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Endothelium-dependent vasodilation is impaired in atherosclerosis. Oxidized low density lipoprotein (ox-LDL) plays an important role, possibly through alterations in G-protein activation. We examined the effect of acute exposure to ox-LDL on the dilator responses of isolated rabbit aorta segments. We sought also to evaluate the specificity of this dysfunction for dilator stimuli that traditionally operate through a Gi-protein mechanism. Aortic segments were prepared for measurement of isometric tension. After contraction with prostaglandin F2alpha, relaxation to thrombin, adenosine diphosphate (ADP), or the endothelium-independent agonists, sodium nitroprusside (SNP) or papaverine was examined. Maximal relaxation to thrombin was impaired in the presence of ox-LDL (17.7+/-3.7% p<0.05) compared to control (no LDL) (52.6+/-4.0%). Ox-LDL did not affect maximal relaxation to ADP or SNP. However, in the presence of charybdotoxin (CHTX: calcium-activated potassium channel inhibitor) ox-LDL impaired relaxation to ADP (17.4+/-3.2%). CHTX did not affect control (no LDL) responses to ADP (69.6+/-5.0%) or relaxation to thrombin or papaverine. In conclusion, ox-LDL impairs relaxation to thrombin, but in the case of ADP, calcium-activated potassium channels compensate to maintain this relaxation.

Centrosomes were microsurgically removed from BSC-1 African green monkey kidney cells before the completion of S phase. Karyoplasts (acentrosomal cells) entered and completed mitosis. However, postmitotic karyoplasts arrested before S phase, whereas adjacent control cells divided repeatedly. Postmitotic karyoplasts assembled a microtubule-organizing center containing gamma-tubulin and pericentrin, but did not regenerate centrioles. These observations reveal the existence of an activity associated with core centrosomal structures-distinct from elements of the microtubule-organizing center-that is required for the somatic cell cycle to progress through G1 into S phase. Once the cell is in S phase, these core structures are not needed for the G2-M phase transition.

Between January 1991 and January 1998, a total of 15 patients underwent direct injection sclerotherapy for painful peripheral venous malformations. Duplex ultrasonography or venography was used in all cases for the detection and localization of tortuous venous structures. Direct injection with absolute ethyl alcohol was performed in 12 patients, and Sotradecol or sodium morrhuate was used in 5 patients. Provocative lidocaine testing was used in 2 patients in whom major nerves were in proximity to the malformations. All patients underwent follow-up in the clinic with duplex examination after each sclerotherapy. Clinical symptoms of all patients improved during average follow-up of 2.5 years (range: 3 months to 6 years.) Duplex examination was useful in detecting the venous component including the size and course of veins, which were often less well seen on magnetic resonance imaging. Duplex study was helpful in follow-up after sclerotherapy in all patients. Direct injection sclerotherapy is an acceptable treatment modality for venous malformations. Complications are manageable, and regular follow-up with Duplex is helpful.

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.

HHT type 2 (HHT 2) is a multi-system vascular dysplasia caused by a mutation in the ALK-1 gene, but the phenotype has not been well defined. We report on 51 members of an HHT 2 kindred with an ALK-1 gene mutation shown to be associated with the disorder. This ALK-1 mutation was detected in 38 kindred members who were evaluated systematically for associated vascular abnormalities. Pulmonary arteriovenous malformations (AVMs) were found in 6% of those screened, cerebral AVM in 7%, hepatic AVM in 17%, and spinal AVM in 3%. We discuss these and other findings in the 38 affected kindred members, as well as findings in the 13 kindred members in whom the mutation was not detected. This study shows that pulmonary, cerebral, spinal, and hepatic AVMs can all occur in HHT 2. It also adds to the evidence suggesting that pulmonary AVMs are more common in HHT 1 than in HHT 2. We identify a higher prevalence of hepatic AVMs than previously reported in either HHT 1 or 2. This may be specific to the mutation in this kindred, but probably reflects the lack of routine screening for this manifestation. Even in this family in which all affected individuals have the same mutation, the clinical manifestations of HHT and their severity varied tremendously. Intrafamilial variation in expression of HHT is clearly significant, emphasizing the difficulty in establishing the diagnosis in individuals and in sub-typing families when DNA testing is not available.

