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Biomedical subjects

S Venkatachalam

Publications and source records attributed to S Venkatachalam.

At least 19 recordsLinked to original sources
PubMed2004

Medical management of uterine fibroids with medroxyprogesterone acetate (Depo Provera): a pilot study.

The aim of this study was to determine the effectiveness of medroxyprogesterone acetate (Depo Provera) in the treatment of menorrhagia attributed to uterine fibroids and to determine whether it reduces fibroid volume. Twenty premenopausal women with menorrhagia attributed to uterine fibroids received Depo Provera (150 mg/month) for 6 months. Control of bleeding was assessed by menstrual diary, haematologic parameters (Hb) and uterine and fibroid size measured sonargraphically. Following a period of 6 months after the initiation of Depo Provera, 30% became amenorrhoeic, 70% noticed improvement in their bleeding pattern and 15% had an increase in their haemoglobin levels. The mean uterine and fibroid volume was also reduced by 48% and 33%, respectively. Medical therapy with Depo Provera with symptomatic fibroids causes significant improvement in bleeding pattern as well as a reduction in fibroid volume.

Adult↗
PubMed2003

Adsorption of ammonium dinitramide (ADN) from aqueous solutions. 1. Adsorption on powdered activated charcoal.

Investigations on the adsorption of ammonium dinitramide (NH(4)N(NO(2))(2)) (ADN) from aqueous solutions on powdered activated charcoal (PAC) were carried out in order to find out an effective and easier method of separating ADN from aqueous solutions. The effectiveness of PAC in the selective adsorption of ADN from aqueous solutions of ADN (ADN-F) and ADN in presence of sulfate (SO(4)(2-)) and nitrate (NO(3)(-)) ions (ADN-PS) was examined and compared using batch and column methods. The adsorption process follows both Langmuir and Freundlich adsorption isotherms and the isotherm parameters for the models were determined. The observed data favor the formation of monolayer adsorption. The adsorption capacities were found to be 63.3, 119, 105.3 and 82 mg of ADN per g of PAC for ADN-F (batch), ADN-PS (batch), ADN-F (column) and ADN-PS (column), respectively. Break-through curves for ADN-F and ADN-PS were obtained for the optimization of separation of ADN from aqueous solutions. Elution curves were generated for the desorption of ADN from PAC using hot water as eluent.

Adsorption↗
PubMed2003

Misoprostol for cervical ripening at and near term--a comparative study.

OBJECTIVE: To compare the safety and efficacy of misoprostol with that of dinoprostone for the induction of labour at term, or near term. DESIGN: Three hundred and ninety-six women with term pregnancies were randomised to receive either oral or vaginal misoprostol, or dinoprostone. Women who had had a previous caesarean section (CS) or those with a malpresentation or who were parity > or = 5, were excluded. The control group received dinoprostone 1 mg inserted in the posterior fornix and repeated 6-hourly to a maximum of three doses. The study group received either oral misoprostol 20 micrograms 2-hourly to a maximum of four doses (80 micrograms), or vaginal misoprostol 25 micrograms in the posterior fornix with a switch to the oral misoprostol regimen if there was no change in the Bishop's score or no palpable uterine contractions. RESULTS: There was no significant difference in vaginal delivery rate within 24 hours between the groups (58.1% v. 58%, p = 0.633). There were no significant differences in CS rates between the groups; however, more CSs were performed for fetal distress in the misoprostol group than in the dinoprostone group (28% v. 25%). There was a significantly higher incidence of hyperstimulation in the vaginal misoprostol group (21.4%) than in the other two groups (oral misoprostol 16.5%, dinoprostone 8.9%) (p = 0.004). The incidence of meconium staining of liquor was comparable between the groups. CONCLUSIONS: In selected women, the efficacy of misoprostol for the induction of labour at term is similar to that of dinoprostone but misoprostol is associated with a higher incidence of hyperstimulation.

