Antimetabolite application: science or voodoo?
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Antimetabolites↗
Biomedical subjects
K Singh
Publications and source records attributed to K Singh.
Hemoglobin E-beta thalassemia in Uttar Pradesh.
OBJECTIVE: To evaluate the molecular make up of hemoglobin E-Beta thalassemia to facilitate diagnosis, genetic counseling and prenatal diagnosis in Uttar Pradesh. DESIGN: DNA analysis. SETTING: Referred hemolytic anemia cases to Genetics OPD of a tertiary care center. SUBJECTS: 21 families of HbE-thalassemia of which 19 were of UP origin. METHODS: The patient and obligate carriers in their families were evaluated at hematological, biochemical and molecular level. A total of 62 cases were evaluated which included the index cases and their family members. Red blood cell indices, osmotic fragility, hemoglobin electrophoresis, quantitation of fetal hemoglobin, HbA2/E, serum iron and total iron binding capacity estimation were carried out in all the blood samples. DNA analysis was done for HbE and beta thalassemia mutations. RESULTS: The commonest, IVSI-5 (G-->C) mutation (57%) was found along with HbE mutation. Only 23/26 cases belonged to the group of common beta-thal mutations as described in literature. CONCLUSION: Establishment of antenatal diagnostic services is necessary in those parts of India where both these mutations are commonly seen.
Adolescent↗
Effects of silymarin on UDP-glucuronic acid and glucuronidation activity in the rat isolated hepatocytes and liver in relation to D-galactosamine toxicity.
Influence of silymarin on UDP-glucuronic acid (UDPGA) and glucuronidation activity of freshly isolated rat hepatocytes in suspension and in rat liver in vivo was examined. Viability of the hepatocytes (> 85%) was not altered in Hank's balanced salt solution at least for 4 hr at 37 degrees C under oxygen. Silymarin at 0.4 mM depleted UDPGA by more than 60% at the end of 4 hr of incubation, the fall in nucleotide pool was rapid and concentration (0.1-0.4 mM)-dependent. The rate of glucuronidation of 3-OH- benzo(a)pyrene (3-OH-BP) determined simultaneously was also reduced significantly; silybin being 3-times more effective than silymarin. Combination of flavonoids with D-galactosamine (GalN) further attenuated the glucuronidation functions of the cells. The flavonoids also offered strong inhibition of UDP-glucose dehydrogenase (UDP-GDH) activity in the liver cytosolic fraction while the activity in hepatocytes was not affected even after 4 hr of incubation. Interestingly, the GalN- induced strong inhibition of UDP-GDH in isolated hepatocytes was completely abolished by flavonoids. Decrease in UDPGA appeared neither due to the activation of UDPGA-pyrophosphatase activity nor to the inhibition of UDP-GDH activity in hepatocytes. Further, the flavonoids also inhibited hepatic UDP-glucuronyltransferase activity towards 3-OH-BP (UGT) both in vitro and in intact cells. On the contrary, silymarin administered (70 mg/kg body wt; i.p.) to rats for 3 hr increased the hepatic UDPGA by 2-fold while GalN (400 mg/kg body wt) reduced the nucleotide content to 50% of control. Coadministration of silymarin and GalN restored the UDPGA content significantly while the activities of UDP-GDH and UGT were comparable to the untreated control. The results indicated that silymarin elicits differential effects on the rate of glucuronidation and contents of UDPGA in the isolated rat hepatocytes and in liver. The flavonoid counteracted D-GalN-induced lowering of UDPGA presumably by relieving UDP-GDH of in vivo inhibition affected by GalN-metabolite.
Animals↗
Differential biochemical response of freshly isolated rat hepatocytes to paracetamol, carbon tetrachloride and D-galactosamine toxicity.
