Local accumulation of cells (hypercellularity) in the intima of the arterial wall as a result of cell proliferation is recognized as one of the major manifestations of human atherosclerosis. In the present study we have used a monoclonal antibody against PCNA to identify the proliferative activity, in uninvolved intima of human aorta classified as diffuse intimal thickening, and in different types of atherosclerotic lesions: specifically, initial lesion, fatty streak, fibroatheroma and fibrous plaque. As compared with a diffuse intimal thickening, the cell number in the initial lesions, fatty streaks and in a fibrolipid plaque (fibroatheroma) was 1.5-3-fold higher, while the cellularity in a fibrous plaque (fibrotic lesion) was lower than in a fibroatheroma and comparable with the cell number in the initial lesions. Using monoclonal antibodies, inflammatory cells (T- and B-lymphocytes as well as monocytes-macrophages) have been revealed in the intima. However, most (84-93%) of the intimal cells were noninflammatory cells classified as resident cells possessing the antigens of smooth muscle cells and pericytes as well as a small number of cells unidentifiable with the antibodies used. The highest number of proliferating cells was found in a fibroatheroma (11-fold higher as compared with a diffuse intimal thickening). A significant, but lesser increase of PCNA-positive cells was revealed in other types of lesions, too. The proliferative 'splash' in lipid-rich lesions suggests a relationship between the lipid accumulation in atherosclerotic intima and the stimulation of proliferation. The highest proliferative index of resident cells (i.e. percentage of the PCNA-positive cells among the total number of resident cells) was revealed in fibrotic lesions. It was approximately eight-fold higher than in a diffuse intimal thickening. The proliferative index of inflammatory cells considerably exceeded that of resident cells. However, in all types of atherosclerotic lesions and in a diffuse intimal thickening it showed no significant differences and was similar to the proliferative index of inflammatory cells isolated from peripheral blood. This suggests that an increased number of resident cells in atherosclerotic lesions can be explained by stimulation of their proliferative activity, whereas an altered inflammatory cell number is rather a result of their penetration from the blood into the subendothelial intima with a constant proliferative index.

Adult↗

PubMed1998

Influence of lipoprotein(a) plasma concentration on neointimal growth in a monkey model of vascular injury.

Lipoprotein(a) [Lp(a)] has been proposed as a risk factor for both restenosis and coronary heart disease. Recently, we identified Lp(a) in the arterial wall during the initial rapid neointimal growth phase that occurs after balloon injury in cynomolgus monkeys. The purpose of this study was to determine the relationship between circulating Lp(a) levels and the extent of early neointimal formation. Initially, 348 cynomolgus monkeys were screened to identify 15 monkeys that had either high or low circulating Lp(a) levels. In the 15 monkeys, circulating Lp(a) levels were confirmed by two separate measurements over 6 weeks using an immunoturbidimetric assay. Cohorts were identified with plasma Lp(a) levels that differed by four fold. Lp(a) levels expressed as total mass averaged 32 +/- 4 (N = 8) and 136 +/- 12 (N = 7) mg/dl in the low and high groups, respectively. Between the two assays absolute Lp(a) levels differed by less than 6%. Iliac arteries were harvested 14 days after injury induced by expansion of the internal vessel diameter 1.4 times its initial size with an angioplasty balloon. The neointimal area in the high Lp(a) monkeys was 16% greater (0.49 +/- 0.12 mm2, N = 8 versus 0.57 +/- 0.10 mm2, N = 7) than in the low animals; however, this difference was not statistically significant (P = 0.63). Medial areas averaged 1.27 +/- 0.11 and 1.44 +/- 0.20 mm2 (P = 0.48) in these groups, respectively. Tissue Lp(a) quantification, using a mouse monoclonal anti-Lp(a) antibody, indicated that the percent total area staining positive for Lp(a) was 1.7-fold higher in the high versus the low Lp(a) group (2.7 +/- 0.4% versus 1.6 +/- 0.4%, N = 6-8); this difference was not statistical significant (P = 0.28). In summary, a four-fold increase in circulating plasma Lp(a) levels did not result in a statistically significant enhanced neointimal formation at 14 days after balloon injury. This finding suggests that studies of longer duration may be needed to amplify the trend toward increased neointimal growth observed in this study.

Animals↗

PubMed1998

Continuous subendothelial network formed by pericyte-like cells in human vascular bed.

