Search PubMed⌕ Search

Biomedical subjects

S Patel

Publications and source records attributed to S Patel.

At least 181 records · Page 10Linked to original sources
PubMed2000

FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells.

In this study, we describe human FDF03, a novel member of the Ig superfamily expressed as a monomeric 44-kDa transmembrane glycoprotein and containing a single extracellular V-set Ig-like domain. Two potential secreted isoforms were also identified. The gene encoding FDF03 mapped to chromosome 7q22. FDF03 was mostly detected in hemopoietic tissues and was expressed by monocytes, macrophages, and granulocytes, but not by lymphocytes (B, T, and NK cells), indicating an expression restricted to cells of the myelomonocytic lineage. FDF03 was also strongly expressed by monocyte-derived dendritic cells (DC) and preferentially by CD14+/CD1a- DC derived from CD34+ progenitors. Moreover, flow cytometric analysis showed FDF03 expression by CD11c+ blood and tonsil DC, but not by CD11c- DC precursors. The FDF03 cytoplasmic tail contained two immunoreceptor tyrosine-based inhibitory motif (ITIM)-like sequences. When overexpressed in pervanadate-treated U937 cells, FDF03 was tyrosine-phosphorylated and recruited Src homology-2 (SH2) domain-containing protein tyrosine phosphatase (SHP)-2 and to a lesser extent SHP-1. Like engagement of the ITIM-bearing receptor LAIR-1/p40, cross-linking of FDF03 inhibited calcium mobilization in response to CD32/FcgammaRII aggregation in transfected U937 cells, thus demonstrating that FDF03 can function as an inhibitory receptor. However, in contrast to LAIR-1/p40, cross-linking of FDF03 did not inhibit GM-CSF-induced monocyte differentiation into DC. Thus, FDF03 is a novel ITIM-bearing receptor selectively expressed by cells of myeloid origin, including DC, that may regulate functions other than that of the broadly distributed LAIR-1/p40 molecule.

Adult↗
PubMed2000

Persistence of human papillomavirus type 16 infection is associated with lack of cytotoxic T lymphocyte response to the E6 antigens.

Our cross-sectional study suggested that cytotoxic T lymphocyte (CTL) responses have a protective effect in squamous intraepithelial lesion (SIL) development. More CTL responses in women with human papillomavirus type 16 (HPV 16) infection without SILs than with SILs were detected. In the current longitudinal study, the role of CTL in clearing HPV 16 infection in women without SILs was investigated. Women with HPV 16 infection (n=51) were enrolled, along with HPV 16-negative control women (n=3). Twenty-two (55%) of 40 women who cleared HPV 16 infection had an E6 CTL response at least once, compared with none of 9 women who had HPV 16 persistence (P=.003). Such a difference was not demonstrated for E7; 25 (63%) of 40 women who cleared HPV 16 infection responded, versus 5 (56%) of 9 women with persistence (P=.720). It appears that lack of response to E6 is important in the persistence of HPV 16 infection.

Adolescent↗
PubMed2000

A target for cholesterol absorption inhibitors in the enterocyte brush border membrane.

Uptake of cholesterol by the intestinal absorptive epithelium can be selectively blocked by specific small molecules, like the sterol glycoside, L-166,143. Furthermore, (3)H-labeled L-166,143 administered orally to hamsters binds specifically to the intestinal mucosa, suggesting the existence of a cholesterol transporter. Using autoradiography, the binding site of (3)H-L-166,143 in the hamster small intestine was localized to the very apical aspect of the absorptive epithelial cells. Label was competed by non-radioactive L-166,143 and two structurally distinct cholesterol absorption inhibitors, suggesting a common site of action for these compounds. L-166,143 blocked uptake of (3)H-cholesterol into enterocytes in vivo, as demonstrated by autoradiography, suggesting that it inhibits a very early step of cholesterol absorption, incorporation into the brush border membrane. This conclusion was confirmed by studies in which intestinal brush borders were isolated from hamsters dosed with (3)H-cholesterol in the presence or absence of L-166,143. Uptake of (3)H-cholesterol into the membranes was substantially inhibited by the compound. In contrast, an inhibitor of acyl CoA:cholesterol acyltransferase, did not affect uptake of (3)H-cholesterol into the brush border membranes. These results strongly support the existence of a specific transporter that facilitates the movement of cholesterol from bile acid micelles into the brush border membranes of enterocytes.

Animals↗
PubMed2000

Infectious agents are not necessary for murine atherogenesis.

