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Biomedical subjects

A B Lee

Publications and source records attributed to A B Lee.

At least 19 recordsLinked to original sources
PubMed2006

Traditional risk factor assessment does not capture the extent of cardiovascular risk in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with accelerated atherosclerosis. However, the degree of endothelial dysfunction and its relationship to traditional and novel cardiovascular risk factors have not been examined in SLE. METHODS: In a case-control design, 35 patients with clinically stable SLE and 35 control subjects matched for age, sex, body mass index and smoking status were studied. Arterial elasticity, lipid profile, homocysteine, measures of inflammation and oxidative stress were determined. RESULTS: Among traditional vascular risk factors, there was a nonsignificant trend towards lower blood pressure in the control subjects, whereas low-density lipoprotein (LDL) cholesterol levels were significantly lower in the SLE group (2.5 vs 3.3 mmol/L, P < 0.001). Patients with SLE had significantly lower small artery elasticity (SAE; 4.9 vs 7.0 ml/mmHg x 100, P < 0.001) and higher plasma homocysteine (11.4 vs 8.3 mmol/L, P = 0.002) than control subjects. Levels of serum sVCAM-1 (614 vs 494 ng/mL, P = 0.002), oxidized LDL (144 vs 97, P < 0.001) and CD40 ligand (4385 vs 1373 pg/ml, P = 0.001) were significantly higher in SLE. Oxidized LDL levels, older age at SLE diagnosis and higher disease damage scores correlated inversely with SAE but not traditional risk factors. CONCLUSION: Impaired endothelial function as shown by decreased SAE, and an adverse profile of novel proatherogenic and prothrombotic vascular disease risk factors were prevalent in clinically quiescent SLE. These findings show the vulnerability of patients with SLE for atherosclerosis, and emphasize that assessments based on traditional risk factors alone may be inadequate.

Adult↗
PubMed2005

Geometric diffusions as a tool for harmonic analysis and structure definition of data: diffusion maps.

We provide a framework for structural multiscale geometric organization of graphs and subsets of R(n). We use diffusion semigroups to generate multiscale geometries in order to organize and represent complex structures. We show that appropriately selected eigenfunctions or scaling functions of Markov matrices, which describe local transitions, lead to macroscopic descriptions at different scales. The process of iterating or diffusing the Markov matrix is seen as a generalization of some aspects of the Newtonian paradigm, in which local infinitesimal transitions of a system lead to global macroscopic descriptions by integration. We provide a unified view of ideas from data analysis, machine learning, and numerical analysis.

Journal Article↗
PubMed2005

Geometric diffusions as a tool for harmonic analysis and structure definition of data: multiscale methods.

In the companion article, a framework for structural multiscale geometric organization of subsets of R(n) and of graphs was introduced. Here, diffusion semigroups are used to generate multiscale analyses in order to organize and represent complex structures. We emphasize the multiscale nature of these problems and build scaling functions of Markov matrices (describing local transitions) that lead to macroscopic descriptions at different scales. The process of iterating or diffusing the Markov matrix is seen as a generalization of some aspects of the Newtonian paradigm, in which local infinitesimal transitions of a system lead to global macroscopic descriptions by integration. This article deals with the construction of fast-order N algorithms for data representation and for homogenization of heterogeneous structures.

Journal Article↗
PubMed2000

Statistics of lateral geniculate nucleus (LGN) activity determine the segregation of ON/OFF subfields for simple cells in visual cortex.

The receptive fields for simple cells in visual cortex show a strong preference for edges of a particular orientation and display adjacent excitatory and inhibitory subfields. These subfields are projections from ON-center and OFF-center lateral geniculate nucleus cells, respectively. Here we present a single-cell model using ON and OFF channels, a natural scene environment, and synaptic modification according to the Bienenstock, Cooper, and Munro (BCM) theory. Our results indicate that lateral geniculate nucleus cells must act predominantly in the linear region around the level of spontaneous activity, to lead to the observed segregation of ON/OFF subfields.

Animals↗
PubMed1998

Spatio-temporal pattern for expression of galectin-3 in the murine utero-placental complex: evidence for differential regulation.