The concept that the product of the concentration (C) of a substance and the length of time (t) it is administered produces a fixed level of effect for a given endpoint has been ascribed to Fritz Haber, who was a German scientist in the early 1900s. He contended that the acute lethality of war gases could be assessed by the amount of the gas in a cubic meter of air (i.e. the concentration) multiplied by the time in min that the animal had to breathe the air before death ensued (i.e. C x t=k). While Haber recognized that C x t=k was applicable only under certain conditions, many toxicologists have used his rule to analyze experimental data whether or not their chemicals, biological endpoints, and exposure scenarios were suitable candidates for the rule. The fact that the relationship between C and t is linear on a log-log scale and could easily be solved by hand, led to early acceptance among toxicologists, particularly in the field of entomology. In 1940, a statistician named Bliss provided an elegant treatment on the relationships among exposure time, concentration, and the toxicity of insecticides. He proposed solutions for when the log-log plot of C and t was composed of two or more rectilinear segments, for when the log-log plot was curvilinear, and for when the slope of the dosage-mortality curve was a function of C. Despite the fact that Haber's rule can underestimate or overestimate effects (and consequently risks), it has been used in various settings by regulatory bodies. Examples are presented from the literature of data sets that follow Haber's rule as well as those that do not. Haber's rule is put into perspective by showing that it is simply a special case in a family of power law curves relating concentration and duration of exposure to a fixed level of response for a given endpoint. Also shown is how this power law family can be used to examine the three-dimensional surface relating C, t, and varying levels of response. The time has come to move beyond the limited view of C and t relationships inferred by Haber's rule to the use of the broader family of curves of which this rule is a special case.

The p34(cdc2) protein kinase, a universal regulator of mitosis, is controlled positively and negatively by phosphorylation, and by association with B-type mitotic cyclins. In addition, activation and inactivation of p34(cdc2) are induced by Ca(2+) and prevented by Ca(2+) chelators in permeabilized cells and cell-free systems. This suggests that intracellular Ca(2+) transients may play an important physiological role in the control of p34(cdc2) kinase activity. We have found that activators of protein kinase C can be used to block cell cycle-related alterations in intracellular Ca(2+) concentration ([Ca(2+)](i)) in early sea urchin embryos without altering the normal resting level of Ca(2+). We have used this finding to investigate whether [Ca(2+)](i) transients control p34(cdc2) kinase activity in living cells via a mechanism that involves cyclin B or the phosphorylation state of p34(cdc2). In the present study we show that the elimination of [Ca(2+)](i) transients during interphase blocks p34(cdc2) activation and entry into mitosis, while the elimination of mitotic [Ca(2+)](i) transients prevents p34(cdc2) inactivation and exit from mitosis. Moreover, we find that [Ca(2+)](i) transients are not required for the synthesis of cyclin B, its binding to p34(cdc2) or its destruction during anaphase. However, in the absence of interphase [Ca(2+)](i) transients p34(cdc2) does not undergo the tyrosine dephosphorylation that is required for activation, and in the absence of mitotic [Ca(2+)](i) transients p34(cdc2) does not undergo threonine dephosphorylation that is normally associated with inactivation. These results provide evidence that intracellular [Ca(2+)](i) transients trigger the dephosphorylation of p34(cdc2) at key regulatory sites, thereby controlling the timing of mitosis entry and exit.

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.

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.

Background: Diabetes mellitus is associated with impairment of NO-mediated vascular relaxation. The purpose of this study was to determine whether adenovirus-mediated gene transfer of endothelial NO synthase (eNOS) or Cu/Zn superoxide dismutase (SOD1) improves responsiveness to acetylcholine in alloxan-induced diabetic rabbits., Methods and Results: After 8 weeks, plasma glucose was greater in diabetic rabbits (418+/-35 mg/dL) (mean+/-SEM) than in normal rabbits (105+/-4 mg/dL). Carotid arteries were removed and cut into ring segments. Arteries were incubated for 2 hours with adenoviral vectors driven by a CMV promoter expressing beta-galactosidase (beta-gal), eNOS, SOD1, or vehicle. After incubation with virus, arteries were incubated for an additional 24 hours to allow transgene expression. Vascular reactivity was examined by recording isometric tension. After precontraction with phenylephrine, responses to the endothelium-independent vasodilator sodium nitroprusside were similar in diabetic and normal arteries. Endothelium-dependent relaxation to acetylcholine (3x10(-6) mol/L) was significantly less in arteries from diabetic animals (68+/-5%) than in normal vessels (90+/-3%). Adenoviral transfection of arteries with eNOS improved relaxation in response to acetylcholine in diabetic (EC(50) eNOS=0.64+/-0.12x10(-7) mol/L versus vehicle =1. 70+/-0.43x10(-7) mol/L) but not normal arteries. Vasorelaxation in response to acetylcholine was inhibited by N(omega)-nitro-L-arginine (100 micromol/L) in all groups. Responses to acetylcholine were unchanged after gene transfection of SOD1 or beta-gal in arteries from diabetic or normal rabbits., Conclusions: Adenovirus-mediated gene transfer of eNOS, but not SOD, improves impaired NO-mediated relaxation in vessels from diabetic rabbits.

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.

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.