Differential response of freshly isolated rat hepatocytes to paracetamol (acetaminophen, AAP), carbon tetrachloride (CCl4) and D-galactosamine (GalN) was examined. The viability of the cells in suspension culture was not altered for 4 hr when incubated in Hank's balanced salt solution (HBSS) supplemented with 4.2 mM NaHCO3, 10 mM HEPES buffer and 0.5% bovine serum albumin. AAP induced time and dose dependent depletion of GSH as an early manifestation of AAP toxicity. Hepatocytes exposed to AAP exhibited lower lactate dehydrogenase (LDH) activity released into the medium than in controls. This was due to the interaction of a reactive metabolite of AAP, i. e. N-acetyl p-benzoquinoneimine (NAPQI) with cell proteins. Hepatocytes isolated from rats pretreated with 3-methylcholanthrene expressed higher sensitivity to AAP toxicity at least by a factor of 5. Furthermore, AAP-induced toxicity was not found to be related to any lipoperoxidative stress. CCl4 on the other hand elicited a highly lipoperoxidative response in hepatocytes and consequent leakage of cellular enzymes with lengths of incubation. Again the sensitivity of the response to CCl4 was enhanced remarkably in hepatocytes isolated from phenobarbital- pretreated rats; LDH leakage increased by 3-fold and thio-barbituric acid reactive substances by 25-fold. Unlike the two toxicants, galactosamine depleted UDP-glucuronic acid in a concentration and time-related manners. The differential biochemical response of hepatocytes to three hepatotoxicants investigated may prove useful as rapid in vitro screen for selection of compounds of hepatoprotective potentials.
Acetaminophen↗
Silymarin mediated differential modulation of toxicity induced by carbon tetrachloride, paracetamol and D-galactosamine in freshly isolated rat hepatocytes.
Influence of silymarin on the modulation of hepatotoxicity induced by carbon tetrachloride (CCl4), paracetamol (AAP) and D-galactosamine (GalN) was examined in freshly isolated rat hepatocytes in suspension culture. While the three hepatotoxicants produced differential biochemical response, the flavone was able to restore biochemical alterations only in hepatocytes exposed to CCl4 and AAP induced toxicity. Silymarin at 0.4 mM was able to counteract lipid peroxidation and enzyme leakage induced by 3 mM CCl4 The flavone also offered protection by more than 60% in hepatocytes isolated from PB pre-treated rats where CCl4 at 2 mM produced enhanced toxicity over hepatocytes isolated from untreated control rats. Similarly, the flavone protected AAP-induced GSH depletion by more than 75% in hepatocytes isolated from untreated and 3-methylcholanthrene treated rats. However, instead of protecting GalN-induced depletion of UDP-glucuronic acid in hepatocytes, the flavone itself reduced the nucleotide content very rapidly compared to GalN, the later exerted time dependent effect. Silymarin at 0.4 mM reduced UDPGA by more than 60%. The results suggested that freshly isolated hepatocytes in suspension culture offer a simple and convenient method for evaluation of pharmaceutical agents of antihepatotxic potentials against various hepatotoxicants.
Acetaminophen↗
Endoscopic management of pancreatic diseases.
Endoscopic management has recently been used for a variety of chronic pancreatic diseases. We used this approach in five patients with pancreatic diseases (calcific pancreatitis 2, pancreatic pseudocyst 3). Nasocystic drain was placed in a patient with pancreatic pseudocyst at the tail end of the pancreas; a 5 Fr stent was placed over 0.021"/0.035" guide wire in the main pancreatic duct in the others. All patients had relief of pain. Nasocystic drain led to resolution of pseudocyst, perisplenic collection and pleural effusion. Endoscopic treatment is safe and effective in various pancreatic disorders.
Adolescent↗
Isolated common bile duct tuberculosis mimicking malignant obstruction.
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Adult↗
Oxidants, antioxidants and diseases--a brief review.