In mice, immunoreactive galectin-3 protein has previously been localized in uterine epithelial cells adjacent to implanting blastocysts as well as in the decidualized endometrium of implantation sites, uterine natural killer cells, and several types of placental trophoblast cells. Because galectin-3 is a soluble extracellular molecule, protein localization by immunohistochemical methods does not demonstrate its cellular origin. Therefore, the present study was undertaken to determine precisely which cell types in the utero-placental complex express galectin-3 mRNA. In situ hybridization results demonstrated that galectin-3 mRNA was expressed throughout the utero-placental complex in all cell types previously shown to contain immunoreactive protein, including uterine epithelium, decidualized endometrium, uterine natural killer cells, and placental trophoblasts. These results indicate that galectin-3 protein is not synthesized in a restricted cell type and translocated through the extracellular spaces to other tissue compartments. Furthermore, Northern blot analysis of total RNA prepared from separated fetal and maternal components of utero-placental complexes demonstrated different patterns of expression for galectin-3 mRNA in the uterus and placenta. Relative levels of galectin-3 mRNA peak at midgestation in the implantation site and during the second half of gestation remain elevated in the placenta but decline in the uterus. Separate mechanisms for regulating expression of galectin-3 on opposite sides of the feto-maternal interface are indicated.

Animals↗
PubMed1995

Medunsa and the training of black doctors for South Africa.

Medunsa, the Medical University of Southern Africa, was founded in 1976 to address both the under-representation of blacks in the health professions and the lack of good health care in the homelands. The university trains most of the black physicians, dentists, veterinarians, and allied health professionals in South Africa, and it places a great emphasis on community service and preventive medicine. Medunsa also has programs to help socially and academically disadvantaged applicants. In some respects, the ongoing development of Medunsa mirrors that of historically black health professions schools in the United States, and Medunsa struggles with some of the same problems. Medunsa can learn from the histories of these American schools as it faces the challenges of the post-apartheid era; in turn, all U.S. schools can learn from Medunsa's history as they struggle with physician supply questions and health care reform issues.

Academies and Institutes↗
PubMed1993

Potassium channel stimulation by natriuretic peptides through cGMP-dependent dephosphorylation.

Natriuretic peptides inhibit the release and action of many hormones through cyclic guanosine monophosphate (cGMP), but the mechanism of cGMP action is unclear. In frog ventricular muscle and guinea-pig hippocampal neurons, cGMP inhibits voltage-activated Ca2+ currents by stimulating phosphodiesterase activity and reducing intracellular cyclic AMP; however, this mechanism is not involved in the action of cGMP on other channels or on Ca2+ channels in other cells. Natriuretic peptide receptors in the rat pituitary also stimulate guanylyl cyclase activity but inhibit secretion by increasing membrane conductance to potassium. In an electrophysiological study on rat pituitary tumour cells, we identified the large-conductance, calcium- and voltage-activated potassium channels (BK) as the primary target of another inhibitory neuropeptide, somatostatin. Here we report that atrial natriuretic peptide also stimulates BK channel activity in GH4C1 cells through protein dephosphorylation. Unlike somatostatin, however, the effect of atrial natriuretic peptide on BK channel activity is preceded by a rapid and potent stimulation of cGMP production and requires cGMP-dependent protein kinase activity. Protein phosphatase activation by cGMP-dependent kinase could explain the inhibitory effects of natriuretic peptides on electrical excitability and the antagonism of cGMP and cAMP in many systems.

Animals↗
PubMed1993

Characterization of a biotinylated somatostatin analog as a receptor probe.