Purpose: To evaluate our experience with percutaneous placement, management, and complications of large-bore (20-24 F) gastrostomy and gastrojejunostomy feeding tubes., Materials and Methods: A retrospective review was performed on 109 consecutive patients who underwent placement of percutaneous large-bore feeding tubes between January 1994 and May 1998. Data were collected with respect to underlying illness, technical success, number of replaced tubes, and immediate and late complications. No patient had a small-bore tube placed during this series., Results: A total of 109 cases were reviewed. Immediate follow-up within the first 2 weeks was available for all 109. Follow-up after 2 weeks was available for 61 (56%) patients. Tubes were placed in patients aged 15 to 94 years. Neurologic dysfunction from a variety of causes was the most common underlying illness and occurred in 52% of patients. There were nine (8.3%) immediate, treatable complications: three major and six minor. There was one procedure-related death (0.9%). Persistent fistula tracts following tube removal occurred in three patients (4.9%). Balloon rupture was the most common reason for tube exchange (40.7%)., Conclusion: Percutaneous large-bore gastrostomy and gastrojejunostomy tubes are safe to place and have technical success, morbidity, and mortality rates comparable to those of tubes placed surgically or endoscopically as well as small-bore tubes placed with fluoroscopic guidance.

Species differences in the handling of particles are topics of interest for setting ambient particulate matter standards as well as for studies involving the phenomenon of lung overload and the implications, if any, of such studies for workplace dust exposure standards. The dosimetry of inhaled particles differs among the three major regions of the respiratory tract (extrathoracic, tracheobronchial, and pulmonary). Particulate dosimetry includes both deposition, which is the process of removing particles from inhaled air to various locations in the respiratory tract during breathing, and clearance, which refers to the rates and routes by which deposited particles are removed from the respiratory tract. Species-specific structure of respiratory-tract regions combines with the route and depth of breathing to greatly influence where particles deposit. The dominant mechanisms for deposition and clearance of inhaled particles differ by region. Inertial impaction is important for head deposition in humans of large particles and for tracheobronchial deposition of particles larger than about 2.5 μm in aerodynamic diameter. Enhanced head deposition of ultrafine particles due to diffusion occurs in both laboratory animals and humans since nasal turbinate surfaces are large compared with the cross-sectional area and are in close proximity to the airstream. Deposition in the tracheobronchial region of rats is due to impaction and sedimentation mechanisms for particles larger than about μm in aerodynamic diameter. Factors such as inhalability, oronasal breathing, and heterogeneity in tracheobronchial path length and acinar volume affect the deposition of particles in laboratory animals and humans to differing degrees. While particles less than 5 μm in aerodynamic diameter are completely inhalable by humans, inhalability in rats decreases from 97 to 65% as aerodynamic particle size increases from 0.5 to 5 μm. Rats are obligate nasal breathers, but humans switch to oronasal breathing when work or exercise requires a minute ventilation that exceeds about 35 L/min. This species difference has significant implications for particulate risk assessments. The monopodial branching system of the tracheobronchial airways of rats compared with bipodial or tripodial branching in humans can impart significant intra- and interspecies heterogeneity in the deposition of particles in the alveolar region. Clearance mediated by alveolar macrophages (AM) is an important factor in lung overload phenomena associated with chronic studies in rodents of poorly soluble particles. Data presented on AM characteristics across species support the notion that various dose metrics need to be examined that may better reflect critical steps in the process of lung overload.

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.

Purpose: To evaluate the ability of 32phosphorus intraluminal irradiation to reduce pseudointimal hyperplasia in a transjugular intrahepatic portosystemic shunt (TIPS)., Materials and Methods: TIPS were successfully placed in 11 swine with normal portal pressures. Six animals received 15.2 Gy intraluminal irradiation to the hepatic parenchyma and venous outflow tract at the time of TIPS placement with use of a NA32P-filled balloon angioplasty catheter. Five control animals underwent TIPS and balloon angioplasty with saline. All animals were followed up for 28 days, at which time percutaneous portography was performed, the animals were killed, and the tissue around the TIPS stent was processed for histologic analysis. Maximum pseudointimal hyperplasia as a percentage of estimated TIPS diameter was calculated for each animal., Results: At the time of euthanasia, all five control TIPS and all but one irradiated TIPS were occluded. Histologic analysis demonstrated considerable variability in the degree of pseudointimal hyperplasia within each TIPS and between animals. No statistically significant difference was found in the maximum pseudointimal hyperplasia, measured as a percentage of stent radius, between control (80.2%+/-17.4%) and irradiated animals (69.2%+/-25.2%)., Conclusions: Irradiation of TIPS with 15.2 Gy 32P delivered at the time of TIPS placement did not significantly improve TIPS patency or reduce the degree of pseudointimal hyperplasia in swine with normal portal pressures.

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.

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.

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.

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.

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.

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.

Techniques for treating hepatic abscess have evolved rapidly during the past decade. For many years, the traditional treatment was surgical drainage. The development of modern imaging modalities, such as CT and US, has not only made the diagnosis more certain, but has also introduced a variety of percutaneous treatment options. Pyogenic hepatic abscess is now accepted as a medical/radiologic disease requiring surgical intervention only for correctable offending causes or for failed radiologic evacuation. Drainage via an indwelling catheter has been the traditional method of percutaneous treatment. However, indwelling catheters have disadvantages, including patient discomfort, the nuisance of catheter maintenance, and postprocedural complications. The technique of simple aspiration and intracavitary antibiotics as advocated by McFadzian et al, with excellent results confirmed by Giorgio et al, is a promising alternative to prolonged catheter drainage, and may be the biggest advancement in the management of hepatic abscess in 80 years. Surgeons have recently accepted radiologic drainage; now we need to see if interventional radiologists and surgeons will accept evacuation without indwelling catheter drainage. The role of interventional techniques for nonpyogenic hepatic abscesses will vary considerably. Mortality will still occur in the pyogenic varieties but should be related to underlying disease rather than the abscess itself.

