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D Bhatnagar

Publications and source records attributed to D Bhatnagar.

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

An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia.

BACKGROUND: Omega-3 fatty acids, such as those present in fish oil, have been reported to prolong life in myocardial infarction survivors. These fatty acids can decrease serum triglyceride concentrations, but so far the doses used in trials examining their effects on coronary end points have had only minimal triglyceride lowering effects. OBJECTIVE: To examine the triglyceride lowering effectiveness, safety, and tolerability of Omacor, a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil (84% of the total as opposed to an average of 35% in fish oil) over one year in patients with established coronary heart disease (CHD) and persisting hypertriglyceridaemia, despite receiving simvastatin in doses similar to those employed in the Scandinavian simvastatin survival study. SUBJECTS AND METHODS: 59 patients with CHD, receiving simvastatin 10-40 mg daily with serum triglycerides > 2.3 mmol/l, were randomised to receive Omacor 2 g twice a day or placebo for 24 weeks in a double blind trial. Forty six patients accepted the offer of active treatment for a further 24 weeks in an open phase of the trial. RESULTS: There was a sustained significant decrease in serum triglycerides by 20-30% (p < 0.005) and in very low density lipoprotein (VLDL) cholesterol by 30-40% (p < 0.005) in patients receiving active Omacor at three, six, and 12 months compared either to baseline or placebo. Omacor did not have any deleterious effect on low density or high density lipoprotein cholesterol or on biochemical and haematological safety tests. There was no adverse effect on glycaemic control in patients with diabetes, who showed a decrease in serum triglyceride, which was at least as great as in non-diabetic patients. One patient receiving placebo died of acute myocardial infarction. Three patients withdrew from the trial (two on placebo and one on active treatment). Omacor was generally well tolerated. CONCLUSION: Omacor was found to be a safe and effective means of lowering serum triglycerides over one year in patients with CHD and combined hyperlipidaemia, whose triglycerides remained elevated despite simvastatin treatment.

Adult↗
PubMed2001

The role of APACHE-II triaging in optimum management of small bowel perforations.

Small bowel perforations with peritonitis pose a serious problem to an emergency surgeon because of the lack of any uniformity of opinion regarding the optimum surgical treatment to be performed. This may be attributed to lack of any common and reliable scoring system. A prospective study to discover the utility of APACHE-II triaging in small bowel perforations was conducted over a period of 14 months on 51 patients with small bowel perforations of various aetiologies. The triaging facilitated definitive surgical treatments based on the predictive value of APACHE-II scoring. The classification of patients into three groups, effectively brought uniformity in the management. A significant reduction in mortality and cost-effective utilization of scarce intensive care unit resources were the dominant outcomes of this study conducted at a busy tertiary centre.

APACHE↗
PubMed2001

Fine needle aspiration cytology, histology and MIB-1 proliferative index in a case of dyshormonogenetic goitre.

The fine needle aspiration (FNA) cytologic findings along with histology and MIB-1 proliferative index in a case of dyshormonogenetic goitre is presented. A 12-year old female child from non-endemic zone presented with a isotopically cold solitary thyroid nodule with a history of goitre being present since birth. Past history of any neck irradiation or maternal ingestion of any goitrogen during the antenatal period and family history of goitre were negative. FNA cytology revealed an extremely cellular preparation with predominantly microfollicular pattern without colloid. Nuclei were round to oval, slightly enlarged with evenly distributed chromatin and inconspicuous nucleoli. Larger tissue fragments also showed foci of solid cell groups with nuclear crowding, overlapping and loss of polarity in addition to the prevalent microfollicular pattern. Occasional tissue fragments showed solid groups of trapped follicular epithelial cells in the matrix of fibrocollagenous tissue. Histology showed an intensely hyperplastic follicular cells with nodule formation, irregular fibrosis, pseudo capsular or vascular wall invasion mimicking malignancy. Immunohistochemistry for calcitonin was negative but thyroglobulin was positive. MIB-1 (Ki-67) proliferation index varied from 0.05 to 0.26 (mean 0.13) in the hyperplastic nodules versus 0.9 to 2.1 (mean 1.34) in the hyperplastic solid microfoci scattered amidst the grossly normal appearing thyroid tissue. The possible cytologic diagnostic pitfalls in favor of follicular neoplasm is discussed.