The localization of pericyte-like cells in adult human vascular bed was studied immunocytochemically using anti-pericyte antibody--3G5. In large, medium- and small-size arteries, pericyte-like cells were identified in the inner intimal layer, predominantly in the subendothelium, in the outer layer of the media and in the adventitia in vasa vasora. In veins, pericytes were found in the subendothelial layer of the intima, in the media and in the adventitia where they were located in vasa vasora. These cells were revealed in the subendothelium of arterioles, venules and capillaries of the pia mater encephali. Examination of intimal en face preparations of various size blood vessels showed that subendothelial pericyte-like cells form a network contacting with their processes. Thus we found a continuous subendothelial network formed by pericyte-like cells in the human vascular bed.

Adult↗

PubMed1998

New toxins acting on sodium channels from the scorpion Leiurus quinquestriatus hebraeus suggest a clue to mammalian vs insect selectivity.

Two new toxins were purified from Leiurus quinquestriatus hebraeus (Lqh) scorpion venom, Lqh II and Lqh III. Lqh II sequence reveals only two substitutions, as compared to AaH II, the most active scorpion alpha-toxin on mammals from Androctounus australis Hector. Lqh III shares 80% sequence identity with the alpha-like toxin Bom III from Buthus occitanus mardochei. Using bioassays on mice and cockroach coupled with competitive binding studies with 125I-labeled scorpion alpha-toxins on rat brain and cockroach synaptosomes, the animal selectivity was examined. Lqh II has comparable activity to mammals as AaH II, but reveals significantly higher activity to insects attributed to its C-terminal substitution, and competes at low concentration for binding on both mammalian and cockroach sodium channels. Lqh II thus binds to receptor site 3 on sodium channels. Lqh III is active on both insects and mammals but competes for binding only on cockroach. The latter indicates that Lqh III binds to a distinct receptor site. Thus, Lqh II and Lqh III represent two different scorpion toxin groups, the alpha- and alpha-like toxins, respectively, according to the structural and pharmacological criteria. These new toxins may serve as a lead for clarification of the structural basis for insect vs mammal selectivity of scorpion toxins.

Amino Acid Sequence↗

PubMed1998

Sodium channel modifiers from scorpion venom: structure-activity relationship, mode of action and application.

Explore the source record for details and available documents.

Animals↗

PubMed1998

A diagnostic in vitro urine assay for interstitial cystitis.

OBJECTIVES: A low molecular weight urine factor that inhibits the proliferation of normal bladder epithelial cells in vitro was previously shown to be present significantly more often in the urine of patients with interstitial cystitis (IC) than in the urine of asymptomatic age-, race-, and sex-matched control subjects. We sought to determine the specificity of this finding for IC by determining whether the urine of patients with other urogenital inflammatory disorders also contains a factor that inhibits bladder epithelial cell proliferation. METHODS: Urine was collected from women with IC, acute bacterial cystitis, or vulvovaginitis, as well as from asymptomatic control women. The proliferation of primary normal adult bladder epithelial cells was determined by measuring 3H-thymidine incorporation in vitro. RESULTS: Osmolality- and pH-corrected urine specimens from 50 (86%) of 58 women with IC significantly inhibited human bladder epithelial cell proliferation compared with 3 (8%) of 36 asymptomatic control women, 7 (12%) of 58 women with bacterial cystitis, and 0 (0%) of 12 women with vulvovaginitis (P < 0.001 for the comparison of mean percent change in 3H-thymidine incorporation with IC urine versus urine from each of the control groups). Optimal sensitivity and specificity values of 91.4% and 90.6%, respectively, were achievable at a cutoff of 25% inhibition of 3H-thymidine incorporation, using all three control groups. CONCLUSIONS: The measurement of urine antiproliferative activity may be a useful noninvasive means for diagnosing IC in women.

Adult↗

PubMed1998

Iron uptake by ferritin: NMR relaxometry studies at low iron loads.