Recent work has revealed correlations between bacterial or viral infections and atherosclerotic disease. One particular bacterium, Chlamydia pneumoniae, has been observed at high frequency in human atherosclerotic lesions, prompting the hypothesis that infectious agents may be necessary for the initiation or progression of atherosclerosis. To determine if responses to gram-negative bacteria are necessary for atherogenesis, we first bred atherosclerosis-prone apolipoprotein (apo) E(-/)- (deficient) mice with animals incapable of responding to bacterial lipopolysaccharide. Atherogenesis was unaffected in doubly deficient animals. We further tested the role of infectious agents by creating a colony of germ-free apo E(-/)- mice. These animals are free of all microbial agents (bacterial, viral, and fungal). Atherosclerosis in germ-free animals was not measurably different from that in animals raised with ambient levels of microbial challenge. These studies show that infection is not necessary for murine atherosclerosis and that, unlike peptic ulcer, Koch's postulates cannot be fulfilled for any infectious agent in atherosclerosis.

Animals↗
PubMed2000

Hormone-sensitive lipase functions as an oligomer.

Hormone-sensitive lipase (HSL) is a cytosolic neutral lipase whose activity is regulated by reversible phosphorylation and which is thought to be the rate-limiting enzyme for the mobilization of FFA from adipose tissue. In the current studies the subunit structure of HSL has been explored using sucrose gradient centrifugation and in vivo and in vitro protein-protein interactions. Evidence is provided to demonstrate that HSL exists as a functional dimer composed of homologous subunits. Dimeric HSL displayed approximately 40-fold greater activity against cholesteryl ester substrate when compared with monomeric HSL without any differences in affinity for the substrate. Truncations of HSL identified the importance of the N-terminal 300 amino acids, as well as other regions, in participating in the oligomerization of HSL. These studies support the notion that the N-terminal region of HSL represents a docking domain for protein-protein interactions and provide an additional mechanism for the posttranslational control of HSL activity in the cell via oligomerization.

Adipose Tissue↗
PubMed2000

NPC1-containing compartment of human granulosa-lutein cells: a role in the intracellular trafficking of cholesterol supporting steroidogenesis.

Steroidogenic cells represent unique systems for the exploration of intracellular cholesterol trafficking. We employed cytochemical and biochemical methods to explore the expression, regulation, and function of the Niemann-Pick C1 protein (NPC1) in human granulosa-lutein cells. NPC1 was localized in a subset of lysosome-associated membrane glycoprotein 2 (LAMP-2)-positive vesicles. By analyzing the sensitivity of NPC1 N-linked oligosaccharide chains to glycosidases and neuraminidase, evidence was obtained for movement of nascent NPC1 from the endoplasmic reticulum through the medial and trans compartments of the Golgi apparatus prior to its appearance in cytoplasmic vesicles. NPC1 protein content and the morphology and cellular distribution of NPC1-containing vesicles were not affected by treatment of the granulosa-lutein cells with 8-Br-cAMP, which stimulates cholesterol metabolism into progesterone. In contrast, steroidogenic acute regulatory (StAR) protein levels were increased by 8-Br-cAMP. Incubation of granulosa-lutein cells with low-density lipoprotein (LDL) in the presence of the hydrophobic amine, U18666A, caused accumulation of free cholesterol in granules, identified by filipin staining, that contained LAMP-2 and NPC1. These granules also stained for neutral lipid with Nile red, reflecting accumulation of LDL-derived cholesterol esters. LDL-stimulated progesterone synthesis was completely blocked by U18666A, leaving steroid output at levels similar to those of cells incubated in the absence of LDL. The hydrophobic amine also blocked the LDL augmentation of 8-Br-cAMP-stimulated progesterone synthesis, reducing steroid production to levels seen in cells stimulated with 8-Br-cAMP in the absence of LDL. Steroidogenesis recovered after U18666A was removed from the culture medium. U18666A treatment caused a 2-fold or more increase in NPC1 protein and mRNA levels, suggesting that disruption of NPC1's function activates a compensatory mechanism resulting in increased NPC1 synthesis. We conclude that the NPC1 compartment plays an important role in the trafficking of LDL-derived substrate in steroidogenic cells; that NPC1 expression is up-regulated when NPC1 action is blocked; and that the NPC1 compartment can be functionally separated from other intracellular pathways contributing substrate for steroidogenesis.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Characteristics of coronary smooth muscle cells and adventitial fibroblasts.

