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Biomedical subjects

S Nagpal

Publications and source records attributed to S Nagpal.

At least 19 recordsLinked to original sources
PubMed2001

Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study.

OBJECTIVE: To determine and compare physicians' and patients' thresholds for how much reduction in risk of stroke is necessary and how much risk of excess bleeding is acceptable with antithrombotic treatment in people with atrial fibrillation. DESIGN: Prospective observational study. SETTING: Tertiary and peripheral referral centres in Nova Scotia, Canada. PARTICIPANTS: 63 physicians who were treating patients with atrial fibrillation and 61 patients at high risk for atrial fibrillation. MAIN OUTCOME MEASURES: Participants underwent a face to face interview with a probability trade-off tool. Thresholds were determined for the minimum reduction in risk of stroke necessary and the maximum increase in risk of excess bleeding acceptable for treatment with aspirin and warfarin in people with atrial fibrillation. RESULTS: The minimum number of strokes that needed to be prevented in 100 patients over two years for warfarin to be justified was significantly lower for patients than for physicians (1.8 (SD 1.9) v 2.5 (1.6), P=0.009), whereas for aspirin there was no difference between patients and physicians (1.3 (1.3) v 1.6 (1.5), P=0.29). The maximum number of excess bleeds acceptable in 100 patients over two years for use of warfarin and aspirin was significantly higher for patients than for physicians (warfarin 17.4 (7.1) v 10.3 (6.1); aspirin 14.7 (8.5) v 6.7 (6.2); P<0.001 for both comparisons). CONCLUSIONS: Patients at high risk for atrial fibrillation placed more value on the avoidance of stroke and less value on the avoidance of bleeding than did physicians who treat patients with atrial fibrillation. The views of the individual patient should be considered when decisions are being made about antithrombotic treatment for people with atrial fibrillation.

Adult↗
PubMed2001

Retinoids inhibit proliferation of human coronary smooth muscle cells by modulating cell cycle regulators.

Retinoids inhibit rat vascular smooth muscle cell (VSMC) proliferation in vitro and intimal hyperplasia in vivo. We examined the mechanism of the antiproliferative effect of retinoids on human coronary artery smooth muscle cells (human CASMCs). The RAR ligands all-trans-retinoic acid (atRA) and ethyl-p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-l-propenyl]-benzoic acid (TTNPB); a pan-RXR/RAR agonist, 9-cis-retinoic acid (9cRA); and the RXR-selective ligand AGN4204 all inhibited DNA synthesis stimulated with platelet-derived growth factor and insulin (IC(50): TTNPB 63 nmol/L, atRA 120 nmol/L, AGN4204 460 nmol/L, 9cRA 1.5 micromol/L). All retinoids blocked cell cycle progression as determined by flow cytometry and inhibited retinoblastoma protein (Rb) phosphorylation. TTNPB, atRA, and AGN4204 inhibited the mitogenic induction of cyclin D1, whereas 9cRA had no effect. None of the retinoids affected the expression of CDK 2, 4, or 6 or cyclin E. All retinoids attenuated mitogen-induced downregulation of CDKI p27(Kip1), a major negative regulator of Rb phosphorylation, partly through stabilizing p27(Kip1) turnover. These data demonstrate that retinoids have antiproliferative activity by modulating G(1) --> S cell cycle regulators in human CASMCs through inhibition of Rb phosphorylation and elevation of p27(Kip1) levels.

Cell Cycle Proteins↗
PubMed2001

Vitamin D analogs: mechanism of action and therapeutic applications.

The physiological VDR ligand, 1 alpha,25-dihydroxyvitamin D3, acts upon a wide variety of tissues and cells, both related to and unrelated to calcium and phosphate homeostasis. The noncalcemic actions of natural and synthetic VDR ligands are exemplified by their potent anti-proliferative, prodifferentiative and immunomodulatory activities. As a result, a VDR ligand is an approved drug for the topical treatment of psoriasis. A plethora of actions of 1 alpha,25-dihydroxyvitamin D3 in various systems have suggested wide clinical applications of VDR ligands in such diverse disease states as inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, photoaging and skin rejuvenation), osteoporosis, cancers (breast, prostate, colon, leukemia and myelodysplastic syndrome) and autoimmune diseases (multiple sclerosis, type I diabetes and systemic lupus erythematosus). VDR ligands have shown therapeutic potential in limited human clinical trials as well as in animal models of these diseases. Some of the VDR ligands have shown not only potent preventive but also therapeutic anabolic activities in animal models of osteoporosis. However, the use of VDR in above mentioned indications as well as in oral therapy for psoriasis and even topical therapy for severe psoriasis is hampered by its associated toxicity, namely hypercalcemia. New VDR ligands have been synthesized which exhibit greater specificity by retaining desirable properties, but with reduced calcemic potential. The discovery of novel vitamin D3 analogs along with an increased understanding of the biological functions and mechanisms of action of VDR are likely to result in improved treatments for responsive indications.