Antigens, Nuclear↗
PubMed2000

Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia.

OBJECTIVES: To assess the feasibility of detecting new cases of heterozygous familial hypercholesterolaemia by using a nurse led genetic register. DESIGN: Case finding among relatives of patients with familial hypercholesterolaemia. SETTING: Two lipid clinics in central and south Manchester. SUBJECTS: 259 (137 men and 122 women) probands and 285 first degree relatives. RESULTS: Of the 200 first degree relatives tested, 121 (60%) had inherited familial hypercholesterolaemia. The newly diagnosed patients were younger than the probands and were generally detected before they had clinically overt atherosclerosis. Concentrations of serum cholesterol were, respectively, 8.4 (1.7 SD) mmol/l and 8.1 (1.9 SD) mmol/l in affected men and women and 5.6 (1.0 SD) mmol/l and 5.6 (1.1 SD) mmol/l in unaffected men and women. Screening for risk factors as recommended in recent guidelines for coronary heart disease prevention would have failed to identify most of the affected relatives in whom hypertension, diabetes mellitus, cigarette smoking, and obesity were uncommon. CONCLUSIONS: By performing cholesterol tests on 200 relatives, 121 new patients with familial hypercholesterolaemia were discovered. Because 1 in 500 people in the United Kingdom are affected by this condition, to detect a similar number by population screening over 60 000 tests would be required, and only a few of these patients would have been detected had cholesterol testing been restricted to those with other risk factors for coronary heart disease. A case exists for organising a genetic register approach, linking lipid clinics nationally.

Adolescent↗
PubMed2000

Cloning of a sugar utilization gene cluster in Aspergillus parasiticus.

At one end of the 70 kb aflatoxin biosynthetic pathway gene cluster in Aspergillus parasiticus and Aspergillus flavus reported earlier, we have cloned a group of four genes that constitute a well-defined gene cluster related to sugar utilization in A. parasiticus: (1) sugR, (2) hxtA, (3) glcA and (4) nadA. No similar well-defined sugar gene cluster has been reported so far in any other related Aspergillus species such as A. flavus, A. nidulans, A. sojae, A. niger, A. oryzae and A. fumigatus. The expression of the hxtA gene, encoding a hexose transporter protein, was found to be concurrent with the aflatoxin pathway cluster genes, in aflatoxin-conducive medium. This is significant since a close linkage between the two gene clusters could potentially explain the induction of aflatoxin biosynthesis by simple sugars such as glucose or sucrose.

Aflatoxins↗
PubMed2000

Cloning and characterization of avfA and omtB genes involved in aflatoxin biosynthesis in three Aspergillus species.

The biosynthesis of aflatoxins (B(1), G(1), B(2), and G(2)) is a multi-enzyme process controlled genetically by over 20 genes. In this study, we report the identification and characterization of the avfA gene, which was found to be involved in the conversion of averufin (AVF) to versiconal hemiacetal acetate (VHA), in Aspergillus parasiticus and A. flavus; a copy of avfA gene was also cloned from a non-aflatoxin producing strain A. sojae. Complementation of an averufin-accumulating, non-aflatoxigenic mutant strain of A. parasiticus, SRRC 165, with the avfA gene cloned from A. flavus, restored the ability of the mutant to convert AVF to VHA and to produce aflatoxins B(1), G(1), B(2), and G(2). Sequence analysis revealed that a single amino acid replacement from aspartic acid to asparagine disabled the function of the enzyme in the mutant strain SRRC 165. The A. parasiticus avfA was identified to be a homolog of previously sequenced, but functionally unassigned transcript, stcO, in A. nidulans based on sequence homology at both nucleotide (57%) and amino acid (55%) levels. In addition to avfA, another aflatoxin pathway gene, omtB, encoding for an O-methyltransferase involved in the conversion of demethylsterigmatocystin (DMST) to sterigmatocystin (ST) and dihydrodemethylsterigmatocystin (DHDMST) to dihydrosterigmatocystin (DHST), was cloned from A. parasiticus, A. flavus, and A. sojae. The omtB gene was found to be highly homologous to stcP from A. nidulans, which has been reported earlier to be involved in a similar enzymatic step for the sterigmatocystin formation in that species. RT-PCR data demonstrated that both the avfA and avfA1 as well as omtB genes in A. parasiticus were expressed only in the aflatoxin-conducive medium. An analysis of the degrees of homology for the two reported genes between the Aspergillus species A. parasiticus, A. flavus, A. nidulans and A. sojae was conducted.