BACKGROUND: Recent findings suggesting the involvement of adventitial cells in coronary repair have raised questions regarding the phenotypic "plasticity" of medial smooth muscle cells (SMCs). Accordingly, the aims of the present study were to examine the characteristics of coronary medial and adventitial cells and to compare the responses of coronary and noncoronary SMCs to stimulation. METHODS AND RESULTS: Enzymatically isolated coronary SMCs (human and porcine) were distinct from noncoronary SMCs, showing poor adhesion and spreading, as well as lower proliferation, collagen synthesis, and LDL degradation. Several extracellular matrix components (Matrigel, collagen I and IV, laminin, vitronectin, fibronectin) or growth factors (epidermal growth factor, platelet-derived growth factor-BB, insulin growth factor-1, interleukin-1alpha) failed to augment the adhesion or proliferation of coronary SMCs to the levels observed in noncoronary SMCs. Unlike coronary SMCs, coronary fibroblasts demonstrated high adhesion, proliferation, collagen synthesis, and avid LDL metabolism. Limited responses of coronary SMCs were associated with sustained expression of differentiation markers (alpha-smooth muscle actin, h-caldesmon, and smooth muscle myosin heavy chain), whereas noncoronary SMCs showed marked phenotypic heterogeneity. CONCLUSIONS: Coronary SMCs appeared to maintain highly differentiated phenotype in response to stimulation, whereas coronary adventitial fibroblasts demonstrated several characteristics that are essential during vascular repair. Coronary SMCs, however, were distinct from noncoronary medial cells, which displayed greater phenotypic heterogeneity and versatility in culture. We postulate that the mechanism of vascular repair may differ among vascular beds, pointing to the importance of coronary artery-specific investigations in vascular biology.

Biomarkers↗
PubMed2000

X-ray structure of yeast Hal2p, a major target of lithium and sodium toxicity, and identification of framework interactions determining cation sensitivity.

The product of the yeast HAL2 gene (Hal2p) is an in vivo target of sodium and lithium toxicity and its overexpression improves salt tolerance in yeast and plants. Hal2p is a metabolic phosphatase which catalyses the hydrolysis of 3'-phosphoadenosine-5'-phosphate (PAP) to AMP. It is, the prototype of an evolutionarily conserved family of PAP phosphatases and the engineering of sodium insensitive enzymes of this group may contribute to the generation of salt-tolerant crops. We have solved the crystal structure of Hal2p in complex with magnesium, lithium and the two products of PAP hydrolysis, AMP and Pi, at 1.6 A resolution. A functional screening of random mutations of the HAL2 gene in growing yeast generated forms of the enzyme with reduced cation sensitivity. Analysis of these mutants defined a salt bridge (Glu238 ellipsis Arg152) and a hydrophobic bond (Va170 ellipsis Trp293) as important framework interactions determining cation sensitivity. Hal2p belongs to a larger superfamily of lithium-sensitive phosphatases which includes inositol monophosphatase. The hydrophobic interaction mutated in Hal2p is conserved in this superfamily and its disruption in human inositol monophosphatase also resulted in reduced cation sensitivity.

Cloning, Molecular↗
PubMed2000

The effect of vitamin E exposure on cadmium toxicity in mouse embryo cells in vitro.

Heavy metals such as cadmium pose a number of environmental problems in addition to being detrimental to human health. Cadmium is known to be embryotoxic in animal models and to cause brain, limb and craniofacial malformations. Among numerous mechanisms proposed for cadmium toxicity are oxidative stress and lipid peroxidation. Vitamin E has been found to have antioxidant and cytoprotective properties in cultured cells but its effect on cadmium embryonic toxicity has not yet been determined. Epithelial-like cells derived from day-8 whole-mouse embryos were used as a model embryonic tissue. Cadmium toxicity in these cultured cells was found to be both time and concentration dependent. Prior exposure to 50 microM alpha-tocopherol or 25 or 50 microM alpha-tocopherol acetate resulted in a marked reduction in the toxicity of 5 microM CdCl2. The apparent cytoprotective effects may be partly non-specific, however, as a general growth enhancement was observed after vitamin E exposure in the absence of cadmium.

Animals↗
PubMed2000

Bone density of women who have recovered from anorexia nervosa.

OBJECTIVE: To examine bone density in 19 women who had previously experienced classical anorexia nervosa from which they had been fully recovered for a mean of 21 years (current characteristics: median age 40.2 years; Eating Attitudes Test [EAT] score 2; body mass index [BMI] 21.1; average 1.8 offspring). METHOD: Probands were compared, blindly, in respect of bone density, with 13 control subjects matched for age and sex and with no history of eating disorders. Dual energy X-ray absorptiometry (DXA) was used to evaluate the bone mineral density (BMD) of the lumbar spine and the head of the femur. RESULTS: Femur BMD was still significantly less among ex-anorectic sufferers. Two subjects had experienced pathological fractures while anorectic, both having been strenuous exercisers. None appeared to have suffered post illness fractures. BMD at follow-up did not relate to the severity or chronicity of previous anorexia nervosa. DISCUSSION: Full clinical recovery from anorexia nervosa does not quite confer full establishment of normal bone density. However, pathological fractures are not a feature thereafter, within middle life.