Twenty ferritin samples were prepared at pH 6.5 with average loadings of 0-89 Fe atoms per molecule. Nuclear magnetic relaxation times T1 and T2 were measured at 3 degrees C, 23 degrees C, and at 37 degrees C and at field strength from 0.025 to 1.5 T. The field dependence, temperature dependence, and approximate equality of T1 and T2 at low fields all suggest that nuclear magnetic relaxation in this range is caused primarily by solitary Fe3+ ions. The relaxivity (relaxation rate per mM ferritin) increases quickly with initial iron loading, reaches a peak at 13-14 Fe atoms per molecule, and then declines. This provides supportive evidence for the formation of antiferromagnetically-coupled clusters during early stages in iron loading; the failure to see a similar peak in an earlier study may be related to the nonphysiological pH that was used. Above 50 atoms per molecule, the relaxivity remains approximately constant, except that 1/T2 at high fields increases slightly, consistent with early core growth. The residual ionic relaxivity in this region is consistent with about three solitary Fe3+ ions remaining on the protein shell, indicating that spin cancellation is not complete. A similar value is obtained by extrapolating relaxation data at high loadings (up to 3000 Fe atoms per molecule), suggesting that these uncoupled spins persist on the protein shell even after an appreciable core has been built.

Animals↗

PubMed1998

Depolarization differentially affects allosteric modulation by neurotoxins of scorpion alpha-toxin binding on voltage-gated sodium channels.

Voltage-gated sodium channels serve as a target for many neurotoxins that bind to several distinct, allosterically interacting receptor sites. We examined the effect of membrane potentials (incited by increasing external K+ concentrations) on the binding modulation by veratridine, brevetoxin, and tetrodotoxin of the scorpion alpha-toxin AaH II to receptor site 3 on sodium channels of rat brain synaptosomes. Depolarization is shown to differentially modulate neurotoxin effects on AaH II binding: Veratridine increase is potentiated, brevetoxin's inhibitory effect is reduced, and tetrodotoxin enhancement is evident mainly at resting membrane potential (5 mM K+). Both tetrodotoxin and veratridine apparently reverse the inhibition of AaH II binding by brevetoxin at resting membrane potential, but only veratridine is able to partially restore AaH II binding at 0 mV (135 mM K+). Thus, the allosteric interactions are grouped into two categories, depending on the membrane potential. Under depolarized conditions, the cooperative effects among veratridine and brevetoxin on AaH II binding fit the previously described two-state conformational model. At resting membrane potential, additional interactions are revealed, which may be explained by assuming that toxin binding induces conformational changes on the channel structure, in addition to being state-dependent. Our results provide a new insight into neurotoxin action and the complex dynamic changes underlying allosteric coupling of neurotoxin receptor sites, which may be related to channel gating.

Allosteric Regulation↗

PubMed1998

Consed: a graphical tool for sequence finishing.

Sequencing of large clones or small genomes is generally done by the shotgun approach (Anderson et al. 1982). This has two phases: (1) a shotgun phase in which a number of reads are generated from random subclones and assembled into contigs, followed by (2) a directed, or finishing phase in which the assembly is inspected for correctness and for various kinds of data anomalies (such as contaminant reads, unremoved vector sequence, and chimeric or deleted reads), additional data are collected to close gaps and resolve low quality regions, and editing is performed to correct assembly or base-calling errors. Finishing is currently a bottleneck in large-scale sequencing efforts, and throughput gains will depend both on reducing the need for human intervention and making it as efficient as possible. We have developed a finishing tool, consed, which attempts to implement these principles. A distinguishing feature relative to other programs is the use of error probabilities from our programs phred and phrap as an objective criterion to guide the entire finishing process. More information is available at http:// www.genome.washington.edu/consed/consed. html.

Base Sequence↗

PubMed1998

Double-blind, placebo-controlled study of magnesium hydroxide for treatment of sensory urgency and detrusor instability: preliminary results.

In a prospective, randomised, double-blind, placebo-controlled study 40 women with sensory urgency or detrusor instability randomly received either magnesium hydroxide (group A) or placebo (group B). Pre- and post-treatment symptoms, frequency-volume charts and cystometry results were compared. Eleven of 20 patients receiving magnesium (55%) reported a subjective improvement of their urinary symptoms, compared with five patients taking placebo (20%). In both study groups there was no statistically significant difference in pre- and post-treatment urodynamic parameters in those reporting symptomatic improvement. Magnesium was well tolerated by patients in group A, and no side effects were reported. These results suggest that magnesium hydroxide may be beneficial for detrusor instability or sensory urgency in women.

Dose-Response Relationship, Drug↗

PubMed1998

Brain natriuretic peptide: identification of a second natriuretic peptide in human aqueous humour.

