, we propose that the completion of kinetochore attachment is the event which limits the time of the metaphase-anaphase transition.

Anaphase↗