Absorptiometry, Photon↗
PubMed2000

Functional repair with neural stem cells.

Approval to commence phase I/II clinical trials with neural stem cells requires proof of concept in well-accepted animal models of human neurological disease or injury. We initially showed that the conditionally immortal MHP36 line of hippocampal origin (derived from the H-2Kb-tsA58 transgenic mouse) was effective in repopulating CA1 neurons in models of global ischaemia and repairing cognitive function, and have now shown that this line is multifunctional. MHP36 cells are effective in restoring spatial memory deficits in rats after excitotoxic lesions of the cholinergic projections to cortex and hippocampus and in rats showing cognitive impairments due to normal ageing. Moreover, grafts of MHP36 cells are effective in reversing sensory and motor deficits and reducing lesion volume as a consequence of occlusion of the middle cerebral artery, the major cause of stroke. In contrast, MHP36 cell grafts were unable to repair motor asymmetries in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine system, the prototype rodent model of Parkinson's disease. These data show that conditionally immortal neuroepithelial stem cells are multifunctional, being able to repair diverse types of brain damage. However, there are limitations to this multifunctionality, suggesting that lines from different regions of the developing brain will be required to treat different brain diseases. ReNeuron is currently developing human neuroepithelial stem cell lines from different brain regions and with similar reparative properties to our murine lines.

Animals↗
PubMed2000

Functional reconstruction of the hippocampus: fetal versus conditionally immortal neuroepithelial stem cell grafts.

Late fetal CA1 hippocampal grafts and stem cell grafts from the conditionally immortal MHP36 clonal line derived from the H-2Kb-tsA58 transgenic mouse neuroepithelium both improved spatial deficits in rats with ischaemic CA1 damage induced by four-vessel occlusion (4VO). However, the distribution of fetal and MHP36 grafts differed. Fetal cells lodged in clumps around the implant sites and along the corpus callosum, whilst MHP36 grafts infiltrated the area of CA1 ischaemic damage, achieving apparent architectural reconstruction of the hippocampus. The migration of MHP36 cells is damage-dependent. Few cells were found in intact brain; after 15 min of 4VO cells repopulated only the discrete area of CA1 cell loss, whereas with more extensive damage after 30 min occlusion cells migrated to all hippocampal fields and to cortex. A higher proportion of grafted MHP36 cells differentiated into neurons in the host CA1 field than grafts of striatal or cortical expanded cell populations. Cortical population grafts were as effective as MHP36 grafts in improving water maze learning, whereas striatal or ventral mesencephalic cells were ineffective, indicating a degree of stem cell specificity. The efficacy of MHP36 cells extends to primates. In marmosets with profound impairments in conditional discrimination tasks after lesions of the CA1 field, MHP36 cells improved performance as effectively as fetal grafts and migrated evenly through the CA1 field, in contrast to clustered fetal cells. These findings suggest that MHP36 stem cell grafts are as effective as fetal grafts in functional repair of hippocampal damage, and that their preference for areas of cell loss and adoption of appropriate morphologies is consistent with a point-to-point repair mechanism.

Animals↗
PubMed2000

Boundary-based warping of brain MR images.

The goal of this work was to develop a warping technique for mapping a brain image to another image or atlas data, with minimum user interaction and independent of gray level information. We have developed and tested three different methods for warping magnetic resonance (MR) brain images. We utilize a deformable contour to extract and warp the boundaries of the two images. A mesh-grid coordinate system is constructed for each brain, by applying a distance transformation to the resulting contours, and scaling. In the first method (MGC), the first image is mapped to the second image based on a one-to-one mapping between different layers defined by the mesh-grid. In the second method (IDW), the corresponding pixels in the two images are found using the above mesh-grid system and a local inverse-distance weights interpolation. In the third proposed method (TSB), a subset of grid points is used for finding the parameters of a spline transformation, which defines the global warping. The warping methods were applied to clinical MR consisting of diffusion-weighted and T2-weighted images of the human brain. The IDW and TSB methods were superior in ranking of diagnostic quality of the warped MR images to the MGC (P < 0.01) as defined by a neuroradiologist. The deformable contour warping produced excellent diagnostic quality for the diffusion-weighted images coregistered and warped to T2 weighted images. J. Magn. Reson. Imaging 2000;12:417-429.

Aged↗
PubMed2000

BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia.