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.

Purpose: To determine the impact of Child class and indication for transjugular intrahepatic portosystemic shunt (TIPS) placement on patient survival and reintervention rate., Materials and Methods: Metal stents were used to successfully create single shunts in 63 patients during a 3-year period. Angioplasty and repeated stent placement were used to maintain shunt patency, and patients were followed up clinically and angiographically. Statistical analysis of survival and patency was performed with Kaplan-Meier product-limit survival functions. A Karnofsky performance status score was derived for each follow-up encounter., Results: Early and late mortalities varied with Child class and procedure indications. Thirty-day mortality was 19% overall (12 of 63 patients) and was 33% for Child class C patients (10 of 30 patients). Thirty-day mortality was 31% (four of 13 patients) for patients with ascites and 16% (eight of 50 patients) for those with bleeding. Reintervention was required in 20 of 33 patients and was not predictable on the basis of Child class., Conclusion: Child class and indication for procedures are significant predictors of survival but not of the need for reintervention. Ninety-day survivors had uniformly good performance status.

Ozone (O3) is a ubiquitous pollutant with an array of established effects following acute and chronic exposure. Absorption of O3 occurs in all regions of the respiratory tract, but injury to the pulmonary region appears to be of greatest concern because of the susceptibility of this region to the development of chronic disease. Processes that affect the uptake and transport of O3 and available dosimetry models are briefly reviewed prior to discussing recent experimental dosimetry data in laboratory animals and humans. Dosimetry model predictions are compared with experimental data, and an example is provided that illustrates the potential for such models to contribute to our understanding of toxicological results.

In the final phase of the mortality study of workers at an automotive iron foundry, a subset (N = 3929) of the original cohort of 8147 men, consisting of those exposed to formaldehyde during the period from January 1960 through May 1987, was analyzed. In addition to the external US population, an internal population (N = 2032), consisting of men who had worked in the same foundry during the same time period but not in formaldehyde-exposed jobs, was also used as a referent. Follow-up continued through December 31, 1989. Smoking status was ascertained for 65.4% of the exposed and for 55.1% of the unexposed cohorts. Detailed work histories and evaluation of occupational exposures by an industrial hygienist enabled us to categorize cumulative formaldehyde and silica exposures. Standardized mortality ratios were used to compare the mortality experience of the exposed cohort with the US population and, because of concerns about the healthy worker effect, with an occupational referent population. Relative risks for race, formaldehyde exposure status, smoking status, and silica exposure level were estimated by fitting a Poisson regression model to four causes of death: cancers of the buccal cavity and pharynx, lung cancer, diseases of the respiratory system, and emphysema. No association between formaldehyde exposure and deaths from malignant or nonmalignant diseases of the respiratory system was found. Cigarette smoking and silica exposure were found to be significantly associated with deaths attributed to lung cancer and disease of the respiratory system.

Nuclear envelope breakdown (NEB) and entry into mitosis are though to be driven by the activation of the p34cdc2-cyclin B kinase complex or mitosis promoting factor (MPF). Checkpoint control mechanisms that monitor essential preparatory events for mitosis, such as DNA replication, are thought to prevent entry into mitosis by downregulating MPF activation until these events are completed. Thus, we were surprised to find that when pronuclear fusion in sea urchin zygotes is blocked with Colcemid, the female pronucleus consistently breaks down before the male pronucleus. This is not due to regional differences in the time of MPF activation, because pronuclei touching each other break down asynchronously to the same extent. To test whether NEB is controlled at the nuclear or cytoplasmic level, we activated the checkpoint for the completion of DNA synthesis separately in female and male pronuclei by treating either eggs or sperm before fertilization with psoralen to covalently cross-link base-paired strands of DNA. When only the maternal DNA is cross-linked, the male pronucleus breaks down first. When the sperm DNA is cross-linked, male pronuclear breakdown is substantially delayed relative to female pronuclear breakdown and sometimes does not occur. Inactivation of the Colcemid after female NEB in such zygotes with touching pronuclei yields a functional spindle composed of maternal chromosomes and paternal centrosomes. The intact male pronucleus remains located at one aster throughout mitosis. In other experiments, when psoralen-treated sperm nuclei, over 90% of the zygote nuclei do not break down for at least 2 h after the controls even though H1 histone kinase activity gradually rises close to, or higher than, control mitotic levels. The same is true for normal zygotes treated with aphidicolin to block DNA synthesis. From these results, we conclude that NEB in sea urchin zygotes is controlled at the nuclear, not cytoplasmic, level, and that mitotic levels of cytoplasmic MPF activity are not sufficient to drive NEB for a nucleus that is under checkpoint control. Our results also demonstrate that the checkpoint for the completion of DNA synthesis inhibits NEB by acting primarily within the nucleus, not by downregulating the activity of cytoplasmic MPF.