Adult↗
PubMed2001

Differential regulation of IL-1beta and TNF-alpha RNA expression by MEK1 inhibitor after focal cerebral ischemia in mice.

Activation of the extracellular-signal-responsive kinase (ERK 1/2) by MAP kinase/ERK kinase (MEK1/2) following ischemia/reperfusion in the brain has been associated with cell death since inhibition of MEK1/2 provides neuroprotection in cerebral ischemia injury. Since inflammation has been implicated in ischemic brain injury, the present study investigated whether MEK1/2 modifies expression of two key inflammatory cytokines, IL-1beta and TNFalpha, that have been shown to exacerbate ischemic brain injury. A mouse model of transient cerebral ischemia was deployed to test the effect of selective MEK1/2 inhibitor (SL327) on infarct size and cytokine expression. SL327 (100 mg/kg, i.p.) administered 15 min prior to ischemia resulted in 64% reduction in infarct size over controls (n = 8, P < 0.01). Under the same condition, SL327 significantly reduced peak expression of IL-1beta mRNA (59% reduction compared to vehicle, P < 0.01, n = 4) but not TNF-alpha mRNA. A parallel reduction in IL-1beta protein (67%, P < 0.05, n = 6) was also observed using ELISA analysis. These data suggest that the neuroprotective effect of MEK1/2 inhibition may be mediated by suppression of IL-1beta. The study also demonstrates for the first time that these two cytokines are differentially regulated by kinase mediated signaling pathways.

Aminoacetonitrile↗
PubMed2001

Review of the clinical results of arthroscopic meniscal repair.

A total of 62 arthroscopic meniscal repairs (60 knees in 59 patients) over a 5-year period were evaluated retrospectively to assess outcome and to identify factors that might improve future clinical results. The overall success rate was 66.1%. Early repair within 3 months of sustaining the tear gave better results (91%) than if carried out later (58%). Suture repair alone yielded better results (78%) than meniscal arrows or a T-fix device (56%). Healing rates of atraumatic meniscus tears were much lower than for traumatic tears (42 vs. 73%). The isolated atraumatic medial meniscal tear appeared to do particularly poorly (33% healing) and may be better treated by meniscectomy.

Adolescent↗
PubMed2001

Is p53 haploinsufficient for tumor suppression? Implications for the p53+/- mouse model in carcinogenicity testing.

The p53 tumor suppressor gene has been shown to be critical in preventing cancer in humans and mice. We have generated and extensively characterized p53-deficient mice lacking one (p53+/-) or both (p53-/-) p53 alleles. The p53-deficient mice are much more susceptible to an array of different tumor types than their wild-type (p53+/+) littermates. The enhanced tumor susceptibility of the p53+/- mice has made them one of several transgenic mouse models that are being considered as substitutes for standard 2-year rodent carcinogenicity assays. In order to fully exploit this model, it will be important to understand some of the basic biological and molecular mechanisms that underlie its enhanced tumor susceptibility. With this in mind, we have explored the fate of the remaining wild-type p53 allele in spontaneously arising p53+/- tumors and have shown that over half of these tumors retain an intact, functional wild-type p53 allele. This suggests that p53 is haploinsufficient for tumor suppression and that mere reduction in p53 dosage is sufficient to promote cancer formation. To support the idea that p53 is indeed a haploinsufficient tumor suppressor, we show here that normal p53+/- cells exhibit reduced parameters of growth control and stress response compared to their p53+/- counterparts. We hypothesize that the reduced p53 dosage in the p53+/- cells provides an environment more conducive to the development of further oncogenic lesions and the initiation of a tumor. Finally, we have assessed p53 loss of heterozygosity (LOH) in carcinogen-induced p53+/- tumors and have found that some agents induce tumors that almost invariably exhibit p53 LOH, whereas other agents induce tumors that often retain the wild-type p53 allele. Our preliminary data suggest that LOH is dependent on both the mechanism of genotoxicity of the agent utilized and the tissue type targeted.

