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Biomedical subjects

E Brown

Publications and source records attributed to E Brown.

At least 55 records · Page 3Linked to original sources
PubMed2000

Mechanisms of calcium decay kinetics in hippocampal spines: role of spine calcium pumps and calcium diffusion through the spine neck in biochemical compartmentalization.

Dendritic spines receive most excitatory inputs in the CNS and compartmentalize calcium. Although the mechanisms of calcium influx into spines have been explored, it is unknown what determines the calcium decay kinetics in spines. With two-photon microscopy we investigate action potential-induced calcium dynamics in spines from rat CA1 pyramidal neurons in slices. The [Ca(2+)](i) in most spines shows two decay kinetics: an initial fast component, during which [Ca(2+)](i) in spines decays to dendritic levels, followed by a slower decay phase in which the spine follows dendritic kinetics. The correlation between [Ca(2+)](i) in spine and dendrite at the breakpoint of the decay kinetics demonstrates diffusional equilibration between spine and dendrite during the slower component. To explain the faster initial decay, we rule out saturation or kinetic effects of endogenous or exogenous buffers and focus instead on (1) active calcium extrusion and (2) buffered diffusion of calcium from spine to dendrite. The presence of an undershoot in most spines indicates that extrusion mechanisms can be intrinsic to the spine. Supporting the two mechanisms, pharmacological blockade of smooth endoplasmic reticulum calcium (SERCA) pumps and the length of the spine neck affect spine decay kinetics. Using a mathematical model, we find that the contribution of calcium pumps and diffusion varies from spine to spine. We conclude that dendritic spines have calcium pumps and that their density and kinetics, together with the morphology of the spine neck, determine the time during which the spine compartmentalizes calcium.

Action Potentials↗
PubMed2000

Profile of endothelial and leukocyte activation in Fabry patients.

Fabry disease is an X-linked recessive disorder resulting in the deposition of globotriaosylceramide in numerous cell types including vascular endothelial cells. Because this disease is associated with vascular injury and a high recurrence rate of thrombotic events, measurements of factors regulating endothelium and leukocyte interaction may provide insight into the mechanisms leading to a prothrombotic state. Twenty-five patients with Fabry disease and 25 control subjects participated in the study. Plasma from all 25 Fabry patients and 15 of the 25 controls were studied for multiple endothelial factors. Leukocyte integrins were measured by flow cytometry in 21 Fabry patients and 10 controls. The concentrations of soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, P-selectin, and plasminogen activator inhibitor were significantly higher and thrombomodulin was significantly lower in Fabry patients. Expression of the integrin CD11b on monocytes was also significantly higher in the Fabry patients. This study reveals measurable evidence for endothelium and leukocyte activation that is consistent with a prothrombotic state in Fabry patients compared with controls. Further investigations of these findings may help to understand the mechanism of stroke in Fabry disease and provide indicators (or markers) of efficacy of future therapeutic intervention.

Adult↗
PubMed2000

Antitumor efficacy, pharmacokinetics, and biodistribution of NX 211: a low-clearance liposomal formulation of lurtotecan.

Lurtotecan is a clinically active water-soluble camptothecin analogue that has been formulated into a low-clearance unilamellar liposome, NX 211. Comparative studies between free drug and NX 211 have been performed assessing pharmacokinetics in nude mice, tissue distribution in tumor-bearing mice, and antitumor efficacy in xenografts. Compared with lurtotecan, NX 211 demonstrated a significant increase in plasma residence time and a subsequent 1500-fold increase in the plasma area under the drug concentration curve. The volume of distribution was also greatly restricted, suggesting altered tissue distribution. Evaluation of tissues 24 h after administration of either [14C]NX 211 or [14C]lurtotecan to ES-2 tumor-bearing mice demonstrated a 40-fold increase in radiolabeled compound in the tumors of NX 211-treated mice compared with mice treated with lurtotecan. In single-dose efficacy studies, NX 211 produced a consistent 3-fold or greater increase in therapeutic index compared with lurtotecan in both the KB and ES-2 xenograft models. When compared at equitoxic levels in repeat-dose efficacy studies, NX 211 generated durable cures lasting >60 days and a 2-8-fold increase in log10 cell kill, compared with lurtotecan and topotecan, respectively. Together, these data demonstrate that NX 211 has significant therapeutic advantage over lurtotecan and that the improved antitumor activity is consistent with increased exposure and enhanced drug delivery to tumor sites.

Animals↗
PubMed2000

Breaking the language barrier: an emergentist coalition model for the origins of word learning.