Several inhalability curves for nose breathing in humans have been developed. No studies have been designed specifically to develop inhalability functions for animals, although it has been shown that pulmonary deposition of large particles (> 4-5 microns) via inhalation is minimal in laboratory animals [Raabe et al., Inhaled Particles VI, pp. 53-63. Pergamon Press, Oxford (1988)]. The logistic function was fitted to these animal deposition data of Raabe et al. (1988) to estimate an inhalability curve for laboratory animals. The logistic function was also fitted to the human data of Breysse and Swift [Aerosol Sci. Technol. 13, 459-464 (1990)] for comparison. The results suggest that ambient concentration is a good predictor (inhalability > 95%) of inhaled concentration for humans for particles < 11 microns dae. In small laboratory animals, however, the inhalable portion of the ambient concentration is predicted to be 95% for 0.7 microns dae particles but declines to 45% for 10 microns dae particles. It is, therefore, important to consider the effects of inhalability when estimating dose delivered to the target tissue in animals. In comparing delivered doses between animals and humans, adjusting for inhalability may change not only the magnitude of the difference but also which species is predicted to receive a greater delivered dose.

In addition to being a respiratory tract irritant and cross-linking agent, glutaraldehyde has a number of properties in common with the rodent nasal carcinogen, formaldehyde. The acute and subchronic responses to glutaraldehyde in the respiratory tract of rats and mice were characterized using histopathology and epithelial cell labeling index as end points. Male and female F344 rats and B6C3F1 mice were whole-body exposed for 1 day, 4 days, 6 weeks, or 13 weeks to 0, 62.5, 125, 250, 500, or 1000 ppb glutaraldehyde using a recycling inhalation chamber. The respiratory tract, with special reference to the nose, was examined by light microscopy and histoautoradiography. Unit length labeling index (ULLI) was determined by nuclear thymidine labeling for selected sites, chosen on the basis of histopathology. A small number of animals exposed to 1000 ppb (rats and mice) or 500 ppb (mice) died before the 6-week time point; these deaths were attributed to glutaraldehyde exposure-associated occlusion of the external nares. Treatment-induced lesions, including epithelial erosions, inflammation, and squamous metaplasia, were confined to the anterior third of the nose and were present in both sexes and species. No histopathological evidence of glutaraldehyde-induced responses was observed in the trachea, central airways, or lungs, while the larynx showed minimal changes. There were clear increases in ULLI in association with acute and subacute cytotoxic responses, with similar concentration-response relationships. Neutrophilic infiltration of the squamous epithelium of the nasal vestibule, present in both rats and mice, became progressively more severe with increasing exposure time and was associated with increased ULLI. The latter responses were generally most severe at the higher glutaraldehyde exposure concentrations, while in female mice they were present at all concentrations of glutaraldehyde studied. Lesions induced by glutaraldehyde were more anterior in the nose than those reported for formaldehyde, they differed in character, and no evidence of "pre-neoplastic" lesions or karyomegaly, reported for formaldehyde, was observed with glutaraldehyde.

To help ensure the fidelity of chromosome transmission during mitosis, sea urchin zygotes have feedback control mechanisms for the metaphase-anaphase transition that monitor the assembly of spindle microtubules and the complete absence of proper chromosome attachment to the spindle. The way in which these feedback controls work has not been known. In this study we directly test the proposal that these controls operate by maloriented chromosomes producing a diffusible inhibitor of the metaphase-anaphase transition. We show that zygotes having 50% of their chromosomes (approximately 20) unattached or monoriented initiate anaphase at the same time as the controls, a time that is well within the maximum period these zygotes will spend in mitosis. In vivo observations of the unattached maternal chromosomes indicate that they are functionally within the sphere of influence of the molecular events that cause chromosome disjunction in the spindle. Although the unattached chromosomes disjoin (anaphase onset without chromosome movement) several minutes after spindle anaphase onset, their disjunction is correlated with the time of spindle anaphase onset, not the time their nucleus breaks down. This suggests that the molecular events that trigger chromosome disjunction originate in the central spindle and propagate outward. Our results show that the mechanisms for the feedback control of the metaphase-anaphase transition in sea urchin zygotes do not involve a diffusible inhibitor produced by maloriented chromosomes. Even though the feedback controls for the metaphase-anaphase transition may detect the complete absence of properly attached chromosomes, they are insensitive to unattached or mono-oriented chromosomes as long as some chromosomes are properly attached to the spindle.