Although oxygen (O2) is needed to the body, partially reduced forms of O2 and some of their derivatives collectively called reactive oxygen species (ROS), are highly toxic prooxidants to the body. To prevent ROS toxicity body's endogenous and exogenous antioxidants (AOS) act in concert. To maintain health a balance between pro and anti oxidants is very necessary.
Acquired Immunodeficiency Syndrome↗
High density lipoprotein subclasses inhibit low density lipoprotein oxidation.
It has been reported earlier that high density lipoprotein (HDL) is a scavenger of superoxide anions, hydroxyl radicals (OH-) and behaves like superoxide dismutase. In the present investigation, we have studied the effect of HDL subclasses: HDL2 and HDL3 on non enzymatically induced oxidation of low density lipoprotein (LDL) by Fe2+ and sodium ascorbate. Both HDL2 and HDL3 showed protection against the oxidative degradation of LDL-lipids, measured as thiobarbituric acid reactive substance, lipid hydroperoxide and conjugated diene. Oxidized LDL was more electronegative, as evidenced by the increase in relative electrophoretic mobility(REM) on agarose gel. HDL3 significantly protected LDL apoprotein as assessed by reversal of REM after oxidation. HDL2 and HDL3 significantly inhibited the generation of OH- in nonenzymic systems in vitro. However, HDL2 was more active against enzymic formation of OH- as compared to HDL3. Alpha-tocopherol could protect LDL lipids and apoprotein components by Fe2+ mediated oxidation but the effects were lower than HDL subclasses. Our findings suggest that HDL subclasses, the potent scavenger of oxygen derived free radicals, play an important role to prevent the oxidative modifications in LDL.
Antioxidants↗
Conjunctival impression cytology in xerophthalmia among rural children.
The advent of Conjunctival Impression Cytology (CIC) has opened a new chapter in the detection of Vitamin A deficiency as it is a simplified field technique. The need for such a technique was of paramount importance in India where as estimated 5 to 7 percent children suffer from eye signs of Vitamin A deficiency. In the present study the results of clinical evaluation of apparently healthy children and those having clinical sings and symptoms of Vitamin A deficiency have been compared with CIC results. Serum Vitamin A levels have also been estimated wherever possible. The findings indicate that CIC results are superior to the clinical assessment and it is suggested that CIC can be used as screening tool for children of school going age (and earlier) for early detection and correction of Vitamin A deficiency.
Child↗
An intrinsic adrenergic system in mammalian heart.
We have identified a previously undescribed intrinsic cardiac adrenergic (ICA) cell type in rodent and human heart. Northern and Western blot analyses demonstrated that ICA cell isolates contain mRNA and protein of enzymes involved in catecholamine biosynthesis. Radioenzymatic catecholamine assays also revealed that the catecholamine profile of adult rat ICA cell isolates differed from that of sympathetic neurons. Unlike sympathetic neuronal cells, isolated ICA cells have abundant clear vesicles on electron microscopy. Endogenous norepinephrine and epinephrine constitutively released by ICA cells in vitro affect the spontaneous beating rate of neonatal rat cardiac myocytes in culture. Finally, ICA cells could be identified in human fetal hearts at a developmental stage before sympathetic innervation of the heart has been documented to occur. These findings support the concept that these cells constitute an ICA signaling system capable of participating in cardiac regulation that appears to be independent of sympathetic innervation.
Adult↗
Seasonal changes in circulating serum concentration and in vitro testicular secretion of testosterone and androstenedione in the male vespertilionid bat (Scotophilus heathi).