Animal Testing Alternatives↗
PubMed2000

Enhanced sensitivity to anti-benzo(a)pyrene-diol-epoxide DNA damage correlates with decreased global genomic repair attributable to abrogated p53 function in human cells.

DNA damage from exposure to environmental chemical carcinogens and failure of repair systems to eliminate these lesions from the genome are considered as the crucial initial steps in the development of various human malignancies. Many cellular proteins are known to play vital roles to overcome the effects of DNA damage. Among such proteins, p53 is known to respond to DNA damage by accumulating in the nucleus and inhibiting cell cycle progression to facilitate DNA repair and the maintenance of genomic stability. In this study, we have investigated the role of p53 protein in modulating nucleotide excision repair of anti-benzo-(a)pyrene-diol-epoxide (BPDE)-DNA adducts and related effects using human fibroblasts with normal (p53-WT) and altered p53 protein (p53Mut and p53-Null). Interestingly, irrespective of the presence or absence of p53, the anti-BPDE dose-dependent p21 protein induction response was qualitatively comparable in all of the three cell lines. However, cells with defective p53 function were deficient for the removal of anti-BPDE-DNA adducts from the overall genome compared to cells with wild-type p53 activity. Strand-specific repair analysis within the individual strands of the p53 gene revealed decreased repair of adducts from the nontranscribed strand in p53-Mut and p53-Null cells. However, the repair of the transcribed strand appeared to be identical in all of the three cell lines. Furthermore, p53-Mut and p53-Null cells were more sensitive than p53-WT cells and displayed increased levels of anti-BPDE-induced apoptosis. Thus, wild-type p53 is required for the efficient global genomic repair of anti-BPDE-induced DNA adducts from the overall genome, but not for transcription-coupled repair of actively transcribed genes. These findings indicate that inefficient DNA repair of potentially cytotoxic and mutagenic lesions from the nontranscribed strand due to the loss of p53, but not the loss of p21, function might be responsible for enhanced cytotoxicity and apoptosis in human cells upon DNA damage.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1999

Ultra-miniature headstage with 6-channel drive and vacuum-assisted micro-wire implantation for chronic recording from the neocortex.

We describe a head-stage, with precision microtranslators for the chronic placement of micro-wire electrodes in the neocortex, that minimizes compressive damage to the brain. The head-stage has a diameter of 5.8 mm and allows six electrodes, separated by 450 microm on a hexagonal grid, to be individually and continuously positioned throughout a depth of approximately 3 mm. Suction is used to transiently support the dura against a curved array of tubes that guide and stabilize the electrodes as a means to prevent compression of the neocortex as the electrodes breach the dura. With this headstage we recorded extracellular signals in a rat immediately after surgery. Single-unit waveforms at a given electrode position were stable for at least several hours in the freely behaving animal and were obtained throughout the depth of the neocortex for at least 2 months. Electrophysiological records and histological examination showed that the upper layers of the neocortex were intact and minimally damaged after the implantation.

Animals↗
PubMed1998

Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation.

Tumor suppressor genes are generally viewed as being recessive at the cellular level, so that mutation or loss of both tumor suppressor alleles is a prerequisite for tumor formation. The tumor suppressor gene, p53, is mutated in approximately 50% of human sporadic cancers and in an inherited cancer predisposition (Li-Fraumeni syndrome). We have analyzed the status of the wild-type p53 allele in tumors taken from p53-deficient heterozygous (p53+/-) mice. These mice inherit a single null p53 allele and develop tumors much earlier than those mice with two functional copies of wild-type p53. We present evidence that a high proportion of the tumors from the p53+/- mice retain an intact, functional, wild-type p53 allele. Unlike p53+/- tumors which lose their wild-type allele, the tumors which retain an intact p53 allele express p53 protein that induces apoptosis following gamma-irradiation, activates p21(WAF1/CIP1) and Mdm2 expression, represses PCNA expression (a negatively regulated target of wild-type p53), shows high levels of binding to oligonucleotides containing a wild-type p53 response element and prevents chromosomal instability as measured by comparative genomic hybridization. These results indicate that loss of both p53 alleles is not a prerequisite for tumor formation and that mere reduction in p53 levels may be sufficient to promote tumorigenesis.