Rationale and Objectives: Nonionic contrast media have been shown to be more effective, better tolerated, and safer than standard high-osmolality contrast media when given intravascularly. The aim of this study was to assess the diagnostic efficacy, tolerance, and safety of a new nonionic contrast agent, iopromide (370 mg I/mL), in comparison with two available similar agents, iopamidol (370 mg I/mL) and iohexol (350 mg I/mL), in two randomized, double-blind clinical studies of patients undergoing abdominal aortography and visceral angiography., Methods: The iopromide group included 80 patients, and the comparator group consisted of 36 iopamidol and 45 iohexol patients. The quality and diagnostic efficacy of all three contrast agents was rated equally as either good or excellent., Results: On a scale of 0 (none) to 3 (severe) for heat and pain, respectively, the mean scores were 1.08 and 0.43 for iopromide in comparison with 1.15 and 0.35 for the comparator media. Minor adverse clinical experiences were noted in 23% of the iopromide group versus 20% of the comparator group. Nausea and vomiting were more common in the comparator group (7% versus 3%), and headache was noted only in the iopromide group (4%). There were no clinically significant changes in laboratory values in any group. Three severe adverse experiences occurred, but all were deemed unrelated to the contrast agents., Conclusion: Based on the results of this study, iopromide appears to be efficacious, safe, well tolerated, and comparable with iohexol and iopamidol for use in abdominal aortography and visceral angiography.

The ability of noninvasive imaging modalities to diagnose lower extremity DVT depends, in part, on the anatomic location of the thrombus. To define the pattern of thrombus formation in symptomatic and asymptomatic high-risk patient populations, 172 consecutive lower extremity venograms were submitted to blinded, retrospective interpretation. Acute DVT was present in 59 venograms (34 symptomatic and 25 asymptomatic patients). Among symptomatic patients with acute DVT, 26 of 34 (76%) patients had an above-knee thrombus and only eight of 34 (24%) patients had a thrombus isolated to the calf. In comparison, only three of 25 (12%) asymptomatic patients with DVT had an above-knee thrombus and 22 of 25 (88%) patients had a thrombus isolated to the calf veins (most involving only one venous segment). Failure to examine the calf veins, particularly in asymptomatic patients, would result in missing at least half of patients with DVT. Alternatively, since all cases of iliac vein DVT extended into the femoropopliteal segment, failure to visualize the iliac veins is unlikely to miss patients with DVT. Our results suggest merit to routine examination of the deep femoral, anterior tibial, and particularly the soleal (but not the gastrocnemius) veins and also to use of an imaging technique to detect congenital duplications of the superficial femoral and popliteal veins.

Surfactant dysfunction contributes to the pathophysiology of adult respiratory distress syndrome (ARDS), and we hypothesized that surfactant treatment would improve experimental ARDS produced by continuous exposure to hyperoxia. Twelve healthy male baboons (10-15 kg) were anesthetized, paralyzed, and mechanically ventilated with 2.5 cmH2O positive end-expiratory pressure (PEEP) for 96 h. Baboons were divided into three groups: 1) the O2 group (n = 5) received 100% O2, 2) the surfactant group (n = 5) received 100% O2 and aerosolized porcine surfactant, and 3) a control group (n = 2) was ventilated at fractional concentration of inspired O2 of 0.21 for 96 h to control for effects of anesthesia and mechanical ventilation. Hemodynamic parameters were obtained every 12 h, and ventilation-perfusion (VA/Q) distribution was measured daily by multiple inert gas elimination technique. PEEP was increased once or twice daily to 10 cmH2O for 30 min to study its effects on measurements of VA/Q. At the end of experiments, lungs were obtained for biochemical analysis. Prolonged hyperoxia resulted in progressive worsening in VA/Q, hemodynamic deterioration, severe lung edema, and altered surfactant metabolism. Surfactant administration increased disaturated phosphatidylcholine in lavage fluid but did not improve lung edema or gas exchange. In the surfactant group, however, the addition of 10 cmH2O PEEP resulted in a greater degree of shunt reduction than did 2.5 cmH2O PEEP (47 vs. 31% in the O2 group, P < 0.05). We conclude that aerosolized porcine surfactant did not prevent pulmonary O2 injury in baboons, but it potentiated the shunt-reducing effect of PEEP.

Purpose: Percutaneous nephrostomy has proved to be an important modality in the nonoperative treatment of bacterial pyonephrosis. The role of this technique in the management of fungal pyonephrosis continues to evolve. The authors retrospectively reviewed their experience with percutaneous nephrostomy in the management of fungal pyonephrosis., Patients and Methods: Seven patients, two neonates and five adults, were identified with proved fungal infections. Eleven percutaneous nephrostomy tubes were placed, all with use of the Seldinger technique., Results: Percutaneous nephrostomy allowed (a) prompt microbiologic diagnosis of fungal infection (Candida albicans in six patients, Torulopsis glabrata in one); (b) urinary diversion with subsequent improvement in renal function, enabling systemic administration of potentially toxic antifungal drugs 5-fluorocytosine and amphotericin B (four patients); (c) local irrigation with amphotericin B (four patients), (d) guidewire fragmentation of fungus balls (two patients); and (e) introduction of a Simpson atherectomy device to obtain biopsy specimens from an obstructing ureteral polypoid lesion (one patient). The funguria was successfully eradicated in six patients, one of whom died on the 39th hospital day of a pulmonary embolus and another of whom died of extensive small bowel infarction during hospitalization. The one patient whose outcome of antifungal treatment remains unknown died at home with a functioning percutaneous nephrostomy 23 days after the procedure., Conclusion: Percutaneous nephrostomy may play a role in the non-operative management of fungal urinary tract infection.