Aflatoxins↗
PubMed2000

Characterization of the Aspergillus parasiticus major nitrogen regulatory gene, areA.

The major nitrogen regulatory gene, areA, was cloned from Aspergillus parasiticus. It encoded a polypeptide of 864 amino acids which contained a nuclear localization signal (NLS), a highly acidic region from positions 497 to 542, a Cys-X(2)-Cys-X(17)-Cys-X(2)-Cys DNA-binding motif and a conserved carboxy-terminus. Electrophoretic mobility shift assays suggested that the A. parasiticus AREA DNA-binding domain fusion protein bound cooperatively to single GATA elements in the A. parasiticus niaD-niiA intergenic region. AREA also bound to the aflR-aflJ intergenic region of the aflatoxin biosynthesis gene cluster. Regions of areA were fused to a yeast GAL4 DNA-binding domain coding region to localize putative transcription activation domain(s) of AREA based on activation of the GAL1(p)::lacZ reporter gene expression. The portion between NLS and the acidic domain demonstrated 16-20-fold higher activation activities than other portions of AREA, which suggests that the transcription activation domain is located in this region.

Aspergillus↗
PubMed2000

Generation of aflR disruption mutants of Aspergillus parasiticus.

The aflR gene of Aspergillus parasiticus and A. flavus encodes a binuclear zinc-finger, DNA-binding protein, AflR, responsible for activating the transcription of all known aflatoxin biosynthetic genes including itself. Studies to determine how environmental and nutritional factors affect aflR expression and hence aflatoxin production in A. parasiticus have been difficult to perform due to the lack of aflR "knockout" mutants. Transformation of an O-methylsterigmatocystin (OMST)-accumulating strain of A. parasiticus with an aflR-niaD gene disruption vector resulted in clones harboring a recombinationally inactivated aflR gene which no longer produced OMST or aflR transcript. By transformation of this aflR disruptant strain with constructs containing mutated versions of the aflR promoter, we identified three cis-acting sites that were necessary for aflR function: an AflR-binding site, a PacC-binding site, and a G + A-rich site near the transcription start site of aflR.

Aflatoxins↗
PubMed2000

Genes encoding cytochrome P450 and monooxygenase enzymes define one end of the aflatoxin pathway gene cluster in Aspergillus parasiticus.

The identification of overlapping cosmids resulted in the discovery of the aflatoxin biosynthetic pathway gene cluster in Aspergillus flavus and A. parasiticus. This finding led to the cloning and characterization of one regulatory and 16 structural genes involved in aflatoxin biosynthesis, including the most recent report on the gene, ordA, which has been identified to be involved in the formation of four aflatoxins (B1, B2, G1 and G2). However, these genes do not account for all the identified chemical/biochemical steps in aflatoxin synthesis and efforts are underway to identify the genes controlling the other steps. We are also attempting to define the outer boundaries of the aflatoxin pathway gene cluster in the Aspergillus genome. For this goal, we extended sequencing in both directions from the existing (60 kb) aflatoxin pathway gene cluster, beyond the pksA gene at one end and the omtA gene at the other. Within the 25-kb genomic DNA sequence determined at the omtA end of the cluster, several new gene sequences were identified. The recently reported genes, vbs and ordA, were found within this 25-kb region. Two additional genes were also found in this region, a cytochrome P450 monooxygenase encoding gene, tentatively named cypX, and a monooxygenase encoding gene, tentatively named moxY, and these are also reported in this study. The sequence beyond these genes showed a 5-kb non-coding region of DNA followed by the presence of a cluster of genes probably involved in sugar metabolism. Northern blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) studies demonstrated that the genes, cypX and moxY, are expressed concurrently with genes involved in aflatoxin biosynthesis. Therefore, the two putative aflatoxin pathway genes cypX and moxY followed by a 5-kb non-coding region of DNA define one end of the boundary of the aflatoxin pathway gene cluster in A. parasiticus.