Animals↗
PubMed2001

An update: women, hypertension and therapeutic efficacy.

One in five Canadians has high blood pressure. The prevalence is as high as 58% in women between the ages of 65 and 74 years. Approximately 40% of stroke cases, 39% of myocardial infarction cases and 28% of end stage renal diseases are attributable to hypertension. Despite the burden that hypertension places on women, the effect of antihypertensive therapy on cardiovascular complications has not been well established. To address this knowledge gap, two meta-analyses with sex-specific results, including the most current randomized, controlled trials to evaluate hypertension treatment, were reviewed. The Individual Data Analysis of Antihypertensive (INDANA) intervention trials group and Quan and colleagues analyzed treatment benefits in 23,000 women and 19,975 men according to subgroup meta-analyses from 12 randomized, controlled trials that compared antihypertensive drug therapy with placebo. The meta-analyses demonstrated a statistically significant treatment benefit for all of the reported clinical outcomes in men of all ages and in black women. In women over the age of 54 years, antihypertensive treatment was associated with a significant reduction of fatal and nonfatal stroke, cardiovascular events and cardiovascular mortality. Overall, there was no significant difference in the relative treatment benefit in women and men; however, the absolute treatment benefit was lower in women than in men. Thus, the number needed to treat for the end points of fatal stroke, nonfatal stroke and cardiovascular events was one- to threefold higher for women than for men. Furthermore, white women between the ages of 30 and 54 years showed no treatment benefit or harm. Data from the 6.7-year follow-up in the Hypertension Detection and Follow-up Program (HDFP) trial suggested that this group of younger women might benefit from a longer duration of treatment. Indications for pharmacological intervention seem quite clear for all subgroups, excluding these younger women. Until further evidence is available for this low risk subgroup, the current recommendations for lifestyle modification cannot be challenged.

Adult↗
PubMed2000

Ethanol utilization by sulfate-reducing bacteria: an experimental and modeling study.

A mixed culture of sulfate-reducing bacteria containing the species Desulfovibrio desulfuricans was used to study sulfate-reduction stoichiometry and kinetics using ethanol as the carbon source. Growth yield was lower, and kinetics were slower, for ethanol compared to lactate. Ethanol was converted into acetate and no significant carbon dioxide production was observed. A mathematical model for growth of sulfate-reducing bacteria on ethanol was developed, and simulations of the growth experiments on ethanol were carried out using the model. The pH variation due to sulfate reduction, and hydrogen sulfide production and removal by nitrogen sparging, were examined. The modeling study is distinct from earlier models for systems using sulfate-reducing bacteria in that it considers growth on ethanol, and analyzes pH variations due to the product-formation reactions.

Acetates↗
PubMed2000

Microbial sulfate reduction in a liquid-solid fluidized bed reactor.

A liquid-solid fluidized bed reactor was used to carry out sulfate reduction with a mixed culture of sulfate reducing bacteria. The bacteria were immobilized on porous glass beads. Stable fluidized bed operation with these biofilm-coated beads was possible. The low specific gravity of the hydrated beads allowed operation at low liquid recirculation rates. H(2)S level in the reactor was controlled by N(2) sparging, which also served as the location for liquid feed and removal. Ethanol was used as the electron donor/carbon source for the bacteria. Sulfate reduction rates up to 6.33 g sulfate L(-1) day(-1) were attained in the reactor at a hydraulic retention time of 5.1 h. The effect of hydraulic retention time and biomass loading on the beads, on reactor performance, and efficiency were examined. The efficiency of sulfate reduction increases considerably as the hydraulic retention increases, until the bacteria became very strongly substrate-limited at 55h HRT. The effect of bead biomass loading on bed expansion at various liquid superficial velocities was studied. A model for the reactor was developed. Simulations of the continuous flow experiments indicate that the model can describe the system well, and thus could be used in the design/scale-up of such reactors. The model suggests that a significant increase in the sulfate reduction capacity of the system is possible by increasing the volume of the bed relative to the total liquid volume of the system.

