Search PubMed⌕ Search

Biomedical subjects

J D Smith

Publications and source records attributed to J D Smith.

At least 37 records · Page 2Linked to original sources
PubMed2001

Modifications in the CD36 binding domain of the Plasmodium falciparum variant antigen are responsible for the inability of chondroitin sulfate A adherent parasites to bind CD36.

Adhesion of mature Plasmodium falciparum parasitized erythrocytes to microvascular endothelial cells or to placenta contributes directly to the virulence and severe pathology of P falciparum malaria. Whereas CD36 is the major endothelial receptor for microvasculature sequestration, infected erythrocytes adhering in the placenta bind chondroitin sulfate A (CSA) but not CD36. Binding to both receptors is mediated by different members of the large and diverse protein family P falciparum erythrocyte membrane protein-1 (PfEMP-1) and involves different regions of the molecule. The PfEMP-1-binding domain for CD36 resides in the cysteine-rich interdomain region 1 (CIDR-1). To explore why CSA-binding parasites do not bind CD36, CIDR-1 domains from CD36- or CSA-binding parasites were expressed in mammalian cells and tested for adhesion. Although CIDR-1 domains from CD36-adherent strains strongly bound CD36, those from CSA-adherent parasites did not. The CIDR-1 domain has also been reported to bind CSA. However, none of the CIDR-1 domains tested bound CSA. Chimeric proteins between CIDR-1 domains that bind or do not bind CD36 and mutagenesis experiments revealed that modifications in the minimal CD36-binding region (M2 region) are responsible for the inability of CSA-selected parasites to bind CD36. One of these modifications, mapped to a 3-amino acid substitution in the M2 region, ablated binding in one variant and largely reduced binding of another. These findings provide a molecular explanation for the inability of placental sequestered parasites to bind CD36 and provide additional insight into critical residues for the CIDR-1/CD36 interaction.

Amino Acid Sequence↗
PubMed2001

Antivimentin antibodies are an independent predictor of transplant-associated coronary artery disease after cardiac transplantation.

BACKGROUND: Transplant-associated coronary artery disease (TxCAD) is the most serious long-term complication after cardiac transplantation. Anti-endothelial antibodies are associated with disease, and one of the major endothelial antigens recognized in the sera of patients has been shown to be the protein filament vimentin. In this study, we investigated whether antivimentin antibodies are associated with TxCAD and whether their presence can be used to identify patients at high risk of developing angiographically detectable TxCAD. METHODS: Up to 5 years after transplantation, 880 sequential sera (7.07+/-1.8 samples/patient) were collected retrospectively from 109 patients; the majority were collected in the first 2 years. Sera were assessed for antivimentin antibodies using ELISA. TxCAD was assessed by annual angiography. RESULTS: Mean titres of antivimentin antibodies, calculated up to 1, 2, and 5 years, were significantly higher in patients who developed TxCAD than those who remained disease free (P<0.0001, P<0.0038, and P<0.0001, respectively). A predictive test based on the first-year mean vimentin titre alone (> or = 120) produced a test with 63% sensitivity and 76% specificity. Inclusion of persistent rejection or high 1-year mean titre (> or = 270) as a risk factor produced a test with 66% sensitivity and 82% specificity. Multivariate analysis of time to occurrence of transplant vasculopathy showed that mean titre at 1 or 2 years was an independent predictor of time until disease in the presence of all other variables. CONCLUSIONS: Antivimentin antibodies are an independent predictor of TxCAD and can be used to identify some of the patients who are at high risk of developing this complication.

Adolescent↗
PubMed2001

Apolipoprotein E deficiency effects on learning in mice are dependent upon the background strain.

Apolipoprotein E (apoE) deficient mice were bred onto the C57BL/6 and FVB/N strain backgrounds. The cognitive behavior of food-restricted apoE-deficient and wildtype male mice from these strains was assessed in an olfactory cued 8-arm radial maze. At 6 weeks of age, all four types of mice improved in maze performance over the course of 5 days. However, at 6 months of age, only the apoE-deficient mice on the C57BL/6 background failed to improve their maze performance over the 5 day course, as gauged by the number of incorrect choices made before retrieving both food rewards. Thus, an age-dependent and strain-specific effect of apoE deficiency on cognitive behavior was observed in these mice. The background strain affected activity levels in the maze, as well as in an open field assay. Plasma corticosterone levels were assessed in control, fasted, and post-restraint stress states. Fasting and restraint stress led to increases in plasma corticosterone levels. Although there were strain specific effects on fasting corticosterone levels, and the effect of apoE deficiency on post-stress corticosterone levels, there was no association between fasted corticosterone levels and impaired cognitive behavior in the 8-arm radial maze assay.