Aflatoxins↗
PubMed2000

The significance of CD105, TGFbeta and CD105/TGFbeta complexes in coronary artery disease.

We have quantified levels of CD105, its ligand TGFbeta and receptor-ligand complexes in sera from healthy individuals (n=31), patients with triple vessel disease documented by coronary angiography (TVD; n=36) and patients with chest pain and a positive exercise electrocardiogram but with normal coronary angiogram (NCA; n=30). Both active TGFbeta1 and active plus acid-activatable TGFbeta1 [(a+l)TGFbeta1] were significantly depressed in patients with TVD compared with the other two groups (P</=0.04). CD105 levels in TVD patients were also diminished but elevated in NCA patients. In contrast, patients with TVD had more CD105/TGFbeta1 complex in their sera than the other two groups, suggesting that this may be the reason why TVD patients had low levels of receptor and ligand. TGFbeta3 levels were similar in the three groups, but elevated CD105/TGFbeta3 levels were noted in patients with NCA compared with those with TVD and healthy individuals (P< or =0.02). CD105 was correlated with both active TGFbeta1 and (a+l)TGFbeta1 (P=0.02). CD105 also strongly correlated with TGFbeta3 and CD105/TGFbeta3 complexes (P=0.001 in both cases). The changes in levels of CD105, TGFbeta1 and the receptor-ligand complexes in sera of patients with atherosclerosis suggest that these molecules may be important in the pathobiology of the atherosclerotic disease. Further studies on sequential samples from a larger cohort of patients are needed to define a causal relationship between these molecules and the disease progression.

Aged↗
PubMed2000

Effects of volatile aldehydes from Aspergillus-resistant varieties of corn on Aspergillus parasiticus growth and aflatoxin biosynthesis.

The fungi Aspergillus flavus and Aspergillus parasiticus produce a potent class of hepatocarcinogens known as aflatoxins. Corn-derived volatile compounds have been previously found to affect growth and aflatoxin production in A. flavus. In this study, the effects on A. parasiticus of three corn-derived volatile compounds, n-decyl aldehyde, hexanal and octanal, were measured. These three compounds were previously found to be variably expressed in five Aspergillus-resistant maize strains and three susceptible strains. In this study, A. parasiticus radial growth was restricted least by n-decyl aldehyde and most by octanal. Treatments of 100 microl of both hexanal and octanal were found to completely inhibit radial growth of the fungus using an agar plate assay method. While the volatile compound n-decyl aldehyde had less of an effect on radial growth than the other volatiles, the n-decyl aldehyde treated colonies had a predominance of uniquely aerial hyphae. These colony structures were found to have more complex hyphae and significantly fewer conidiophores than the control and other aldehyde treatments. Furthermore, aflatoxin production by the fungus was reduced by n-decyl aldehyde and hexanal, but was stimulated by octanal. The results presented here indicate that all three volatile compounds reduce radial growth but only n-decyl aldehyde significantly inhibits aflatoxin biosynthesis in A. parasiticus.

Aflatoxins↗
PubMed2000

adhA in Aspergillus parasiticus is involved in conversion of 5'-hydroxyaverantin to averufin.