Bioreactors↗
PubMed2000

Kaposi sarcoma is a therapeutic target for vitamin D(3) receptor agonist.

Kaposi sarcoma (KS) is responsive to a number of different steroid hormones, such as glucocorticoids and retinoids. An active metabolite of vitamin D, 1alpha,25 dihydroxyvitamin D(3), was used to study the effect of this steroid hormone in KS. Steroid hormones exert their effect through their cognate nuclear receptors, which for vitamin D metabolites is the vitamin D receptor (VDR). It was first shown that KS cell lines and primary tumor tissue express high levels of VDR, whereas endothelial cells had minimal expression and fibroblasts had no expression. Second, KS cell growth was inhibited by VDR agonist 1alpha,25 dihydroxyvitamin D(3) with a 50% inhibitory concentration of 5 x 10 -8 mol/L, whereas endothelial cells and fibroblast cells showed no response. Studies on the mechanism of KS tumor growth inhibition by 1alpha,25 dihydroxyvitamin D(3) showed that production of autocrine growth factors interleukin (IL)-6 and IL-8 was reduced in a dose-dependent manner, whereas no effect was observed on vascular endothelial growth factor and basic fibroblast growth factor. Transcription initiated at the IL-6 promoter was repressed by VDR agonist. The DNA sequences required to mediate this repression were localized to nucleotides -225/-110 in the 5'-flanking region. The antitumor activity of VDR agonists was also confirmed in KS tumor xenograft and after topical application in patients with KS. 1alpha,25 Dihydroxyvitamin D(3) and its analogs may thus be candidates for clinical development in KS.

Adult↗
PubMed2000

Peroxisome proliferator-activated receptor and retinoid X receptor ligands inhibit monocyte chemotactic protein-1-directed migration of monocytes.

Monocyte chemotactic protein-1 (MCP-1)-directed transendothelial migration of monocytes plays a key role in the development of inflammatory diseases. Infiltration of tissues by monocytes requires degradation of extracellular matrices, a process that involves matrix metalloproteinases. We studied the effects of peroxisome proliferator-activated receptor (PPAR) gamma, alpha, and retinoid X receptor alpha (RXRalpha) ligands on MCP-1-directed migration and matrix metalloproteinase expression of a human acute monocytic leukemia cell line (THP-1). PPARgamma ligands attenuated MCP-1-induced migration, with 50% inhibition (IC(50)) at 2.8 microM for troglitazone and 4.8 microM for rosiglitazone. PPARalpha ligands WY-14643 (IC(50): 0.9 microM) and 5,8,11,14-eicosatetranoic acid (IC(50): 9.9 microM), and the potent RXRalpha ligand AGN 4204 (IC(50): 3.6 nM) also blocked monocyte migration. Troglitazone, rosiglitazone, or AGN 4204 inhibited phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 expression. PPARalpha activators WY-14643 and 5,8,11,14-eicosatetraynoic acid, however, had no inhibitory effect. AGN 4204 increased PMA-induced tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) expression, whereas all PPAR ligands showed no effect. All PPAR and RXRalpha ligands blocked chemotaxis of THP-1 monocytes in the absence of a matrix barrier. This study demonstrates that activated PPARs and RXRalpha, block MCP-1-directed monocyte migration, mediated, at least in part, through their effects on matrix metalloproteinase-9 or TIMP-1 production, or chemotaxis.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed2000

Humoral hyporesponsiveness to a conjugate contraceptive vaccine and its bypass by diverse carriers using permissible adjuvant.

A contraceptive vaccine directed against human chorionic gonadotropin (hCG) has previously undergone clinical testing that demonstrated the feasibility of the approach in preventing pregnancy in women. Some immunized volunteers however, did not respond with an adequate anti-hCG antibody response despite employing highly immunogenic bacterial toxoids as carriers. Since there is some evidence that T cell responses to a complex protein typically focus on a few immunodominant epitopes, we investigated the responsiveness to hCG in mice of different haplotypes using the protein carrier diphtheria toxoid (DT). Our data showed a differential carrier effect of DT. With the aim of making a more potent immunogen employing promiscuous pathogen-derived Th peptides as carriers, peptide:antigen stoichiometric ratios were optimized. When tested individually using alum as the adjuvant, three such peptide conjugates improved the anti-hCG response, though not consistently to levels higher than the DT conjugate. Immunization with a combination of these synthetic epitopes generated anti-hCG responses higher than those achieved with DT or with the individual peptides. Antibodies were of high affinity and capable of neutralizing the bioactivity of hCG, but were devoid of anti-peptide reactivity. These results support our view that differential hyporesponsiveness in a diverse population may arise from inadequate carrier effect and that it can be overcome by use of pathogen-derived broadly reactive non-B Th epitopes employing only alum, a permissible adjuvant.