Animals↗
PubMed1998

Murine tumor suppressor models.

Tumor suppressor genes have been shown to be necessary for proper maintenance of cell growth control. Inactivation of these genes in the germline of humans is linked to inherited cancer predisposition. Moreover, sporadically arising human tumors often have somatic mutations in tumor suppressor genes. During the past few years, advances in molecular and cellular biology have led to the creation of animal models that have germline mutations of various tumor suppressor genes. Such mice potentially represent important animal models for familial cancer predisposition syndromes, and the study of the tumorigenesis process has been greatly assisted by their development. Such models have also demonstrated the importance of tumor suppressor function in embryonic development. In this review, we describe mice with inactivated germline tumor suppressor genes that are genetically analogous to 10 different inherited cancer syndromes in humans. We describe the variable usefulness of the mutant mice as models for human disease.

Animals↗
PubMed1997

Coordinate reduction in cell proliferation and cell death in mouse olfactory epithelium from birth to maturity.

We investigated cell proliferation and cell death in the olfactory epithelium (OE) of mice from birth to maturity using bromodeoxyuridine and terminal deoxynucleotidyl transferase nick end labeling. We show that cell death events and proliferative activity diminish concomitantly with age in the OE. Thus, the age-dependent and coordinate diminution in cell proliferative activity and cell death events may serve to maintain the thickness of the OE as mice mature and age.

Aging↗
PubMed1997

Repair analysis of promutagenic (+)-anti-BPDE DNA adduct in transcriptionally active sequences of plasmid DNA in Escherichia coli.

The extent of formation and repair of promutagenic (+)-anti-BPDE-N2-dG in transcriptionally active thymidine kinase (tk) gene insert and vector DNA fragments was assessed in the (+)-anti-BPDE treated plasmid p220-tk within the Escherichia coli hosts of varying repair potential. Polyclonal antibody (BP1), specific for (+)-anti-BPDE DNA adduct, was utilized for quantitative estimation of this bulky lesion in nanograms amounts of membrane transblotted DNA fragments. A carcinogen dose-dependent quantitative antibody binding response, due to selective recognition of the major (+)-anti-BPDE adduct, was seen with various DNA fragments separated by gel electrophoresis. The sensitivity of the immunodetection at 0.2 fmol (+)-anti-BPDE DNA adduct, allowed a linear detection in the range of modification level of 0.64 x 10(-7) to 86 x 10(-7) adducts per nucleotide in plasmid DNA. Based on this sensitivity, detection of 0.07 and 0.46 (+)-anti-BPDE DNA adducts in respective tk and vector DNA fragments was achieved upon immunoanalysis of the in vitro modified DNA. Adduct concentration dependent antibody binding was independent of size of the vector or insert fragments. Antibody binding response, to DNA modified in vivo, was dependent upon the dose of (+/-)-anti-BPDE to plasmid DNA replicating within bacterial hosts. The repair of (+)-anti-BPDE DNA adducts was determined as the loss of antibody binding sites in the specific fragments of plasmid DNA within host E. coli. About 50% of the initial DNA damage was repaired from the individual fragments during 15 min post-incubation in the repair-proficient (wild-type) E. coli cells. Complete adduct removal occurred in approx. 60 min of post-incubation period. A significant (91%) decrease in the survival of mutant (uvrA- recA-) cells was observed at 4 microM (+/-)-anti-BPDE treatment without any reduction in the colony forming units in the wild-type cells. On the contrary, no repair was seen in the excision repair-deficient (uvrA-) E. coli cells. The results indicate (1) the selectivity of the immunological method and the unique ability of the (+)-anti-BPDE specific antibodies to monitor the direct loss of this promutagenic base lesion from the in vivo modified DNA (2) the role of host excision repair pathway in efficient removal of adducts from bacterial genome determines the survival of the bacterial cells and (3) the repair of (+)-anti-BPDE DNA adducts in episomally replicating, transcriptionally active sequences occur at a rapid rate presumably due to the ease of accessibility of repair enzymes to lesions within DNA.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1997

Modulation of (+/-)-anti-BPDE mediated p53 accumulation by inhibitors of protein kinase C and poly(ADP-ribose) polymerase.