Two routes for the conversion of 5'-hydroxyaverantin (HAVN) to averufin (AVF) in the synthesis of aflatoxin have been proposed. One involves the dehydration of HAVN to the lactone averufanin (AVNN), which is then oxidized to AVF. Another requires dehydrogenation of HAVN to 5'-ketoaverantin, the open-chain form of AVF, which then cyclizes spontaneously to AVF. We isolated a gene, adhA, from the aflatoxin gene cluster of Aspergillus parasiticus SU-1. The deduced ADHA amino acid sequence contained two conserved motifs found in short-chain alcohol dehydrogenases-a glycine-rich loop (GXXXGXG) that is necessary for interaction with NAD(+)-NADP(+), and the motif YXXXK, which is found at the active site. A. parasiticus SU-1, which produces aflatoxins, has two copies of adhA (adhA1), whereas A. parasiticus SRRC 2043, a strain that accumulates O-methylsterigmatocystin (OMST), has only one copy. Disruption of adhA in SRRC 2043 resulted in a strain that accumulates predominantly HAVN. This result suggests that ADHA is involved in the dehydrogenation of HAVN to AVF. Those adhA disruptants that still made small amounts of OMST also accumulated other metabolites, including AVNN, after prolonged culture.

Alcohol Dehydrogenase↗
PubMed2000

Lipid peroxidation and antioxidant enzymes in isoproterenol induced oxidative stress in rat erythrocytes.

Isoproterenol, upon oxidation, produces quinones which react with oxygen to produce superoxide anions (O2.-) and H2O2. In the present study, isoproterenol was administered to rats in two doses so as to evaluate its beta adrenergic and toxicological action in terms of lipid peroxidation (LPO) and antioxidant enzymes in erythrocytes. Isoproterenol (30 mg/100 g body wt.) was administered to rats and the animals were followed up to 7 days after administration. Some of these animals were treated with a second dose of isoproterenol 24 h after the first dose and the animals were followed up to 12 h. The result showed increased lipid peroxidation (LPO) and superoxide dismutase (SOD) activity in erythrocytes in response to isoproterenol. Catalase (CAT) activity in erythrocytes decreased with isoproterenol between day 2-7 as compared to control. The second injection of isoproterenol showed increased CAT activity in erythrocytes which decreased at 12 h as compared to control. The erythrocyte GSH content and glutathione-S-transferase (GST) activity decreased with isoproterenol treatment as compared to control. However, erythrocyte GSH content as well as GST activity both recovered towards control with time. Elevated serum lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and glutamate oxaloacetate transaminase (GOT) activity was observed after isoproterenol treatment. The results show increased LPO and altered antioxidant system in erythrocytes in response to isoproterenol induced oxidative stress.

Adrenergic beta-Agonists↗
PubMed2000

Hepatic and renal oxidative stress in acute toxicity of N-nitrosodiethylamine in rats.

Nitrosoamines such as N-nitrosodiethylamine (NDEA) produce oxidative stress due to generation of reactive oxygen species and may alter antioxidant defence system in the tissues. NDEA was administered ip as a single dose to rats in LD50 or in lower amounts and the animals were sacrificed after 0-48 hr of treatment. The results showed that lipid peroxidation in liver increased, however no significant increase in kidney LPO was observed after NDEA administration. Superoxide dismutase (SOD) and glutathione reductase (GSH-R) activity increased in liver, however, catalase (CAT) activity in liver was inhibited in NDEA treated rats. Kidney showed an increase in SOD activity after an initial decrease along with increase in GSH-R activity in NDEA treated rats. However, kidney CAT activity was not significantly altered in NDEA intoxicated rats. Serum transaminases, serum alkaline phosphatase blood urea nitrogen, serum creatinine and scrum proteins were elevated in NDEA treated rats. The results indicate NDEA-induced oxidative stress and alteration in antioxidant enzymes in liver and kidney to neutralise oxidative stress.

Alkylating Agents↗
PubMed1999

Lipid peroxidative damage on pyrethroid exposure and alterations in antioxidant status in rat erythrocytes: a possible involvement of reactive oxygen species.