How do children learn their first words? The field of language development has been polarized by responses to this question. Explanations range from constraints/principles accounts that emphasize the importance of cognitive heuristics in language acquisition, to social-pragmatic accounts that highlight the role of parent-child interaction, to associationistic accounts that highlight the role of "dumb attentional mechanisms" in word learning. In this Monograph, an alternative to these accounts is presented: the emergentist coalition theory. A hybrid view of word learning, this theory characterizes lexical acquisition as the emergent product of multiple factors, including cognitive constraints, social-pragmatic factors, and global attentional mechanisms. The model makes three assumptions: (a) that children cull from multiple inputs available for word learning at any given time, (b) that these inputs are differentially weighted over development, and (c) that children develop emergent principles of word learning, which guide subsequent word acquisition. With few exceptions, competing accounts of the word learning process have examined children who are already veteran word learners. By focusing on the very beginnings of word learning at around 12 months of age, however, it is possible to see how social and cognitive factors are coordinated in the process of vocabulary development. After presenting a new method for investigating word learning, the development of reference is used as a test case of the theory. In 12 experiments, with children ranging in age from 12 to 25 months of age, data are described that support the emergentist coalition model. This fundamentally developmental theory posits that children construct principles of word learning. As children's word learning principles emerge and develop, the character of word learning changes over the course of the 2nd year of life.

Child, Preschool↗
PubMed1999

The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23.

The vitronectin receptor, alphavbeta3 integrin, plays an important role in tumor cell invasion, angiogenesis, and phagocytosis of apoptotic cells. CD47, a member of the multispan transmembrane receptor family, physically and functionally associates with vitronectin receptor (VnR). Although vitronectin (Vn) is not a ligand of CD47, anti-CD47 and beta3 mAbs suppress Vn, but not fibronectin (Fn) binding and function. Here, we show that anti-CD47, anti-beta3 mAb and Vn, but not Fn, inhibit sCD23-mediated proinflammatory function (TNF-alpha, IL-12, and IFN-gamma release). Surprisingly, anti-CD47 and beta3 mAbs do not block sCD23 binding to alphav+beta3+ T cell lines, whereas Vn and an alphav mAb (clone AMF7) do inhibit sCD23 binding, suggesting the VnR complex may be a functional receptor for sCD23. sCD23 directly binds alphav+beta3+/CD47(-) cell lines, but coexpression of CD47 increases binding. Moreover, sCD23 binds purified alphav protein and a single human alphav chain CHO transfectant. We conclude that the VnR and its associated CD47 molecule may function as a novel receptor for sCD23 to mediate its proinflammatory activity and, as such, may be involved in the inflammatory process of the immune response.

Animals↗
PubMed1999

Idiopathic thrombocytopenic purpura presenting as postmyringotomy hemorrhage.

Acute idiopathic thrombocytopenic purpura has an annual incidence of about 4 per 100000 children and usually presents after a viral illness with new-onset petechiae, easy bruisability, and, occasionally, mucosal bleeding. It usually follows an uneventful course en route to a spontaneous recovery. We describe a patient with chronic otitis media who developed idiopathic thrombocytopenic purpura as a postmyringotomy complication.

Child, Preschool↗
PubMed1999

Comments on the hypotheses underlying fracture risk assessment in osteoporosis as proposed by the World Health Organization.

It was shown in a recent multivariate analysis of lumbar vertebral (L1-L3) CT scans of 171 women without fractures and 57 fractures somewhere in their skeletons, that regional assessment of the spinal mineral distribution can result in the discrimination of the above patient groups with an accuracy of about 90%. This level of discrimination was possible even in those cases with bone densities below the fracture threshold, where the overlap of patients with and without fractures is the greatest and clinically the most significant. In this region this new analytical technique could also identify a subgroup of patients who not yet had a fracture, but for whom all three lumbar vertebrae were classified as osteoporotic. From these results it follows that the osteoporosis model proposed by the World Health Organization (WHO), which assumes that fragility depends only on a single mean value of bone mineral density (BMD) for a patient, is overly simplistic and requires upgrading to include indices representing the distribution of bone mineral.

Absorptiometry, Photon↗
PubMed1999

Creatine kinase-MB elevation after coronary intervention correlates with diffuse atherosclerosis, and low-to-medium level elevation has a benign clinical course: implications for early discharge after coronary intervention.