The neuropeptide somatostatin (SRIF) triggers its biological effects by binding to high affinity membrane receptors. To develop a ligand useful for receptor affinity purification and localization, we have examined the ability of a novel monobiotinylated SRIF derivative to bind to receptors and streptavidin. Unlabeled [N-Biotinyl, Leu8, D-Trp22, Tyr25]SRIF28 (Bio-SRIF28) competed for [125I-Tyr11]SRIF binding to GH4C1 pituitary cell membranes with a Ki of 337 +/- 95 pM, comparable to that of native SRIF (193 +/- 16 pM). Studies using HPLC purified [125I]Bio-SRIF28 showed that equilibrium binding to membranes occurred within 120 min at 30 C and that the peptide-receptor complex dissociated slowly (t1/2 = 4.7 h). Analysis of saturation binding data gave an equilibrium dissociation constant for [125I]Bio-SRIF28 of 66 +/- 20 pM. Photoaffinity cross-linking of [125I]Bio-SRIF28 to membranes covalently labeled a broad 85 kDa band, as previously reported with the photolabile SRIF analog, [125I-Tyr11, Azidonitrobenzoyl-Lys4]SRIF. The binding of [125I]Bio-SRIF28 was potently inhibited by SRIF (Ki = 171 +/- 36 pM) and SRIF28 (299 +/- 102 pM) but not by structurally unrelated peptides. Furthermore, [125I]Bio-SRIF28 did not bind to membranes from GH(1)2C1 pituitary cells, which do not respond to SRIF and which lack [125I-Tyr11]SRIF binding sites. Finally, GppNHp and GTP gamma S both decreased [125I]Bio-SRIF28 binding whereas AppNHp did not. These studies showed that [125I]Bio-SRIF28 bound with high affinity to specific, G-protein coupled SRIF receptors. [125I]Bio-SRIF28 also bound with high affinity to streptavidin and this binding was very stable (t1/2 for dissociation = 19 h). Therefore, the affinity of the receptor for the Bio-SRIF28-streptavidin complex was determined by measuring the potency with which this preformed complex competed for [125I-Tyr11]SRIF binding. The Ki of the Bio-SRIF28-streptavidin complex (1110 +/- 47 pM) was only 3 times higher than that of uncomplexed Bio-SRIF28 (Ki = 337 +/- 95 pM). Dissociation of the [125I]Bio-SRIF28-streptavidin complex from receptors was slow (t1/2 = 3.9 h) but was increased over 200-fold by 1 microM GTP gamma S (t1/2 < 1 min). These data show that Bio-SRIF28 was able to bind simultaneously and with high affinity both to SRIF receptors and to streptavidin to form a stable ternary complex. Further, receptor binding of the Bio-SRIF28-streptavidin complex could be regulated by the addition of guanine nucleotides. Thus, Bio-SRIF28 should be useful for the affinity purification and in situ localization of SRIF receptors.

Affinity Labels↗
PubMed1992

Monoclonal antibodies specific for rat relaxin. VI. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts histological changes associated with cervical softening at parturition in rats.

Relaxin, which is secreted by the corpora lutea throughout the second half of rat pregnancy, promotes the growth and softening of the cervix. The mechanisms at both the cellular and molecular levels by which relaxin brings about these effects remain to be determined. The present study examined the influence of endogenous relaxin on the histological changes associated with cervical softening. A monoclonal antibody for rat relaxin, designated MCA1, was injected iv daily on days 12-22 of gestation. Cervices were removed on day 22, fixed in 10% buffered formalin, embedded in paraffin, and processed for histological staining. Tissue sections (5 microns thick) were stained with Gomori's trichrome stain (collagen), Orcein stain (elastin), or periodic acid-Schiff (polysaccharide). Qualitative and quantitative analyses identified several histological parameters in MCA1-treated rats that differed markedly from those in control rats. Cervices obtained from MCA1-treated rats contained collagen fiber bundles with greater compactness; elastin fibers with greater density, length and interdigitation; arteries with smaller cross-sectional areas; and luminal involutions with smaller areas than controls. The cervices of MCA1-treated rats appeared to contain fewer vacuolated epithelial cells, which secrete polysaccharide-rich material, than did cervices obtained from controls. It seems plausible that most, if not all, of these relaxin-induced modifications of the histological characteristics of the cervix facilitate birth.

Animals↗
PubMed1992

Evidence for a dual source of relaxin in the pregnant rat: immunolocalization in the corpora lutea and endometrium.