Although both gametes may contribute a centrosome to the zygote at fertilization, only one of these centrosomes is used in development. Thus, specific mechanisms must exist to control centrosome inheritance in all sexually reproducing organisms. We use starfish as a model system to characterize these control mechanisms because the eggs complete meiosis I and meiosis II after fertilization; this allows us to directly follow the fate of all parental centrosomes in vivo. Only the paternal centrosome is used in starfish development. Although the microtubule organizing center activity of the maternal centrosome persists, the functional loss of this centrosome involves the suppression of its ability to double, or reproduce, at successive mitoses (Sluder et al., 1989. Dev. Biol. 131, 567-579). To determine when the reproductive capacity of the maternal centrosome is degraded, we transfer meiosis I and meiosis II spindles from just fertilized eggs into other zygotes that are in prophase of first mitosis. Meiosis I spindles are stable during first mitosis and are disassembled in first telophase in concert with the host spindle. In 61% of the cases a variable number of formerly meiotic centrosomes are active at second mitosis and reproduce in a normal fashion between subsequent mitoses. However, when meiosis II spindles are transferred in the same manner, in only 26% of the cases do any of the centrosomes persist past first mitosis or reproduce in a normal fashion thereafter. In the remainder of the cases the remnants of the maternal centrosomes organize a single monaster that does not double between mitoses. Control transfers of first mitosis spindles indicate that these results are not due to nonspecific damage to the meiotic spindles or to the recipient zygotes. These observations indicate that the reproductive capacity of maternal centrosomes is degraded during meiosis I, not during oogenesis. Our results also show that the cytoplasmic conditions which eliminate this reproductive capacity are no longer active once the zygote has entered the first mitotic cell cycle.

Purpose: Although color Doppler flow imaging (CDFI) has been shown to accurately depict calf vein thrombosis in symptomatic patients, this technique has not been proved accurate for detection of calf vein thrombosis in a population restricted to asymptomatic postoperative patients., Patients and Methods: To evaluate the accuracy of CDFI in asymptomatic postoperative patients, both CDFI and contrast venography were performed on 78 limbs of 76 patients without symptoms of deep venous thrombosis (DVT) who had undergone either hip or knee replacement. CDFI and venographic examination were interpreted blindly with respect to the results of the other modality or clinical findings. Venography was the standard for comparison of results., Results: Fifty-six percent of CDFI examinations of the calf vein were technically adequate. The remaining studies were compromised technically by limb swelling and/or obesity. For the technically adequate CDFI studies, calf vein thrombosis was detected in eight of 10 patients. Calculated sensitivity in this cohort was 80%, and specificity was 97%. The sensitivity of CDFI for acute calf DVT in all patients, regardless of image quality, was 42%., Conclusion: These observations suggest that state-of-the-art CDFI is not an accurate examination for acute calf vein DVT in asymptomatic postoperative patients. CDFI is associated with a high rate of technically compromised studies and relatively low sensitivity in studies that are deemed technically satisfactory. These observations do not preclude the use of CDFI in postoperative patients for detection of thrombus extension into the popliteal vein or for detecting thrombosis of more proximal lower extremity veins.

The Workshop on Approaches to Evaluating the Toxicity and Carcinogenicity of Man-Made Fibers (MMF) was held in Durham, North Carolina, on November 11-13, 1991. The goal of the workshop was to reach a consensus, or to determine the extent to which a consensus existed, in two areas. Participants were asked to identify scientifically sound approaches for evaluating the toxicity and carcinogenicity of man-made fibers based on today's science and to determine research appropriate for study during the next 5 years that can provide an improved scientific basis for future revisions of approaches used to evaluate man-made fiber toxicity and carcinogenicity. During the first day, a series of "state of knowledge" presentations were made to provide all participants with a common data base from which to interact and discuss scientific issues. The workshop participants were assigned to one of four discussion groups, which met separately in three half-day sessions following the first day of presentations. All groups discussed the same topics: exposure assessment, hazard identification, and dose-response information needed to integrate to characterize risk in the first session; approaches to obtaining the needed information in the second session; and recommended approaches and guidelines for evaluating the toxicity and carcinogenicity of MMF and research needs in the third session. The workshop participants reconvened as a whole after each discussion session, and one member from each group reported the group's conclusions. A closure period was also included at the end of the workshop for review and discussion of items that had been considered during the workshop. The primary conclusions reached were the following: -All fiber types capable of depositing in the thorax are not alike in their pathogenic potential. -Only fiber samples with dimensions similar to those to which humans can inhale should be tested. -A complete characterization (i.e., dimensions, fiber number, mass, and aerodynamic diameter) of the fiber aerosol and retained dose is essential. -Appropriate aerosol generation methods must be used for inhalation studies in order to preserve fiber lengths. -A tiered approach to toxicity evaluation is recommended that includes: 1. In vitro screening for durability, surface properties, cytotoxicity, and similar properties, etc; 2. Short-term inhalation or other in vivo studies; 3. That chronic inhalation studies are the "gold standard" (i.e., provide most appropriate data for risk characterization). -The rat is the most appropriate species for inhalation studies. -In chronic inhalation studies, animals should be retained to at least 20% survival after 2-year exposure. -Serial lung burden analyses are an essential component of inhalation studies and are essential for understanding exposure-dose-response relationships. -Studies oriented to understanding mechanisms of toxicity and carcinogenicity are important adjuncts to traditional toxicity studies. -Histopathological analyses of tissues of the respiratory tract represent primary endpoints for evaluating effects of inhaled fibers. Major effects include pulmonary fibrosis, lung tumors, and mesotheliomas. Experimental tissues should be archived for future studies; wherever possible, handling and preservation of tissues should be done in a way that maximizes their future use in mechanistic studies. -Potential human exposures throughout the entire life-cycle of the fiber must be considered and fibrous material for toxicologic studies prepared accordingly. -Intracavity studies are inappropriate for risk characterization but can play a useful screening role in assessing fiber toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