OBJECTIVES: The study evaluated the incidence and predictors of creatine kinase-MB isoenzyme (CK-MB) elevation after successful coronary intervention using current devices, and assessed the influence on in-hospital course and midterm survival. BACKGROUND: The CK-MB elevation after coronary intervention predominantly using balloon angioplasty correlates with late cardiac events of myocardial infarction (MI) and death. Whether CK-MB elevation after nonballoon devices is associated with an adverse short and midterm prognosis is unknown. METHODS: The incidence and predictors of CK-MB elevation after coronary intervention were prospectively studied in 1,675 consecutive patients and were followed for in-hospital events and survival. RESULTS: CK-MB elevation was detected in 313 patients (18.7%), with 1-3x in 12.8%, 3-5x in 3.5% and >5x normal in 2.4% of patients. Procedural complications or electrocardiogram changes occurred in only 49% of the CK-MB-elevation cases; CK-MB elevation was more common after nonballoon devices (19.5% vs. 11.5% after percutaneous transluminal coronary angioplasty; p < 0.01). Predictors of CK-MB elevation on multivariate analysis were diffuse coronary disease (p = 0.02), systemic atherosclerosis (p = 0.002), stent use (p = 0.04) and absence of beta-blocker therapy (p = 0.001). Adverse in-hospital cardiac events were more frequent in patients with >5x CK-MB elevation, with no significant difference between 1-5x CK-MB elevation versus normal CK-MB group. During a mean follow-up of 13 +/- 3 months, the incidence of death in the CK-MB-elevation group was 1.6% versus 1.3% in the normal CK-MB group (p = NS). CONCLUSIONS: The CK-MB elevation after coronary intervention was observed even in the absence of discernible procedural complications and was more common in patients with diffuse atherosclerosis. In-hospital clinical events requiring prolonged monitoring were higher in >5x CK-MB-elevation patients only. Midterm survival of CK-MB-elevation patients was similar to those with normal CK-MB. Our prospective analysis shows a lack of adverse in-hospital cardiac events and suggests that early discharge of stable 1-5x normal CK-MB-elevation patients after successful coronary intervention is safe.

Aged↗
PubMed1999

Osteoblast-derived acetylcholinesterase: a novel mediator of cell-matrix interactions in bone?

The adhesive interactions that occur between bone cells and the developing matrix during bone formation help guide coupled remodeling and the maintenance of bone mass. Here, we provide evidence that acetylcholinesterase (AChE) is a novel osteoblast-derived mediator of cell-matrix interactions in bone. These findings complement an increasing body of evidence which suggests that AChE, in addition to its role in terminating cholinergic signaling, may be instrumental in regulating cellular differentiation and adhesion. We have shown, using RT-PCR, that osteosarcoma cell lines and primary cultures of osteoblasts express AChE mRNA. Expression appeared to be differentiation-dependent, and restricted to AChE splice variants containing the T subunit (exon 6). Immunofluorescent localization demonstrated that these osteoblastic cells expressed protein for AChE with an intracellular vesicular distribution. Immunohistochemistry on tissue sections confirmed AChE expression by osteoblasts in vivo, and revealed the presence of AChE along cement lines, also identified by enzyme histochemistry. In vitro functional studies indicated that osteoblast-like cells adhered specifically to and spread on AChE substrates, but did not interact with butyrylcholinesterase, a closely related protein. Our evidence strongly implicates AChE as a novel bone matrix protein, capable of mediating cell-matrix interactions, and as such may be a principal participant in organized bone formation and the regulation of remodeling.

Acetylcholinesterase↗
PubMed1999

Inbreeding depression and partial selfing: evolutionary implications of mixed-mating in a coastal endemic, silene douglasii var. oraria (Caryophyllaceae)

Recent studies have found moderate to high levels of selfing in plants despite high inbreeding depression. Because both factors influence the evolution and persistence of rare plants, we conducted glasshouse and field studies of pollination and inbreeding in Silene douglasii var. oraria, a perennial tetraploid endemic to coastal prairies. We detected: (i) variation in reproduction or inbreeding depression among life stages, years and maternal families; (ii) partial selfing yet higher relative fitness in outcrossed than selfed progeny; (iii) differing values of selfing and inbreeding depression using population means vs. matched maternal families. Fruit and seed production varied significantly with pollination treatment and year in flowers manipulated in situ during three seasons of growth. Hand-pollinations providing pollen in excess of ovule production in 1996 yielded more seeds than marked, open-pollinated flowers, implying pollen limitation of seed production. However, among-year differences in reproductive success after open-pollination (i.e. values equivalent to autogamy, selfing or outcrossing) suggest that pollination levels also vary temporally. In pollinations matched by maternal family, selfing yielded significantly fewer seeds than outcrossing. Fitness differences between inbred and outbred progeny were significant (P < 0.05) for seed production, percentage germination, and biomass or fecundity, but not for survival. Maternal family data gave selfing rates intermediate between obligate outcrossers and predominant selfers (S = 0.34-0.51), but population-wide means gave unusually high values (S = 1.1-1.6). Cumulative inbreeding depression was 76% for maternal families, and 70-85% using population means; in all cases, inbreeding depression values were high in early and late life stages, and lowest for survival. Thus far, reproductive assurance offers the most cogent explanation for the coexistence of moderate selfing and high inbreeding depression in this strongly protandrous Silene once thought to be highly outcrossing. This possibility merits further study in other rare plants with mixed-mating systems, where inbreeding depression and pollinator scarcity may both compromise population persistence and raise the threshold below which selfing is favoured by evolution.

