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Biomedical subjects

R Singh

Publications and source records attributed to R Singh.

At least 361 records · Page 20Linked to original sources
PubMed1996

Chromosome 14 alteration is associated with increased collagenase expression and the metastatic potential of murine melanomas.

The purpose of this study was to correlate abnormalities in chromosome 14 with the invasive metastatic phenotype of K-1735 murine melanoma cells. Low metastatic K-1735 clone 10 and clone 23 cells were transfected with either basic fibroblast growth factor (bFGF), Kaposi's fibroblast growth factor (kFGF), or c-H-ras gene. A high number of bFGF- and H-ras-transfected cells exhibited chromosome 14 rearrangements. These cells also had increased expression of collagenase IV. The kFGF-transfected cells were highly metastatic but did not have increased expression of collagenase type IV. The kFGF-transfected cells were highly metastatic but did not have increased expression of collagenase type IV, nor abnormalities in chromosome 14. The data imply that karyotypic changes in chromosome 14 are associated with increase expression of collagenase type IV.

Animals↗
PubMed1996

Topical liposomal system for localized and controlled drug delivery.

A liposomal reservoir system bearing the local anesthetic, benzocaine, was developed for controlled and localized delivery via topical route. The liposomal suspension was incorporated into an ointment and gel base. The developed systems were studied for various physical and kinetic attributes in vitro. The systems delivered the drug at a controlled rate over 24 h, whereas plain drug ointment showed a rapidly decreased release rate over 24 h, with more than 92% released. The drug delivery across human cadaver skin following liposomal ointment application was noted to be considerably slow. The in vivo study revealed a longer duration of action in the case of liposomal formulations. An effort was made to study the effect of ultrasound as a reversible means to effect pulsatile delivery of the drug from the liposomal depot. The work proved the potential of liposomes as a slow release vehicle which follows apparent zero order kinetics and its use in modulating drug input via skin.

Administration, Topical↗
PubMed1996

The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy postmenopausal women participating in a randomised, controlled tamoxifen prevention study.

BACKGROUND: The role of hormone replacement therapy (HRT) in women who have been treated for breast cancer remains controversial. The addition of tamoxifen may protect these women from any proliferative effect of exogenous oestrogen on the breast. The aim of this analysis was to determine if tamoxifen and HRT may be safely administered together. METHODS: We studied the interaction between HRT and tamoxifen on serum cholesterol, fibrinogen, antithrombin III (AT III) and bone mineral density (BMD) in postmenopausal healthy women enrolled in a randomised tamoxifen chemoprevention trial. RESULTS: Tamoxifen decreased serum cholesterol by a mean of 13% from pretreatment values (n = 153). The addition of HRT to tamoxifen did not result in further reduction in serum cholesterol (n = 20). HRT alone led to a reduction of serum cholesterol by a mean of 5% in 14 women on placebo. The addition of tamoxifen to HRT resulted in further reduction in serum cholesterol by a mean of 7% (n = 44). Significant reductions of plasma fibrinogen by 14% and AT III by 8% were seen in women who received tamoxifen. There were no further significant changes in these coagulation factors in women on tamoxifen/HRT combinations. Tamoxifen resulted in an annual increase in BMD of the femur and spine by 2% and 1.5%, respectively, when compared to placebo (n = 38). The addition of HRT to tamoxifen resulted in further 2% annual increase in BMD of the femur. CONCLUSIONS: We conclude that there were no significant adverse intereactions with tamoxifen and HRT in this small series of patients. The combination results in a reduction of serum cholesterol, increase in BMD especially in the femur and appears not to have any adverse effect on coagulation factors. Multicentre studies should be conducted to evaluate the effect of this combination on relieving menopausal symptoms, disease relapse and overall survival in women who have received treatment for breast cancer.

Aged↗
PubMed1996

Arginase activity in endothelial cells: inhibition by NG-hydroxy-L-arginine during high-output NO production.