Seasonal changes in the testicular activity were studied in the male Greater Yellow bat, Scotophilus heathi, in Varanasi, India (25 degrees N, 83 degrees E). The seasonal pattern of body weight of male bats was also recorded and compared with circulating androstenedione (A) and testosterone (T) concentration. There was a gradual increase in the body weight of the bat from September onward mainly due to accumulation of adipose tissue. Finally, body weight reached a peak level in November. Two periods of peak testicular weight and serum T concentration but only one peak of serum A concentration were observed. The first peak of T coincided closely with the peak A concentration and increased body weight. The first peak of T occurs several months before the time of mating and ovulation. The second peak of T correlated closely with the period of mating. In vitro study showed seasonal variation of the testicular responsiveness to LH stimulation. In vitro study also showed two peaks in the T but only one peak in the A production by testes in response to LH during different phases. Preliminary study showed that IGF-I but not insulin augmented hCG induced T production by testes in vitro. Our observation of an increase in serum A concentration during the period of overfeeding and weight gain and decline in A during the period of weight loss in S. heathi adds strength to the concept that nutritional status can influence hormonal function. This may be the reason for asynchrony between male and female gametic cycle found among vespertilionid bats.
Androstenedione↗
Centromere mapping and orientation of the molecular linkage map of rice (Oryza sativa L.).
Rice has become a model cereal plant for molecular genetic research. Rice has the most comprehensive molecular linkage maps with more than 2000 DNA markers and shows synteny and colinearity with the maps of other cereal crops. Until now, however, no information was available about the positions of centromeres and arm locations of markers on the molecular linkage map. Secondary and telotrisomics were used to assign restriction fragment length polymorphism markers to specific chromosome arms and thereby to map the positions of centromeres. More than 170 restriction fragment length polymorphism markers were assigned to specific chromosome arms through gene dosage analysis using the secondary and telotrisomics and the centromere positions were mapped on all 12 linkage groups. The orientations of seven linkage groups were reversed to fit the "short arm on top" convention and the corrected map is presented.
Centromere↗
Regulation of cytokine-inducible nitric oxide synthase in cardiac myocytes and microvascular endothelial cells. Role of extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and STAT1 alpha.
Adult rat ventricular myocytes and cardiac microvascular endothelial cells (CMEC) both express an inducible nitric oxide synthase (iNOS or NOS2) following exposure to soluble inflammatory mediators. However, NOS2 gene expression is regulated differently in response to specific cytokines in each cell type. Interleukin-1 beta (IL-1 beta) induces NOS2 in both, whereas interferon gamma (IFN gamma) induces NOS2 expression in myocytes but not in CMEC. Therefore, we examined the specific signal transduction pathways that could regulate NOS2 mRNA levels, including activation of 44- and 42-kDa mitogenactivated protein kinases (MAPKs; ERK1/ERK2) and STAT1 alpha, a transcriptional regulatory protein linked to cell membrane receptors. Although IL-1 beta treatment increased ERK1/ERK2 activities in both cell types, IFN gamma activated these MAPKs only in myocytes. STAT1 alpha phosphorylation, consistent with IFN gamma-induced signaling, was readily apparent in both cell types, and binding of activated STAT1 alpha from cytoplasmic or nuclear fractions from IFN gamma-treated adult myocytes to a sis-inducible element could be demonstrated by gel-shift assay. The farnesyl transferase inhibitor BZA-5B blocked activation of ERK1/ERK2 and induction of NOS2 by IFN gamma and IL-1 beta in myocytes. IL-1 beta and IFN gamma-induced NOS2 gene expression in myocytes was also down-regulated by both protein kinase C (PKC) desensitization and by the PKC inhibitor bisindolylmaleimide, implicating PKC-linked activation of Ras or Raf in the induction of NOS2 by IL-1 beta and IFN gamma in cardiac muscle cells. In CMEC, the MAPK kinase inhibitor PD 98059 blocked activation of ERK1/ERK2 and down-regulated IL-1 beta-mediated NOS2 induction, whereas activation of ERK2 in the absence of cytokines by okadaic acid, an inhibitor of phosphoserine protein phosphatases, also induced NOS2 mRNA. These data demonstrate that ERK1/ERK2 activation appears to be necessary for the induction of NOS2 by IL-1 beta and IFN gamma in cardiac myocytes and CMEC. In the absence of ERK1/ERK2 activation by IFN gamma in CMEC, phosphorylation of STAT1 alpha is not sufficient for NOS2 gene expression. These overlapping yet distinct cellular responses to specific cytokines may serve to target NOS2 gene expression to specific cells or regions within the heart and also provide for rapid escalation of NO production if required for host defense.