Aging↗
PubMed2001

Decoding the language of var genes and Plasmodium falciparum sequestration.

Sequestration and rosetting are key determinants of Plasmodium falciparum pathogenesis. They are mediated by a large family of variant proteins called P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 proteins are multispecific binding receptors that are transported to parasite-induced, 'knob-like' binding structures at the erythrocyte surface. To evade immunity and extend infections, parasites clonally vary their expressed PfEMP1. Thus, PfEMP1 are functionally selected for binding while immune selection acts to diversify the family. Here, we describe a new way to analyse PfEMP1 sequence that provides insight into domain function and protein architecture with potential implications for malaria disease.

Amino Acid Sequence↗
PubMed2001

Journey to the center of the category: the dissociation in amnesia between categorization and recognition.

The authors' theoretical analysis of the dissociation in amnesia between categorization and recognition suggests these conclusions: (a) Comparing to-be-categorized items to a category center or prototype produces strong prototype advantages and steep typicality gradients, whereas comparing to-be-categorized items to the training exemplars that surround the prototype produces weak prototype advantages and flat typicality gradients; (b) participants often show the former pattern, suggesting their use of prototypes; (c) exemplar models account poorly for these categorization data, but prototype models account well for them; and (d) the recognition data suggest that controls use a single-comparison exemplar-memorization process more powerfully than amnesics. By pairing categorization based in prototypes with recognition based in exemplar memorization, the authors support and extend other recent accounts of cognitive performance that intermix prototypes and exemplars, and the authors reinforce traditional interpretations of the categorization-recognition dissociation in amnesia.

Amnesia↗
PubMed2001

A portable pulsed cavity ring-down transmissometer for measurement of the optical extinction of the atmospheric aerosol.

A small portable system is described which is used to directly determine the optical extinction of the atmospheric aerosol. The requisite highly sensitive measurement of the optical extinction is accomplished simultaneously at two wavelengths in the near-infrared (1064 nm) and visible (532 nm), using the pulsed cavity ring-down (CRD) approach. The measurement at the two wavelengths can aid in separating the scattering and absorption components of the optical extinction. Rayleigh equivalent optical extinction of approximately 10 x 10(-6) m(-1) from particulate matter in the atmospherically important 0.1-2.5 pm diameter size range (fine particle accumulation mode) can be readily observed with short (<5 s) integration times. Optical extinction is inversely related to the visual range, and so the instrument provides a direct measurement of this particulate-related air quality indicator. The instrument can also provide particle size range-selected multiwavelength optical property measurements, which can be inverted to provide valuable information about the extant airborne particulate distribution.

Journal Article↗
PubMed2001

Astrocytes down-regulate neuronal beta-amyloid precursor protein expression and modify its processing in an apolipoprotein E isoform-specific manner.

Alzheimer's disease is the most frequent neurodegenerative disorder in the aged population and is characterized by the deposition of the 40/42-residue amyloid beta protein (A beta), a proteolytic fragment of the beta-amyloid precursor protein (APP). A common apolipoprotein E (apoE) polymorphism is associated with an increased risk of developing the disease. In order to assess the putative relationship between apoE and amyloidogenesis in the CNS, we prepared primary cortical neurons overexpressing humanized APP695 bearing the Swedish mutation (hAPP(695sw)) and we analysed APP expression and processing after: (i) coculture with primary astrocytes from wild-type, apoE-deficient (E0) mice, or mice overexpressing human apoE2, E3, or E4; (ii) treatment with conditioned media from apoE0, E2, E3 or E4 astrocytes; and (iii) treatment with human recombinant ApoE or human apoE purified from conditioned media of stably transfected RAW264 cells (E2, E3 and E4). Interestingly, a strong decrease in APP expression was observed only when neurons were cocultured with astrocytes (and independently of the apoE genotype considered), suggesting that cell-cell contact is required. Moreover, apoE4-secreting astrocytes, but not recombinant or purified apoE4, significantly increased A beta production and decrease sAPP alpha secretion only when cultured in direct contact with neurons, whereas apoE2 astrocytes had a protective effect. We conclude that astrocytes: (i) strongly regulate neuronal APP expression in primary neurons, and (ii) promote the amyloidogenic pathway in an apoE4-dependent manner. Thus, apoE and astrocytic factor(s) may modulate the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed2001

Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments.