Uterine tissue was collected from intact pregnant rats on days 4, 10-15, 18, and 22 of pregnancy and day 2 postpartum and from rats on day 22 of pregnancy after ovariectomy (day 9) and progesterone-estrogen treatment. Placental, cervical, mammary, and pituitary tissues were collected from intact pregnant rats on day 22. Ovarian tissue was collected from intact pregnant rats on days 15, 20, and 22. These tissues were evaluated for relaxin immunostaining at the light microscope level using an antiserum to purified rat relaxin and the avidin biotin immunostaining technique. Since the corpus luteum is the major source of relaxin in the rat, this tissue was used as a positive control. Relaxin immunostaining in the corpus luteum was observed in a discrete region of the cytoplasm. This pattern of staining corresponded with the discrete clustering of relaxin-containing secretory granules found in the rat luteal cells. Relaxin was not observed in the day 22 placenta, cervix, mammary gland, pituitary gland, or day 4-13 pregnant uterus. Relaxin immunostaining was detected in endometrial epithelial cells on days 14-22 of pregnancy and day 2 postpartum. Relaxin immunostaining was more evident at implantation sites than between implantation sites. Antimesometrial epithelial cells at implantation sites contained relaxin immunostaining. The mesometrial surface, which consists of the placenta and decidualized endometrium, did not contain relaxin immunostaining. Relaxin immunostaining was also present in the endometrial epithelial cells of the day 22 pregnant rats that had been ovariectomized on day 9 and given subsequent replacement therapy with ovarian steroids. The presence of relaxin immunostaining in the ovariectomized rat indicates the endometrium is not sequestering relaxin secreted from the corpus luteum. These data provide evidence that the pregnant rat endometrium is a source of relaxin in addition to the corpus luteum. The appearance of relaxin in endometrial epithelial cells after implantation and its prominence at implantation sites may indicate that locally secreted conceptus factors stimulate endometrial relaxin synthesis.

Animals↗
PubMed1991

Monoclonal antibodies specific for rat relaxin. V. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts development of the mammary apparatus and, hence, lactational performance in rats.

There were two related objectives to this study. The first was to determine the influence of relaxin on development of the mammary apparatus (nipples and glands) during the second half of pregnancy. The second was to determine whether the relaxin-dependent development of the mammary apparatus was required for normal postpartum lactational performance. Both objectives were accomplished by neutralizing endogenous relaxin throughout the second half of pregnancy with a monoclonal antibody specific for rat relaxin (MCA1). MCA1 was administered iv to rats daily from days 12-22 of pregnancy. On day 22 the morphology of the mammary apparatus of MCA1-treated rats differed from that of controls; nipples were dramatically smaller, collagen fibers had significantly greater mean density and consistency, and elastin fibers had greater mean density, length, and interdigitation. In addition, the mean number of alveoli surrounding lactiferous ducts was significantly smaller in MCA1-treated rats than in controls. There were no differences between MCA1-treated rats and controls in the mean thickness of connective tissue surrounding ducts, the height or density of luminal cells lining lactiferous ducts, or the sizes of either adipocytes or arteries. To examine lactational performance, MCA1-treated and control rats were cesarean sectioned between 2100-2400 h on day 22 of pregnancy and given foster pups born of untreated intact donors. Although both MCA1-treated rats and control rats exhibited a high incidence of maternal behavior after cesarean delivery, mean pup weight and incidence of live pups declined markedly during days 1-5 of fosterage in MCA1-treated rats compared to controls. Furthermore, unlike controls, there was no observable postpartum nipple development in MCA1-treated rats by day 5 of fosterage. Mammary glands obtained from MCA1-treated rats on day 5 of fosterage had markedly lower mean weight than controls. This study demonstrates that passive immunization of endogenous relaxin throughout the second half of pregnancy disrupts development of the nipples and mammary glands in the rat. Moreover, it establishes that relaxin's effects on the development of the mammary apparatus during pregnancy are essential for growth and survival of the young during lactation.

Animals↗
PubMed1990

Identification of somatostatin receptors by covalent labeling with a novel photoreactive somatostatin analog.