Rat aortic endothelial cells were found to contain both constitutive and lipopolysaccharide (LPS)-inducible arginase activity. Studies were performed to determine whether induction of nitric oxide synthase (NOS) by LPS and cytokines is accompanied by sufficient arginase induction to render arginine concentrations rate limiting for high-output NO production. Unactivated cells contained abundant arginase activity accompanied by continuous urea formation. LPS induced the formation of both inducible NOS (iNOS) and arginase, and this was accompanied by increased production of NO, citrulline, and urea. Immunoprecipitation experiments revealed the constitutive presence of arginase-I in both unactivated and LPS-activated cells and arginase-II induction by LPS. Arginase-I and iNOS were verified by reverse transcriptase-polymerase chain reaction. Induction of large amounts of iNOS by LPS plus several cytokines resulted in large quantities of NO, citrulline, and NG-hydroxy-L-arginine (NOHA), but urea production was markedly diminished. Decreased urea production was attributed to increased formation of NOHA, the precursor to NO and citrulline and a potent inhibitor of arginase-I activity with an inhibitory constant of 10-12 microM. Inhibition of iNOS activity by NG-methyl-L-arginine decreased NO and NOHA production and increased urea production. This study reveals for the first time that substantial arginase activity is present constitutively in rat aortic endothelial cells, a different isoform of arginase is induced by LPS, and intracellular arginase activity can be markedly inhibited during cytokine induction of iNOS because of NOHA formation. The inhibition of arginase activity that occurs by NOHA during marked iNOS induction may be a mechanism to ensure sufficient arginine availability for high-output production of NO.

Animals↗
PubMed1996

Antifertility potential of 2-[piperdinoethoxyphenyl]-3-[4- methoxyphenyl]-2H benzopyran: a potent anti-oestrogenic compound in rats.

The present study was carried out to investigate the artifertility potential of 2-[piperdinoethoxyphenyl]-3-[4-methoxyphenyl]-2H benzopyran (K-7) in rats. A single oral administration of 250 micrograms K-7 kg-1 body mass after coitus prevented pregnancy in rats. The minimum effective dose in rats given K-7 orally for 1-4 days after coitus was 100 micrograms kg-1 body mass. K-7 had weak oestrogenicity in ovariectomized immature rats but had no androgenic or anti-gonadotrophic activity. Studies in vivo showed that K-7 was a potent anti-oestrogenic compound and that at 100 micrograms kg-1 it could mitigate the effect of 1.0 microgram oestradiol. On the basis of the above results, K-7 appeared to exert its antifertility action(s) by its weak oestrogenic and its strong anti-oestrogenic activity. The anti-oestrogenic activity of K-7 was substantiated further by performing studies on the competition of K-7 for binding of [3H]oestradiol to rat uterine oestrogen receptors. A high affinity for binding to oestrogen receptors was displayed by K-7, with a relative binding affinity of 71%. These findings show that K-7 is an effective anti-oestrogenic compound and is a potent antifertility agent.

Animals↗
PubMed1996

A triphasic oral contraceptive pill, CTR-05: clinical efficacy and safety.

OBJECTIVE: The primary objective of this study was to compare the safety, contraceptive efficacy, and menstrual cycle patterns in women using triphasic oral contraceptive pills, namely CTR-05, containing 50/100/150 micrograms desogestrel and 35/30/30 micrograms ethinylestradiol, and Orthonovum777 containing 500/750/1000 micrograms norethindrone and 35/35/35 micrograms ethinylestradiol. METHOD: Forty-six female volunteers, satisfying the selection criteria, were evaluated for six cycles, in an open-label, randomized study. Volunteers using CTR-05 were studied for 13 additional cycles for efficacy and safety. RESULTS: No serious adverse effects were observed in either group. The incidences of other drug-related adverse effects, such as headache and nausea, were transient in both groups. CTR-05 did not lower levels of high density lipoprotein (HDL) cholesterol. This may be attributed to the lower androgenicity of its progestin component, desogestrel. No pregnancies were reported in either group. Clinical and laboratory parameters remained within normal limits in both groups. In the CTR-05 group, the lower dose of ethinylestradiol did not affect the safety, efficacy and acceptability of the product. CONCLUSION: Desogestrel, with little estrogenic activity and only minimal androgenic activity, leads to lipoprotein changes, resulting in a favorable cardiovascular profile, as well as minimal androgen-related effects, such as hirsutism and acne.

Adult↗
PubMed1996

Effect of captopril on serum angiotensin converting enzyme and blood pressure in hypertensive patients.

The effect of chronic captopril therapy on serum angiotensin converting enzyme (ACE) was studied in 30 patients with essential hypertension. Patients were assessed for serum ACE levels serially every week for 4 weeks. Thirty healthy individuals served as controls. The basal serum ACE level among hypertensives (57.4 +/- 37.2 u/l) was found to be significantly higher (p < 0.001) than the controls (33.3 +/- 8.8 u/l). One week after starting captopril therapy, serum ACE levels fell to almost half the basal values (p < 0.001). However, thereafter, it rose to levels higher than the basal level even though the blood pressure remained well controlled. Our study suggests that besides its action on ACE, captopril may lower the blood pressure by other mechanisms as well.

Adult↗
PubMed1996

Sex influences on the penetrance of HLA shared-epitope genotypes for rheumatoid arthritis.