Cerebral apolipoprotein E (apoE) has been implicated in neuronal protection and repair. Due to the variable levels and types of estrogen receptors within different brain regions, the effect of estrogen on apoE and the mechanism of this effect may vary within different regions. Ovariectomized female C57BL/6 mice were treated with pharmacological levels of 17 beta-estradiol or placebo for 5 days, resulting in supraphysiological plasma levels of estradiol in the treated mice. ApoE and glial fibrillary acidic protein (GFAP) levels were measured in the cortex, hippocampus and diencephalon. 17 beta-Estradiol up-regulated apoE but not GFAP in the cortex and diencephalon, whereas in the hippocampus, GFAP and apoE were equally up-regulated. Treatment of estrogen receptor (ER) alpha knockout mice with 17 beta-estradiol or treatment of C57BL/6 mice with 17 alpha-estradiol, a poor estrogen receptor agonist, specifically induced apoE in the cortex, but not in the diencephalon. These results indicate that 17 beta-estradiol effects on apoE are either directly or indirectly mediated by ER alpha in the diencephalon, while the effects in the cortex may be mediated by a non-classical mechanism or by ER beta. Measurement of mRNA levels in estrogen versus placebo-treated wild-type mice indicated that the effect of 17 beta-estradiol on apoE was not associated with changes in apoE mRNA levels.

Animals↗
PubMed2001

Anesthesia-associated carbon monoxide exposures among surgical patients.

OBJECTIVE: To estimate the extent of, and evaluate risk factors for, elevated carboxyhemoglobin levels among patients undergoing general anesthesia and to identify the source of carbon monoxide. DESIGN: Matched case-control study to measure carboxyhemoglobin levels. SETTING: Large academic medical center. PARTICIPANTS: 45 surgical patients who underwent general anesthesia RESULTS: Case-patients were more likely than controls to undergo surgery on Monday or Tuesday (10/15 vs 7/30; matched odds ratio [mOR], 7.7; 95% confidence interval [CI95], 1.8-34; P=.01), in one particular room (7/15 vs 4/30; mOR, 8.5; CI95, 1.5-48; P=.03) or in a room that was idle for > or =24 hours (11/15 vs 1/30; mOR, 95.5; CI95, 8.0-1,138; P< or =.001). In a multivariate model, only rooms, and hence the anesthesia equipment, that were idle for > or =24 hours were independently associated with elevated intraoperative carboxyhemoglobin levels (OR, 22.4; CI95, 1.5-338; P=.025). Moreover, peak carboxyhemoglobin levels were correlated with the length of time that the room was idle (r=0.7; CI95, 0.3-0.9). Carbon monoxide was detected in the anesthesia machine outflow during one case-procedure. No contamination of anesthesia gas supplies or CO2 absorbents was found. CONCLUSIONS: Carbon monoxide may accumulate in anesthesia circuits left idle for > or =24 hours as a result of a chemical interaction between CO2-absorbent granules and anesthetic gases. Patients administered anesthesia through such circuits may be at increased risk for elevated carboxyhemoglobin levels during surgery or the early postoperative period.

Adult↗
PubMed2001

Up-regulation of endoglin, a TGF-beta-binding protein, in rats with experimental renal fibrosis induced by renal mass reduction.

BACKGROUND: The central process in chronic renal failure is the progressive accumulation of extracellular matrix in the glomeruli and in the tubulo-interstitial space, resulting in renal fibrosis. Transforming growth factor-beta1 (TGF-beta1) up-regulation plays a major role in the genesis of renal fibrosis. Endoglin is a membrane glycoprotein that binds TGF-beta1 and TGF-beta3 with high affinity. An increased level of endoglin immunostaining has been demonstrated previously in biopsies from patients with chronic progressive renal disease. We have assessed the expression of endoglin in the rat 5/6th renal mass reduction (RMR) model. METHODS: One, 3 and 5 months after RMR, mean arterial pressure and renal function were measured, animals were sacrificed, renal fibrosis was evaluated quantitatively and the expression of endoglin was assessed by western blot, northern blot and immunohistochemistry. RESULTS: RMR induced a progressive increase in mean arterial pressure and urinary protein excretion. Renal corpuscular area, and mesangial and interstitial fibrosis increased with time after RMR. Immunohistochemical staining for endoglin demonstrated its expression mainly on the endothelial surface of major vessels. In kidneys 1 and 3 months after RMR, the expression of endoglin in renal corpuscles was limited to Bowman's parietal epithelium. In rats 5 months after RMR, the immunoexpression in glomerular endothelium was more marked. Northern blot analysis revealed that rats with RMR showed an increase in the expression of mRNA for endoglin, only at 5 months after RMR. Western blot analysis gave a different time course: a marked increase in the first month, a decrease in the 3rd month and a further increase in the 5th month after RMR. CONCLUSIONS: The present study demonstrates increased endoglin expression in rats with severe hypertension and renal damage. This increased endoglin expression coincides with the period of higher renal damage and renal dysfunction.