Pyrethroid pesticides are used preferably over organochlorines and organophosphates due to their high effectiveness, low toxicity to non-target organisms and easy biodegradibility. However, it is possible that during the pyrethroid metabolism, there is generation of reactive oxygen species (ROS) and pyrethroids may produce oxidative stress in intoxicated rats. The present study was therefore, undertaken to determine pyrethroid-induced lipid peroxidation (LPO) and to show whether pyrethroid intoxication alters the antioxidant system in erythrocytes. A single dose of cypermethrin and/or fenvalerate (0.001% LD50) was administered orally to rats and the animals were sacrificed at 0, 1, 3, 7 and 14 days of treatment. The results showed that lipid peroxidation (LPO) in erythrocytes increased within 3 days of pyrethroid treatment. The increased oxidative stress resulted in an increase in the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT). The increase in reduced glutathione (GSH) content in erythrocytes may probably be an initial adaptive response to increased oxidative stress in pyrethroid intoxicated rats. Erythrocytes and serum acetylcholinesterase (AChE) activity was measured in pyrethroid-induced oxidative stress as it may mimic inhibition in target tissues such as muscle and brain. The inhibition in erythrocytes and serum AChE activity was partially relieved over a period of time indicating recovery from pyrethroid intoxication. The increase in erythrocyte LPO correlated with the inhibition in erythrocyte AChE activity and so erythrocyte AChE can be a marker enzyme in pyrethroid toxicity. The results show oxidative stress and alteration in antioxidant enzymes in erythrocytes of pyrethroid intoxicated rats.

Acetylcholinesterase↗
PubMed1999

Indications for cholesterol-lowering medication: comparison of risk-assessment methods.

BACKGROUND: Recommendations for the prescription of lipid-lowering drugs emphasise the importance of an assessment of absolute coronary heart disease (CHD) risk based on all risk factors, rather than simply the serum cholesterol concentration. If, however, the methods recommended for risk assessment are inaccurate, recommended prescribing will not occur. We compared several sets of guidelines for such treatment in a series of patients referred to a lipid clinic, to assess the difference in degree of risk of CHD at which lipid-lowering medication is recommended by each set of guidelines. METHODS: For a series of 570 patients (50% men) without pre-existing clinical evidence of atherosclerosis referred to a lipid clinic, we compared the algorithms, charts, and tables used by the US National Cholesterol Education Program (NCEP), the joint guidelines of the European Society of Cardiology, the European Atherosclerosis Society, and the European Society of Hypertension, and the report of the UK Standing Medical Advisory Committee with the Framingham risk equation programmed into a computer. FINDINGS: In 386 patients for whom the NCEP and UK guidelines could be compared, 62% of the men and 72% of the women met NCEP criteria for lipid-lowering medication, whereas only 9% of the men and less than 1% of the women met the UK criteria. The Framingham equation estimated a CHD risk of more than 3% per year in 22% of the men and 7% of the women, which shows that the UK tables underestimated CHD risk. European guidelines could be applied to only 261 patients, and were reasonably accurate in assessment of a CHD risk of 2% per year. INTERPRETATION: Guidelines for the use of statin treatment in patients with CHD differ in their assessment of CHD risk. The method of risk assessment recommended in future guidelines for CHD prevention should be critically tested in relevant groups of patients.

Algorithms↗
PubMed1999

Purification and characterization of 40-kDa sterigmatocystin O-methyltransferase involved in aflatoxin biosynthesis.

Sterigmatocystin-O-methyltransferase (ST-OMTase), an enzyme catalyzing O-methylation of sterigmatocystin with S-adenosylmethionine (SAM), was purified to electrophoretic homogeneity by immunoaffinity chromatography. A novel spectrofluorometric method was established to quantitatively determine the enzymatic activity of ST-OMTase. The purified protein, with a molecular weight of 40 kDa by SDS-PAGE, was sensitive to thiol reagents and low concentrations of heavy metal ions. Using a nutritional shift assay, the expression patterns for ST-OMTase and the transcripts of its corresponding gene, omtA, correlated well with that for aflatoxin B(1) formation. Neither methyltransferase activity nor omtA, mRNA was detected in the fungal cultures of nonaflatoxigenic isolates, including A. flavus, A. sojae, A. nidulans and A. versicolor under optimal growing conditions for aflatoxin B(1) production.

Aflatoxins↗