The purpose of the present study was to determine whether sympathetic coronary vasoconstrictor responses are altered after brief ischemia and reperfusion. Adult mongrel dogs were anesthetized and instrumented for measurements of heart rate, arterial pressure, left ventricular pressure, left ventricular dP/dt, anterior myocardial wall thickening, and left circumflex coronary artery (LCX) and left anterior descending coronary artery (LAD) blood flow velocities. Changes in coronary vascular resistance were recorded during intravenous bolus doses of norepinephrine and bilateral electrical stimulation of the stellate ganglia. After beta-adrenergic blockade and bilateral vagotomy, electrical stimulation of the stellate ganglia increased coronary vascular resistance in the LAD and LCX beds by 38 +/- 5% and 39 +/- 5%, respectively. After a 15-minute LAD occlusion, repeat electrical stimulation produced increases in coronary resistance of 16 +/- 3% and 45 +/- 8%, respectively (p less than 0.05 for the LAD before versus after the occlusion). The peak increase in coronary vascular resistance to two doses of norepinephrine was unchanged. After a shorter period of myocardial ischemia (7 minutes), similar increase in coronary resistance to stellate stimulation were observed before (27 +/- 4%) and after (26 +/- 6%) myocardial ischemia. The mechanism of this impaired sympathetic coronary vasoconstriction was further tested by examining the responses to bretylium and tyramine. Brief ischemia did not alter the coronary constrictor responses to either bretylium or tyramine, suggesting that mechanisms governing prejunctional release of norepinephrine are intact in the postischemic coronary arterial bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Electron microscopic morphometry was used to study the development of lung injury during and after chronic (78 weeks) exposure to a pattern of ozone (O3) designed to simulate high urban ambient concentrations that occur in some environments. The daily exposure regimen consisted of a 13-hr background of 0.06 ppm, an exposure peak that rose from 0.06 to 0.25 ppm, and returned to the background level over a 9-hr period, and 2-hr downtime for maintenance. Rats were exposed for 1, 3, 13, and 78 weeks. Additional groups of rats exposed for 13 or 78 weeks were allowed to recover in filtered clean air for 6 or 17 weeks, respectively. Rats exposed to filtered air for the same lengths of time were used as controls. Samples from proximal alveolar regions and terminal bronchioles were obtained by microdissection. Analysis of the proximal alveolar region revealed a biphasic response. Acute tissue reactions after 1 week of exposure included epithelial inflammation, interstitial edema, interstitial cell hypertrophy, and influx of macrophages. These responses subsided after 3 weeks of exposure. Progressive epithelial and interstitial tissue responses developed with prolonged exposure and included epithelial hyperplasia, fibroblast proliferation, and interstitial matrix accumulation. The epithelial responses involved both type I and type II epithelial cells. Alveolar type I cells increased in number, became thicker, and covered a smaller average surface area. These changes persisted throughout the entire exposure and did not change during the recovery period, indicating the sensitivity of these cells to injury. The main response of type II epithelial cells was cell proliferation. The accumulation of interstitial matrix after chronic exposure consisted of deposition of both increased amounts of basement membrane and collagen fibers. Interstitial matrix accumulation underwent partial recovery during follow-up periods in air; however, the thickening of the basement membrane did not resolve. Analysis of terminal bronchioles showed that short-term exposure to O3 caused a loss of ciliated cells and differentiation of preciliated and Clara cells. The bronchiolar cell population stabilized on continued exposure; however, chronic exposure resulted in structural changes, suggesting injury to both ciliated and Clara cells. We conclude that chronic exposure to low levels of O3 causes epithelial inflammation and interstitial fibrosis in the proximal alveolar region and bronchiolar epithelial cell injury.