The association between rheumatoid arthritis (RA) and HLA DRB1 alleles may arise through linkage disequilibrium with a disease locus or the direct involvement of HLA alleles in RA. In support of the latter possibility, the shared-epitope hypothesis has been postulated, stating that conformationally similar DR beta chains encoded by several DRB1 alleles confer disease susceptibility. To examine these alternative hypotheses of marker-disease association and to investigate gender differences in RA susceptibility, we analyzed the distributions of PCR-based DRB1 genotypes of 309 Caucasian RA patients and 283 Caucasian controls. Initially, the marker-association-segregation chi 2 method was used to evaluate evidence for linkage disequilibrium and the direct involvement of markers DR4 Dw4, DR4 Dw14, and DR1 in RA susceptibility. Additional shared-epitope models that grouped DRB1 alleles into five classes (*0401, *0404/*0102, *0405/*0408/*0101, *1001, and all others) and postulated relationships between genotypes and RA susceptibility were also fitted to observed genotypic distributions by the method of minimal chi 2. For females, a linkage-disequilibrium model provided a good fit to the data, as did a shared-epitope model with RA most penetrant among individuals with the *0401,*0401 genotype. For males, the best model indicated highest RA penetrance among shared-epitope compound heterozygotes. Clinically, male RA patients had more subcutaneous nodules and greater use of slowly acting antirheumatic drugs, while female RA patients had earlier disease onset. This study therefore suggests that sex-related factors influence the RA penetrance associated with DRB1 shared-epitope genotypes and that DRB1 effects on RA prognosis and pathogenesis should be considered separately for men and women.

Alleles↗
PubMed1996

Molecular basis of phenylketonuria and a correlation between genotype and phenotype in a heterogeneous southeastern US population.

OBJECTIVE: To determine the molecular basis of phenylketonuria (PKU) and related hyperphenylalaninemia (HPA) and to establish correlations between phenylalanine hydroxylase (PAH) genotypes and biochemical and clinical phenotypes in an ethnically diverse US population, PAH genotypes were determined in 35 patients with PKU or HPA and 1 carrier from the Medical Genetics Clinic of the Emory University School of Medicine. METHODOLOGY: Patients were identified through Georgia's population-based newborn screening program. PAH genotypes in these individuals were determined from dried blood spots or whole-blood samples using a combination of polymerase chain reaction-mediated amplification, denaturing gradient gel electrophoresis, and direct-sequence analysis. The phenotypic severity of patients with PKU and HPA was based on pretreatment serum phenylalanine (PHE) levels during the neonatal period and on dietary tolerance of PHE later in life. RESULTS: Sixty-eight (96%) of 71 mutant alleles were identified. Major mutations in this population included R408W (11 of 71), I65T (11 of 71), Y414C (6 of 71), L348V (4 of 71), and IVS10 (4 of 71). Five new nucleotide substitutions, E76A (1 of 71), R241L (1 of 71), Q304R (2 of 71), C334S (1 of 71), and R400R (2 of 71) were also detected. Thirty-two of the thirty-five nonrelated patients examined in this study were completely genotyped. Strong correlations were observed between the level of PAH activity predicted from the genotype, when known from previous in vitro expression studies of the mutant proteins, and pretreatment serum PHE levels (r = .841) or clinical severity (Kendall rank-order correlation coefficient, .936). CONCLUSIONS: These results demonstrate strong correlations between PAH genotype and biochemical and clinical phenotypes in this heterogeneous American sample population, extending our previous findings from relatively homogeneous European populations. These correlations further demonstrate the clinical utility of genotype analysis in the treatment of patients with PKU and HPA.

Alleles↗
PubMed1996

Luminescent oxygen channeling assay (LOCI): sensitive, broadly applicable homogeneous immunoassay method.

Luminescent oxygen channeling assay (LOCI) is a homogeneous immunoassay method capable of rapid, quantitative determination of a wide range of analytes--including high and very low concentrations of large and small molecules, free (unbound) drugs, DNA, and specific IgM. Assays have been carried out in serum and in lysed blood. Reliable detection of 1.25 microU/L thyrotropin (TSH) and 5 ng/L hepatitis B surface antigen (HBsAg) corresponds to detection limits approximately 3- and approximately 20-fold lower, respectively, than those of the best commercially available assays. An assay of chorionic gonadotropin is capable of quantification over a 10(6)-fold range of concentrations without a biphasic response. Latex particle pairs are formed in the assay through specific binding interactions by sequentially combining the sample and two reagents. One particle contains a photosensitizer, the other a chemiluminescer. Irradiation causes photosensitized formation of singlet oxygen, which migrates to a bound particle and activates the chemiluminescer, thereby initiating a delayed luminescence emission. Assay times range from 1 to 25 min.