Animals↗
PubMed2001

Amyloplasts that sediment in protonemata of the moss Ceratodon purpureus are nonrandomly distributed in microgravity.

Little is known about whether or how plant cells regulate the position of heavy organelles that sediment toward gravity. Dark-grown protonemata of the moss Ceratodon purpureus displays a complex plastid zonation in that only some amyloplasts sediment along the length of the tip cell. If gravity is the major force determining the position of amyloplasts that sediment, then these plastids should be randomly distributed in space. Instead, amyloplasts were clustered in the subapical region in microgravity. Cells rotated on a clinostat on earth had a roughly similar non-random plastid distribution. Subapical clusters were also found in ground controls that were inverted and kept stationary, but the distribution profile differed considerably due to amyloplast sedimentation. These findings indicate the existence of as yet unknown endogenous forces and mechanisms that influence amyloplast position and that are normally masked in stationary cells grown on earth. It is hypothesized that a microtubule-based mechanism normally compensates for g-induced drag while still allowing for regulated amyloplast sedimentation.

Bryopsida↗
PubMed2001

Genetic modifiers of atherosclerosis in mice.

Common atherosclerosis has a genetic component, but it is difficult to determine the specific genes that play a role in atherosclerosis susceptibility in humans. We have used the apoE-deficient mouse as a model system to examine the effects of candidate genes on atherosclerosis as well as to perform genomic experiments to map and isolate other genes giving rise to atherosclerosis susceptibility. We have tested the effects of mutations in the MCSF and VCAM-1 genes on atherosclerosis, and in both of these cases mutations led to gene dosage-dependent decreases in atherosclerosis. By successive back breeding, we have established apoE-deficiency on the C57BL/6 and FVB/N inbred mouse strains. Lesions in C57BL/6 mice are about eightfold larger than those in FVB/ N mice, and lesions in F1 hybrids are intermediate in size. We have performed quantitative trait locus mapping on two F2 cohorts and discovered atherosclerosis susceptibility loci on chromosomes 10, 14, and 19.

Animals↗
PubMed2001

Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage.

- Vascular cell adhesion molecule-1 (VCAM-1/Vcam1) is a cytokine-inducible member of the immunoglobulin gene superfamily that is expressed by arterial endothelial cells in regions predisposed to atherosclerosis and at borders of atherosclerotic plaques. To determine whether VCAM-1 expression regulates atherosclerotic lesion formation, we crossed Vcam1 domain 4-deficient (D4D) mice, which partially circumvent the embryonic lethality of Vcam1 null mice, with apolipoprotein E null (Apoe(-/-)) mice, which spontaneously develop hypercholesterolemia and atherosclerosis. In the Apoe(-/-) background, mice homozygous for the Vcam1 D4D allele had markedly reduced arterial VCAM-1 expression, monocyte adherence in the aortic root, and fatty streak formation. Heterozygous Vcam1 D4D mice revealed a Vcam1 gene-dosage effect and had intermediate, yet significant, reductions in these parameters. Our data demonstrate that VCAM-1 plays a pivotal role in the initiation of atherosclerosis in Apoe(-/-) mice.

Animals↗
PubMed2001

Relief of fibromyalgia symptoms following discontinuation of dietary excitotoxins.

BACKGROUND: Fibromyalgia is a common rheumatologic disorder that is often difficult to treat effectively. CASE SUMMARY: Four patients diagnosed with fibromyalgia syndrome for two to 17 years are described. All had undergone multiple treatment modalities with limited success. All had complete, or nearly complete, resolution of their symptoms within months after eliminating monosodium glutamate (MSG) or MSG plus aspartame from their diet. All patients were women with multiple comorbidities prior to elimination of MSG. All have had recurrence of symptoms whenever MSG is ingested. DISCUSSION: Excitotoxins are molecules, such as MSG and aspartate, that act as excitatory neurotransmitters, and can lead to neurotoxicity when used in excess. We propose that these four patients may represent a subset of fibromyalgia syndrome that is induced or exacerbated by excitotoxins or, alternatively, may comprise an excitotoxin syndrome that is similar to fibromyalgia. We suggest that identification of similar patients and research with larger numbers of patients must be performed before definitive conclusions can be made. CONCLUSIONS: The elimination of MSG and other excitotoxins from the diets of patients with fibromyalgia offers a benign treatment option that has the potential for dramatic results in a subset of patients.

Adult↗