Hypoxic-ischemic (H-I) injury to the brain in the perinatal period often leads to significant long-term neurological deficits. In a model of neonatal H-I injury in postnatal day 7 rats, our previous data have shown that cell death with features of apoptosis is prominent between 6 and 24 h after H-I and that neurotrophins, particularly BDNF, can markedly protect against tissue loss. During brain development, caspase-3 is required for normal levels of programmed cell death. Utilizing an antibody specific for the activated form of caspase-3, CM1, we now show that caspase-3 is specifically activated in neuronal cell bodies and their processes beginning at 6 h and peaking 24 h following unilateral carotid ligation and exposure to hypoxia in postnatal day 7 rats. Caspase-3 activation began to occur in cortex at 6 h and in striatum and hippocampus at 12-18 h. Caspase-3 activation was also observed in developing oligodendrocytes. Intracerebroventricular injection of BDNF prior to H-I injury almost completely abolished evidence of H-I-induced caspase-3 activation in vivo. Utilizing a specific molecular marker of an apoptotic pathway, these findings demonstrate that H-I injury to the developing brain is a strong apoptotic stimulus leading to caspase-3 activation, that BDNF can block this process in vivo, and that the ability of BDNF to inhibit caspase activation and subsequent apoptosis likely accounts in large part for its protection against neuronal injury in this model.

Animals↗
PubMed2000

Picture archiving and communication systems project management using web-based tools.

As the technology of picture archiving and communications systems (PACS) improves and implementation becomes more widespread, the project management of deploying substantially large, multiple-facility systems becomes an integral part of success. A successful deployment requires project support from the initial planning and surveying to the final acceptance, even encompassing support during active use of the PACS. The sharing of information between project stakeholders of a PACS implementation can be daunting at times, but with the flexibility of the worldwide web, this aspect can be eased. This report speaks to the tools and usability of the worldwide web to disseminate project management information for planning, implementation, and support of any PACS implementation--anywhere. This sharing of knowledge prepares the end user for what will be available for them when the complete systems is in place, allowing for a smoother migration to PACS.

Humans↗
PubMed2000

Plasma esterase activities in young and old patients undergoing open inguinal hernia repair.

Previous research has shown substantial decrements in enzymes of drug metabolism (esterases) in older patients following fracture neck of femur and hip replacement surgery. The main aim of this study was to examine the effect of open inguinal hernia repair on the activities of four plasma esterases in old and young patients. Seventeen older patients (mean age+/-S.E.M. was 67.6+/-1.8) and 12 young patients (mean age+/-S.E.M. was 38+/-3.3) undergoing open hernia repair for clinical reasons were recruited. The activities of plasma benzoylcholinesterase, butyrylcholinesterase, acetylcholinesterase, and aspirin esterase were determined spectrophotometrically, before the operation, 1 day post operatively and 1 week later. There was no significant effect of hernia repair surgery on any of the four enzymes measured in young or old patients. Neither was there any significant difference in enzyme activity between young and old at any of the three time points. Hernia repair surgery is not associated with decrements in enzymes of drug metabolism in man. This contrasts with the previous findings in hip replacement surgery.

Journal Article↗
PubMed2000

NAADP-induced calcium release in sea urchin eggs.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent activator of Ca2+ release from intracellular stores described. It acts on a mechanism distinct from inositol trisphosphate and ryanodine receptors, the two major Ca2+ release channels characterised. NAADP-gated Ca2+ release channels do not appear to be regulated by Ca2+ and may be better suited for triggering Ca2+ signals rather than propagating them. They exhibit a remarkable pharmacology for a putative intracellular Ca2+ release channel in that they are selectively blocked by potassium and L-type Ca2+ channel antagonists. Furthermore, in contrast to microsomal Ca2+ stores expressing IP3Rs and RyRs, those sensitive to NAADP are thapsigargin-insensitive, suggesting that they may be expressed on a different part of the endoplasmic reticulum. Perhaps the most unusual feature of the NAADP-gated Ca2+ release mechanisms is its inactivation properties. Unlike the mechanisms regulated by IP3 and cADPR in sea urchin eggs which after induction of Ca2+ release appear to become refractory to subsequent activation, very low concentrations of NAADP are able to inactivate NAADP-induced Ca2+ release fully at concentrations well below those required to activate Ca2+ release. The mechanism and physiological significance of this most unusual desensitisation phenomenon are unclear. More recently, NAADP has been shown to mobilise Ca2+ in ascidian oocytes, brain microsomes and pancreatic acinar cells suggesting a more widespread role in Ca2+ signalling. A possible role for this novel Ca2+ release mechanism in sea urchin egg fertilisation is discussed.

Animals↗