We have synthesized two photoreactive derivatives of somatostatin, namely [125I-Tyr11,azidonitrobenzoyl (ANB)-Lys4]somatostatin and [125I-Tyr11,ANB-Lys9]somatostatin, and used them to characterize somatostatin receptors biochemically in several cell types. Saturation binding experiments carried out in the dark demonstrated that [125I-Tyr11,ANB-Lys4]somatostatin bound with high affinity (KD = 126 +/- 39 pM) to a single class of binding sites in GH4C1 pituitary cell membranes. The affinity of this analog was similar to that of the unsubstituted peptide [125I-Tyr11]somatostatin (207 +/- 3 pM). In contrast, specific binding was not observed with [125I-Tyr11,ANB-Lys9]somatostatin. The binding of both [125I-Tyr11,ANB-Lys4]somatostatin and [125I-Tyr11]somatostatin was potently inhibited by somatostatin (EC50 = 300 pM) whereas at 100 nM unrelated peptides had no effect. Furthermore, both pertussis toxin treatment and guanyl-5'yl imidophosphate (Gpp(NH)p) markedly reduced [125I-Tyr11,ANB-Lys4]somatostatin binding. Thus, [125I-Tyr11,ANB-Lys4]somatostatin binds to G-protein coupled somatostatin receptors with high affinity. To characterize these receptors biochemically, GH4C1 cell membranes were irradiated with ultraviolet light following the binding incubation, and the labeled proteins were identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. A major band of 85 kDa was specifically labeled with [125I-Tyr11,ANB-Lys4]somatostatin but not with [125I-Tyr11,ANB-Lys9]somatostatin or [125I-Tyr11]somatostatin. The binding affinity of the 85-kDa protein for [125I-Tyr11,ANB-Lys4]somatostatin was very high (Kd = 34 pM). Labeling of this protein was inhibited competitively by somatostatin (EC50 = 140 +/- 80 pM) but not by unrelated peptides. Furthermore, this band was not labeled in pertussis toxin-treated membranes or in untreated membranes incubated with Gpp(NH)p. Finally, [125I-Tyr11,ANB-Lys4]somatostatin specifically labeled bands of 82, 75, and 72 kDa in membranes prepared from mouse pituitary AtT-20 cells, rat pancreatic acinar AR4-2J cells, and HIT hamster islet cells, respectively. Thus, [125I-Tyr11,ANB-Lys4]somatostatin represents the first photolabile somatostatin analog able to bind to receptors with high affinity. Our studies demonstrate that this novel peptide covalently labels specific somatostatin receptors in a variety of target cell types.

Affinity Labels↗
PubMed1985

The radionuclide evaluation of septal wall motion following coronary bypass surgery.

We investigated the diagnostic accuracy of radionuclide global and regional left ventricular (LV) function after coronary revascularization. A consecutive series of 43 patients was studied. First-pass radionuclide angiograms were performed preoperatively (4 days +/- s.d. 3 days, range 1-18 days) and postoperatively (7 days +/- s.d. 3 days, range 3-19 days). Regional radionuclide LV function was assessed using the two-dimensional display of systole and the three-dimensional ejection fraction image. Electrocardiograms were obtained the day prior to surgery and every 8 h for the first three postoperative days. Creatine kinase (CK) and lactate dehydrogenase (LDH) isoenzymes were obtained the day prior to surgery and every 8 h for the first three postoperative days. In 39 patients who did not develop perioperative myocardial infarction by isoenzyme or ECG criteria, we found that 38 patients showed unchanged or improved global and regional LV function, while one patient without isoenzyme or ECG evidence of perioperative myocardial infarction developed a new septal wall motion abnormality. Thus, the specificity of the radionuclide radioventriculogram for new septal wall motion abnormalities was very high. In four patients who developed isoenzyme and ECG evidence of myocardial infarction, septal wall motion worsened in all four patients while global left ventricular ejection function fell significantly in three patients. Thus, the radionuclide radioventriculogram also had high diagnostic sensitivity. In summary, contrary to past and recent reports, this investigation demonstrated that the radionuclide radioventriculogram can be used to assess global and regional LV function after coronary artery bypass surgery and furthermore, that it reliably indicates the presence of a new postoperative myocardial infarction.

Adult↗
PubMed1984

Influence of length of aortic occlusion with cold potassium cardioplegia on early and late mortality in cardiac valve replacement.