Antigens, Viral↗
PubMed1996

B lymphocytic clonal expansion in rheumatoid arthritis.

OBJECTIVE: To learn whether rheumatoid factor (RF), HLA-DR4, or current therapy influences clonal expansion of B lymphocytes (B cells) in persons with rheumatoid arthritis (RA). METHODS: We measured clonal expansion by analysis of cell surface staining for immunoglobulin light chains. Double staining methods detected a B cell marker (CD19) plus either kappa or lambda on peripheral blood lymphocytes from subjects with RA (n = 26) and controls (n = 26). The difference between frequency histograms of surface kappa and lambda staining was determined by the Kolmogorov-Smirnov statistic D that represents the fraction of clonally expanded B cells. RESULTS: The mean D value in RA was over 50% higher than in the controls [0.225 +/- SD 0.155 versus 0.144 +/- 0.025 (p < 0.0001)]. Ten subjects with RA had values exceeding +2 SD for controls (p = 0.0007). Mean D correlated with RF titer (Spearman's rank correlation coefficient rSp + 0.53, p = 0.006). All 10 high D values were found in the RA subgroups with positive serum tests for RF and with the HLA-DR4 positive genotype. The channel of maximal difference between kappa and lambda staining was higher in the RA group than in controls, showing that clonal expansion was most marked among brightly staining cells. Patients with RA currently receiving low dose methotrexate (MTX) tended to have higher D values than those not receiving MTX (mean 0.29 versus 0.18, respectively, p < 0.025). The RA group currently receiving MTX had a higher frequency of abnormal D values (7 of 11 versus 3 of 15 not currently receiving MTX, p = 0.03). This probably reflects preferential use of MTX for severely affected individuals. Confirmatory studies to detect clonal immunoglobulin gene rearrangements were attempted in selected individuals with high D values, but none was demonstrated in total leukocytic or B cell enriched fractions. CONCLUSION: Findings consistent with B cell clonal expansion occur in about 40% of persons with RA, particularly in the subgroups with positive serum tests for RF and with the HLA-DR4 genotype. However, the clonal expansion level must be below the sensitivity of confirmatory methods.

Adult↗
PubMed1996

In vitro antifilarial activity of Sencio nudicaulis Buch. Ham. Effect on Setaria cervi (Nematoda Filarioidea).

The effect on aqueous and alcoholic extracts of the leaves of Sencio nudicaulis Buch. Ham. was studied on the spontaneous movements of the whole worm and nerve-muscle preparation of Setaria cervi and on the survival of micro-filariae in vitro. Aqueous as well as alcoholic extracts caused inhibition of spontaneous motility of the whole worm and nerve-muscle preparation of S. cervi characterized by decreased amplitude, rate and tone of contractions. The concentration required to inhibit the movements of n.m. preparation was 1/3rd for aqueous and 1/20th for alcoholic extract suggesting a cuticular permeability barrier. The effect of S nudicaulis extracts was different than that produced by calcium channel blocker nifedipine on the whole worm and n.m. preparation. While nifedipine blocks the stimulant effect of Ach the extracts of S. nudicaulis fails to do so. While the response bears similarity with DEC which also does not block Ach response. Both aqueous and alcoholic extracts exhibited microfilaricidal action in vitro LC50 and LC90 being 10 and 15 ng/ml for aqueous extract, 5 and 12 ng/ml for alcoholic extract.

Animals↗
PubMed1996

Age-related decline in multiple unit action potentials of cerebral cortex correlates with the number of lipofuscin-containing neurons.

The present study examined whether there is any obvious correlation between the density of lipofuscin-containing neurons and the spontaneous neuronal action potentials (Multiple Unit Activity, MUA) in the parietal cortex of the aging rat brain. The results showed that MUA counts were decreased with age while the number of lipofuscin-containing neurons was increased. The cortex with the highest percentage of lipofuscin-containing neurons had the lowest MUA counts while the cortex with the lowest percentage of lipofuscin-containing neurons had the highest MUA counts. The inverse correlation between MUA and lipofuscin-containing neuron number was also evident when the population of the lipofuscin-containing neurons was pharmacologically altered in vivo by the administration of anti-lipofuscin drug centrophenoxine. The inverse relationship between MUA and the lipofuscin-containing neuron numbers is consistent with: (i) the correlations of MUA with age-related changes in lipid peroxidation and biochemically measured lipofuscin concentration, and (ii) the oxidative stress-induced impairments of neuronal electrophysiology.

Action Potentials↗