The rapid accumulation of the p53 gene product is considered to be an important component of the cellular response to a variety of genotoxins. In order to gain insights on the biochemical pathways leading to p53 stabilization, the effect of (+/-) 7,8-dihydroxy-anti-9, 10-epoxy-7,8,9,10-tetrahydrobenzo(a)-pyrene [(+/-)-anti-BPDE] induced DNA damage on p53 protein levels was investigated in various repair-proficient and repair-deficient human cells. Brief exposure of normal human fibroblasts to 0.05-1 microM (+/-)-anti-BPDE resulted in elevated p53 protein levels as compared to the constitutive levels of control cells. The rapid induction response, detectable within a few hours, was sustained up to a period of at least 24 h. Repair-proficient and repair-deficient (XPA) human lymphoblastoid cells showed a similar response. The poly(ADP-ribose) polymerase inhibitor, 3-aminobenzamide (3-AB), diminished the p53 induction response by concomitantly decreasing the extent of (+/-)-anti-BPDE induced DNA damage in cells pretreated with the inhibitor. However, the direct involvement of poly ADP-ribosylation was also apparent as 3-AB was able to attenuate (approximately 50%) the p53 response by post-damage inhibitor treatment of the cells. Inhibition of cellular DNA replication by hydroxyurea and AraC, in the presence or absence of DNA damage, also resulted in rapid p53 accumulation in repair-deficient cells. On the contrary, inhibition of protein kinase C (PKC) by calphostin-C led to an abrogation of (+/-)-anti-BPDE mediated p53 induction. Analysis of the downstream effects of carcinogen treatment showed that the lymphoblastoid cells undergo DNA fragmentation indicative of apoptosis while fibroblasts exhibit cell cycle arrest at the G1-S boundary.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1996

Site-specific induction and repair of benzo[a]pyrene diol epoxide DNA damage in human H-ras protooncogene as revealed by restriction cleavage inhibition.

Most genotoxic DNA base modifications localized at key genomic sequences constitute the molecular alterations crucial or mutagenesis and tumorigenesis. We have utilized lesion-rendered inhibition of restriction endonuclease cleavage for the analysis of site-specific DNA damage induced by (+/-)-7,8-dihydroxy-anti-9, 10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (benzo[a]pyrene diol epoxide, anti-BPDE) in human genes. The H-ras protooncogene and insulin gene sequences were used as targets for modification in vitro and in vivo. Selective induction of individual facultative bands, resulting from covalent modification of the cognate recognition sites, was observed in modified plasmid DNA for a number of restriction nucleases. The ras gene-specific damage, at the PstI, BstYI, NotI and BstEII recognition sites, was visualized and quantitated in human genomic DNA adducted by anti-BPDE. Repair of lesions at hexanucleotide sequences and/or regions surrounding the restriction site, was assessed as a gradual disappearance of facultative bands in DNA from repair-proficient human fibroblasts exposed to the carcinogen in confluent culture. Efficiency of the PstI site-specific repair was compared at low and high levels of initial damage. Higher genotoxic dose caused a decrease in the extent of adduct removal from the bulk DNA, while the specific site of the ras gene was still subject to fast repair. No measurable PstI site-specific repair was detected in the insulin gene. These results show the region-selective induction of bulky anti-BPDE DNA damage in non-related genomic targets and suggest that repair of these lesions in human cells proceeds with the efficiency tightly controlled at different levels of initial genotoxic load.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