Animals↗
Use of a laparoscopic trocar for percutaneous introduction of drains into intra-abdominal abscesses.
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Abdominal Abscess↗
Urinary incontinence during pregnancy in a racially mixed sample: characteristics and predisposing factors.
The objectives of the study were to assess the prevalence of urinary incontinence symptoms during pregnancy in a racially mixed sample and to identify potential predisposing variables. Five hundred and twenty-three women were interviewed in the hospital on postpartum day 2 or 3 and by telephone at 6-week follow-up. A significantly larger proportion of white women reported accidental loss of urine than did black women (62.6% vs. 46.4%; P < 0.01). A breakdown by type of incontinence indicated that the race effect was largely attributable to the significantly higher prevalence of the symptom of stress incontinence among white women (P < 0.0001). In stepwise logistic regression modeling, previous incontinence, education level, parity and nocturia were selected as the strongest predictors of incontinence in white women. Attendance at childbirth classes was the only predictor of incontinence for black women. The results raise the possibility that higher rates of incontinence among white women might be due to differences in the pelvic floor.
Adolescent↗
Electrostatic parameters of the theoretical quaternary structure of bovine alpha-crystallin.
By changing the ionic strength, the effects of charge modification on the electrostatic properties of our predicted "open' micellar quaternary structure composed of bovine alpha A subunits were determined. The electrostatic potential values (phi) at 6 arbitrary points surrounding the protein and at all atomic sites of the protein were calculated using the non-linear Poisson-Boltzmann equation. The effective charge (q) of our predicted aggregate ranged from 16 at 0.0022 M to 45 at 0.1472 M ionic strengths. The variation of potential (phi), as well as charge, is a hyperbolic function of ionic strength (R2, 0.901). Plotting the inverse charge (l/q) against inverse ionic strength (1/l) it is possible to calculate maximum charge (q(max)) (approximately 48) at saturation. This value is close to previously reported experimental (50 +/- 5), and our theoretical charge (45), values at physiological ionic strength (0.145 M). These data indicate that maximal repulsion among the alpha-crystallin aggregates occurs at or near physiological ionic strength. Also, half-maximal charge (q(max)/2) at 0.003-0.004 M indicates a transition state at very low ionic strength. The calculated volume available for the mobile solvent in our quaternary structure is approximately 70%. These data are in good agreement with experimental values for bovine alpha-crystallin in solution reported by Xia et al. (Biophys. J., 1994; 66: 861-872). This agreement provides support for our predicted models of alpha-crystallin and a level of confidence in the reliability of the theoretical calculations. Since an ionic gradient exists between the lens cortical and nuclear regions, the modification of charge on alpha-crystallin by varying ionic strength could contribute to the function of alpha-crystallin as a modulator of lens supermolecular order during fiber cell maturation.
Animals↗
Early burn wound excision in "major' burns with "pregnancy': a preliminary report.
Burn injury in pregnant patients is not uncommon in developing countries. The results of the management of six pregnant burns patients, admitted during an 18-month period, were analysed. Successful management of burn injuries ranging from 25 to 65 per cent TBSA occurred in patients during the second and third trimester of pregnancy, using early burn wound excision and skin grafting in four patients and by late skin grafting of a granulating wound in one patient. All five patients delivered live babies with no congenital anomalies. One patient with 60 per cent TBSA burns who was unsuitable for early excision, died of septicaemia. This report suggests the need for early burn wound excision and skin grafting in burns patients with pregnancy, in order to improve maternal and fetal survival. However, in developing countries early surgery is not advisable in patients with extensive burns because of the non-availability of biological skin substitutes.
Adolescent↗