Adjuvants, Immunologic↗
PubMed2000

Recent developments in receptor-selective retinoids.

Natural (all trans-retinoic acid, RA) and synthetic retinoids exhibit potent anti-proliferative, normalization of differentiation and anti-inflammatory activities which appear to account for their therapeutic effects in acne, psoriasis, photoaging, precancerous lesions and established cancers. Although RA has shown considerable promise in dermatologic indications, certain side effects have restricted its use as a choice of agent for chronic administration. Systematic synthesis of receptor-selective retinoids has resulted in two topical drugs, Tazorac/Zorac (tazarotene) and Differin (adapalene). Tazorac is indicated for psoriasis and acne and Differin gel for the treatment of acne. These drugs bind to the retinoic acid receptor (RAR) family members. Various RAR subtype-specific and function-selective retinoids have been synthesized. These retinoids, which are in various stages of pre-clinical development for the treatment of cancers, psoriasis and as an antidote to Accutane-mediated mucocutaneous toxicity, will also be discussed in this review. Discovery of another retinoid receptor, retinoid X receptor (RXR), revealed that RXR-specific retinoids already existed in retinoid chemical libraries. Structure activity relationship studies based upon binding and transactivation assays led to the synthesis of RXR-specific ligands with high affinities for RXR subtypes. These compounds were found to be effective in the treatment of hyperglycemia in animal models of type II diabetes. The discovery of novel retinoids along with an increased understanding of the biological functions and mechanisms of action of retinoid receptors are likely to result in improved treatments for existing responsive indications and identification of new retinoid therapeutic targets.

Adapalene↗
PubMed2000

The carboxy-terminal hydrophobic domain of TIG3, a class II tumor suppressor protein, is required for appropriate cellular localization and optimal biological activity.

TIG3 is a recently discovered class II tumor suppressor protein, originally isolated from retinoid-treated cultured epidermal keratinocytes, that suppresses the proliferation of a variety of epithelial cell types. In the present study, we examine the ability of this protein to reduce CHO, T47D and HaCaT cell proliferation, and the role of the carboxy-terminal hydrophobic domain in this regulation. Vector-mediated expression of the full length TIG3 protein, TIG31-164, results in a 50-70% reduction colony formation efficiency. Expression of a truncated mutant, TIG31-134, that lacks the putative carboxy-terminal membrane-anchoring domain, results in a partial loss of ability to suppress colony formation. The fact that the truncated protein remains partially active suggests that both the amino- and carboxy-terminal regions of TIG3 are required for optimal growth suppression. The full-length protein is distributed in a perinuclear location, and is not present in the nucleus. TIG31-134, in contrast, is distributed in the cytoplasm. Thus, a change in location is associated with the partial loss of activity. We also monitored the distribution of green fluorescent protein (GFP)-TIG3 fusion proteins. GFP-TIG31-164 was localized in a pattern similar to that observed for TIG31-164, while GFP-TIG31-134 displayed a distribution pattern similar to GFP. This suggests that the c-terminal hydrophobic domain has an important role in determining the intracellular localization of TIG3. In addition, GFP-TIG31-164 retains the ability to inhibit cell function, while GFP-TIG31-134 is inactive.

Amino Acid Sequence↗
PubMed2000

Expression of a retinoid-inducible tumor suppressor, Tazarotene-inducible gene-3, is decreased in psoriasis and skin cancer.

Tazarotene-induced gene-3 (TIG-3), isolated from human keratinocytes treated with the retinoic acid receptor-selective retinoid Tazarotene, is homologous to H-rev, a class II tumor suppressor. TIG-3 gene localized to chromosome 11q23, a site of loss of heterozygosity in several malignancies. Retinoids influence epidermal differentiation and are used to treat and prevent skin cancer. Therefore, we studied TIG-3 mRNA expression in psoriasis and in basal and SCCs by in situ hybridization and a quantitative QT-RT-PCR assay. Psoriasis lesions had significantly lower staining (median, 3) than paired normal control skin (median, 4; P = 0.012). TIG-3 mRNA was significantly higher in normal control skin (P = 0.001), in paired adjacent skin (median, 3; P = 0.007), and in overlying epidermis (median, 3.0; P = 0.0001) than in 21 SCC specimens as a group (median, 1.5).