AIMS/BACKGROUND: To measure aqueous humour levels of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in humans. To compare peptide levels in glaucomatous and control eyes to test the hypothesis that these peptides are increased in glaucoma. BNP and ANP are cyclic endopeptides whose principal biological effects are natriuresis and vasodilatation. Experimental glaucoma in animal models results in elevated aqueous ANP. Intravenous ANP administration in both animals and humans causes lowering of intraocular pressure (IOP). There are equivocal data to support a role for ANP in IOP regulation in human eyes. There are as yet no published data on BNP in human aqueous humour. METHOD: This was a case-control study. Cases were primary open angle, pseudoexfoliation, and mixed mechanism glaucoma eyes undergoing trabeculectomy. Controls were cataract extraction eyes. There were 47 trabeculectomy eyes (44 patients) and 47 cataract extraction eyes (46 patients) matched for age, sex, race, systemic medications, and type of anaesthetic. 100-200 microliters of aqueous humour were aspirated by paracentesis as the first step in the surgical procedure. Peptide levels were later measured by radioimmunoassay. RESULTS: The presence of BNP and ANP in human aqueous humour was confirmed. BNP was present in higher concentrations than ANP. BNP levels tended to be greater in control eyes--glaucoma median 56.5 (range 0-3526.5) pg/ml versus control median 65.16 (range 0-1788) pg/ml (Wilcoxon signed rank test p = 0.78). ANP levels tended to be greater in glaucoma eyes than in controls: glaucoma median 3 (range 0-68.5) pg/ml versus control median 0 (range 0-60) pg/ml (Wilcoxon signed rank test p = 0.82). ANP and BNP were log linearly related in both groups (r glaucoma group = 0.961, r control group = 0.894). CONCLUSION: This is the first report of BNP and ANP in human aqueous humour. Peptide levels did not differ significantly between glaucoma and cataract extraction eyes. A linear relation between log BNP and ANP was found. Further studies are required to clarify the role of these peptides in aqueous humour production and IOP regulation.

Adult↗

PubMed1998

A strategic information system to facilitate the use of performance indicators in hospitals.

Hospital management teams receive voluminous data from a wide variety of sources, but are unable to distill the essential data they require to make good decisions. We have used a methodology which helps teams define and use important management data coupled with an information system that makes this data accessible. Results of our evaluation indicate that the process of developing a balanced scorecard (BSC) indicator system helps management teams to define meaningful strategic objectives and measurable performance indicators. The framework combined with the information acts as an integrating force, providing a shared understanding of the unit's goals. We conclude that a customized decision support system which integrates multiple measures in a BSC framework is a powerful tool for enabling complex decision making by a management team.

Canada↗

PubMed1998

Hospital management decision support: a balanced scorecard approach.

Hospital management teams receive voluminous data from a wide variety of sources, but are unable to distill the essential data they require to make good decisions. We have used a methodology, which helps teams define and use important management data coupled with an information system that makes this data accessible. Results of our evaluation indicate that the process of developing a Balanced Scorecard indicator system helps management teams to define meaningful strategic objectives and measurable performance indicators. The framework combined with the information acts as an integrating force, providing a shared understanding of the unit's goals. We conclude that a customized decision support system, which integrates multiple measures in a balanced Scorecard framework, is a powerful tool for enabling complex decision making by a management team.

Cardiovascular Diseases↗

PubMed1998

Successful treatment of advanced interstitial pregnancy with methotrexate and hysteroscopy. A case report.

BACKGROUND: Data concerning medical treatment of interstitial ectopic pregnancies are scarce. These pregnancies are characterized by late and serious clinical manifestations. We report a case of advanced interstitial pregnancy treated successfully by combining methotrexate (MTX) and hysteroscopy. CASE: A routine ultrasonic evaluation of a 10-week pregnancy revealed a right interstitial gestational sac 58 mm in diameter and containing an embryo with a crownrump length of 29 mm and embryonic heartbeats. Serum beta-human chorionic gonadatropin (hCG) level was 97,950 mIU/mL. The patient was treated with a systemic MTX/leucovorin regimen. At the end of the one-week course, no embryonic cardiac activity was detected, and a decrease in beta-hCG levels commenced. Persistent trophoblastic tissue, manifested by a low (26 mIU/mL) beta-hCG level in plateau, was successfully removed by way of hysteroscopy. CONCLUSION: Early detection of interstitial pregnancy may facilitate conservative medical treatment.

Abortifacient Agents, Nonsteroidal↗