Journal Article↗
PubMed1999

Variability in Pollen Load: Implications for Reproduction and Seedling Vigor in a Rare Plant, Silene douglasii var. Oraria.

Habitat fragmentation can markedly influence the levels of pollen deposition and seed production in natural populations, and rare plants may be especially susceptible to any associated reductions in pollen quantity and quality. In order to ascertain the potential for pollen limitation of maternal fitness in a rare plant, Silene douglasii var. oraria, which is endemic to western coastal prairies, we counted ovules and measured conspecific and heterospecific pollen deposition on stigmas collected from open-pollinated plants. We further investigated the effect of increasing pollen intensity on fruit production, seed number and weight, as well as several measures of progeny vigor. Three levels of outcross pollen were added to plant stigmas for comparison with autogamous and open pollination in the largest naturally occurring population. Both seed and fruit production were significantly greater (P<0.05) for supplemented versus nonsupplemented stigmas, but flowers receiving different levels of pollen addition were statistically indistinguishable. Seed germination and seedling survival were also lowest for the offspring of nonsupplemented flowers; however, in natural populations, opportunities for pollen competition are very limited since open-pollinated flowers averaged fewer viable pollen grains than ovules. Seed production was equivalent for open- and autogamously pollinated flowers in 1996, indicating that natural pollen transfer may have involved mostly self pollen. Overall, the low reproductive success of var. oraria likely reflects both low pollen quantity and quality. Multiyear empirical studies of pollen intensity in field populations are needed so that we can better understand the fitness consequences of pollen limitation in rare perennials.

Journal Article↗
PubMed1999

Clinical, radiological and serum amyloid P component scintigraphic features of beta2-microglobulin amyloidosis associated with continuous ambulatory peritoneal dialysis.

BACKGROUND: Beta2-Microglobulin (beta2M) amyloidosis occurs in patients with end-stage renal failure (ESRF) who undergo long-term continuous ambulatory peritoneal dialysis (CAPD), but its prevalence in patients treated exclusively by CAPD is unknown. In addition, its features may differ from those of haemodialysis-associated beta2M amyloidosis because CAPD is more biocompatible. METHODS: We performed serum amyloid P component (SAP) scintigraphy, a specific technique for imaging amyloid deposits, in 13 consecutive patients with ESRF who had been dialysed for >5 years, at least 80% of the time by CAPD. Clinical and radiological features of beta2M amyloidosis were sought and compared with the results of SAP scintigraphy. RESULTS: SAP scans showed articular amyloid deposits in seven patients, all of whom had evidence of carpal tunnel syndrome and four of whom had arthralgia characteristic of dialysis amyloidosis. Typical radiographic bone cysts were present in only one case who had been dialysed for >17 years. The remaining six patients had no clinical, radiological or scintigraphic evidence of beta2M amyloidosis. CONCLUSIONS: The prevalence of beta2M amyloidosis in this study was comparable with that in reported haemodialysis populations. Many of the amyloid deposits demonstrated by SAP scintigraphy were not associated with symptoms, but larger and longer term studies are required to determine whether CAPD favourably influences their clinical expression.

Adult↗
PubMed1999

Interleukin-8 stimulates placental prostacyclin production in preeclampsia.

PROBLEM: Our purpose was to determine placental interleukin (IL)-8 production and its correlation with the prostacyclin production in normal and preeclamptic pregnancies and to evaluate the beneficial effect of IL-8 on prostacyclin production. METHOD OF STUDY: We determined 1) the in vitro production of IL-8 and prostacyclin by placental villous tissues from normal and preeclamptic pregnancies and 2) the production of prostacyclin by villous tissues from preeclampsia treated with recombinant human IL-8 (rhIL-8). IL-8 levels were measured by enzyme-linked immunosorbent assay and prostacyclin by radioimmunoassay of 6-keto PGF1alpha, the stable metabolite of prostacyclin. RESULTS: 1) Placental production of IL-8 and 6-keto PGF1alpha were significantly less in preeclampsia than in normal pregnancies, P<0.05. 2) Placental production of 6-keto PGF1alpha and IL-8 was significantly correlated in preeclampsia, P<0.01. 3) Placental tissues treated with IL-8 exhibited a concentration-dependent increase in 6-keto PGF1alpha production. CONCLUSIONS: Placental tissues from preeclampsia produce significantly less IL-8 than tissues from normal pregnancies, which correlates with decreased prostacyclin production. IL-8 improves placental prostacyclin production in preeclampsia.

6-Ketoprostaglandin F1 alpha↗