This study determines if prolonged aortic crossclamp time (ACC) with the use of cold potassium cardioplegia during elective cardiac valve replacement contributed to the risk of operative mortality in 225 patients. In Group I (143 patients), the ACC was less than 120 minutes (mean 86) and in Group II (82 patients), it was greater than 120 minutes (mean 146). The preoperative variables showed that Group II contained more severely ill patients who were undergoing more complex operations than in Group I. The operative mortality rate was 7% in Group I and 10% in Group II (p = not significant). Postoperative inotropic support was required in 13% of Group I and 30% of Group II patients (p less than 0.005). Operative mortality in patients in New York Heart Association (NYHA) functional class I and II was 0 and in patients in classes III and IV it was 13% (p less than 0.00008). Five percent of patients in NYHA classes I and II and 32% in classes III and IV required inotropic support (p less than 0.000005). The actuarial survival at 60 months was 88 +/- 3% for Group I and 77 +/- 7% for Group II (NS). For the NYHA class I and II patients, however, it was significantly better (98 +/- 2%) than class III and IV patients (75 +/- 5%) (p less than 0.0001). Analysis by logistic equation revealed that the NYHA functional classes III and IV were significant incremental risk factors for probability of in-hospital mortality (p less than 0.0001) but not the ACC time (p greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

Improved cardiovascular hemodynamics with atrioventricular sequential pacing compared with ventricular demand pacing.

To determine the advantages of atrioventricular (AV) sequential pacing over ventricular demand pacing, paired cardiovascular hemodynamic studies were performed in each pacing mode at a constant heart rate. The paired studies included determination of ejection fraction (EF) by echocardiography and gated blood pool radionuclide scanning, and of cardiac output (CO) by the indicator-dilution method. There was no significant difference in EF with either pacing mode. Determined by echocardiography, EF with AV sequential pacing was 57% compared with 56% with ventricular demand pacing; by the gated blood pool method, EF with AV sequential pacing was 58% compared with 57% in the ventricular mode. Significant improvement with AV sequential pacing was seen in CO (4.75 L/min from 3.75 L/min; p less than 0.01); stroke volume (58 ml from 48 ml; p less than 0.02); arteriovenous oxygen content difference (4.9 vol% from 5.6 vol%; p less than 0.01); total peripheral resistance (1,724 dynes sec cm-5 from 2,025 dynes sec cm-5; p less than 0.01); and cardiac contractility, as reflected by mixing time (6.9 seconds from 8.0 seconds; p less than 0.02). No significant changes were noted in mean arterial or atrial pressure or in systemic oxygen consumption. In a second group of 6 patients, similar paired studies were done in AV sequential pacing modes before and after therapeutic reduction of total peripheral resistance. A significant increase in CO (43%) was observed following reduction in total peripheral resistance. We conclude that AV sequential pacing improves CO more effectively than ventricular demand pacing. Cardiac output can be further enhanced in patients with congestive heart failure by pretreatment with agents to reduce total peripheral resistance.

Adult↗
PubMed1984

Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise.

To study the mechanisms of myocardial ischemia during isometric exercise, handgrip was sustained, for 4.5 min at 25% of maximum by 11 patients with at least one significant coronary stenosis each, during cardiac catheterization. After recovery, the handgrip that was repeated with simultaneous infusion of nitroglycerin (50 micrograms over 4 min) directly into the diseased vessel. The cardiovascular response was assessed by hemodynamic and by computer-assisted measurements of stenosis. During the first handgrip test pulmonary capillary wedge pressure rose 56% (15 to 23 mm Hg; p less than .001), the heart rate-systolic pressure product rose 33% (p less than .01), and the diseased epicardial arteries constricted. Luminal area in the stenotic segment was reduced by 35% (p less than .01), resulting in a 243% increase in estimated stenotic flow resistance (30 to 103 mm Hg/ml/sec; p less than .001). During handgrip with intracoronary nitroglycerin, the pressure-rate product again increased 33%, but relative to resting control, capillary wedge pressure fell 4 mm Hg in association with a 32% increase in luminal area of the stenosis and a 28% reduction in flow resistance (all significantly different from the response to handgrip alone: p less than .001, .01, and .005, respectively). Thus, coronary vasoconstriction, not increased pressure-rate product, is the dominant mechanism for ischemic left ventricular dysfunction during isometric exercise in patients with significant coronary stenoses.

Adult↗