Aged↗
PubMed2000

Management of high blood cholesterol levels in Nova Scotian adults: comparison with the NCEP II and European clinical practice guidelines.

OBJECTIVE: To compare the prevalence of dietary and drug treatment for high blood cholesterol levels with indication for treatment according to the National Cholesterol Education Program (NCEP) II and European clinical practice guidelines. STUDY DESIGN: A population-based, cross-sectional study. PATIENTS AND METHODS: Data were from the 1995 Nova Scotia Health Survey. Patients were 2078 respondents aged 20 to 74 years who provided blood samples. Based on cardiovascular risk factors, respondents were compared with guidelines to determine eligibility for dietary and antilipemic drug therapy. RESULTS: According to the NCEP II and European guidelines, 21% and 13%, respectively, of the population were estimated to be dietary therapy candidates and 12% and 4%, respectively, were estimated to be candidates for antilipemic drug therapy. Less than half of the dietary therapy candidates, according to either guideline, reported being diagnosed, and only about half of those diagnosed reported having received dietary therapy. Overall, 6% to 15% of the NCEP II drug therapy candidates and 12% to 37% of the European drug therapy candidates were estimated to be receiving antilipemic drugs. Only about 45% of the NCEP II and 60% of the European drug therapy candidates reported being diagnosed as having high blood cholesterol levels, and only about 50% of the NCEP II- and 60% of the European-diagnosed drug therapy candidates reported having received dietary therapy. The estimated prevalence of antilipemic drug therapy among diagnosed drug therapy candidates was 12% to 29% for the NCEP II and 12% to 52% for the European guidelines. CONCLUSIONS: Dietary therapy and antilipemic drug therapy were underused relative to the NCEP II and European guidelines as a result of underdiagnosis and low use of treatment after diagnosis. Large differences in the recommendations of the 2 guidelines, however, show lack of consensus as to who should be treated and point to the need for additional research on this issue.

Adult↗
PubMed1999

Structure-function analysis of tritrypticin, an antibacterial peptide of innate immune origin.

The structural requirements for the antibacterial activity of a pseudosymmetric 13-residue peptide, tritrypticin, were analyzed by combining pattern recognition in protein structures, the structure-activity knowledge-base, and circular dichroism. The structure-activity analysis, based on various deletion analogs, led to the identification of two minimal functional peptides, which by themselves exhibit adequate antibacterial activity against Escherichia coli and Salmonella typhimurium. The common features between these two peptides are that they both share an aromatic-proline-aromatic (ArProAr) sequence motif, and their sequences are retro with respect to one another. The pattern searches in protein structure data base using the ArProAr motif led to the identification of two distinct conformational clusters, namely polyproline type II and beta-turn, which correspond to the observed solution structures of the two minimal functional analogs. The role of different residues in structure and function of tritrypticin was delineated by analyzing antibacterial activity and circular dichroism spectra of various designed analogs. Three main results arise from this study. First, the ArProAr sequence motif in proteins has definitive conformational features associated with it. Second, the two minimal bioactive domains of tritrypticin have entirely different structures while having equivalent activities. Third, tritrypticin has a beta-turn conformation in solution, but the functionally relevant conformation of this gene-encoded peptide antibiotic may be an extended polyproline type II.

Amino Acid Sequence↗
PubMed1999

Retinoid-dependent recruitment of a histone H1 displacement activity by retinoic acid receptor.

Targeted recruitment of histone acetyltransferase (HAT) activities by sequence-specific transcription factors, including the retinoic acid receptors (RARs) and retinoid X receptors (RXRs), has been proposed to lead to destabilization of nucleosomal cores by acetylation of core histones. However, biochemical evidence indicates that destabilization and depletion of linker H1 histones must also occur at the promoter regions of actively transcribing genes. Mechanisms by which nuclear receptors and other transcription factors affect the removal of histone H1 from transcriptionally silent chromatin have not been previously described. In this report, we show that RARs interact in a ligand-dependent manner with HMG-I, which is known to displace histone H1 from chromatin. We further show that HMG-I and a novel related protein, HMG-R, also interact with other transcription factors. Using sense and antisense constructs of HMG-I/R in transient transfection assays with a retinoid responsive reporter, we also demonstrate that HMG-I/R is important for retinoid dependent transcriptional activity of RAR. These findings suggest a step wise mechanism by which RARs and other transcription factors can cause a targeted unfolding of compact chromatin as a first step in transcriptional activation, which would then be followed by recruitment of HAT activity and subsequent events.

Acetylation↗