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Biomedical subjects

I Singh

Publications and source records attributed to I Singh.

At least 73 records · Page 4Linked to original sources
PubMed2001

Pharmacokinetic study of paclitaxel as a 3-hour infusion in an Indian population: 135 mg/m2 vs. 175 mg/m2.

The objective of this clinical study was to determine the pharmacokinetic parameters of paclitaxel at doses of 135 and 175 mg/m2 when given as a 3-hour infusion in an Indian population. Twelve cancer patients of both sexes participated in the study and a parallel experimental design was adopted for the assignment of doses to patients. A solid phase extraction technique was used for sample clean-up followed by a reversed phase HPLC assay for the analysis of paclitaxel in plasma samples. Pharmacokinetic parameters such as Cmax, AUC0-infinity, T1/2 beta, AUMC0-infinity, VSS, VZ and CLT were determined by a compartment model-independent method using a PCNONLIN package. Teff and AUCeff were also calculated and compared at the two doses by considering a plasma concentration of > or = 0.05 microM as threshold. The mean Cmax and AUC0-infinity values were 2.57 microM and 12.06 microM at the 135 mg/m2 dose level while at the 175 mg/m2 dose the values increased to 4.96 microM and 9.52 microM.h/l, respectively. It was found that the 135 mg/m2 dose resulted in greater mean CLT and VSS values than the 175 mg/m2 dose. The disposition of paclitaxel was found to be nonlinear and the pertinent pharmacokinetic parameters were comparable to those from previous clinical studies. It was concluded from the present study that further clinical trials of paclitaxel alone or in combination with other drugs should be undertaken cautiously, taking into consideration its nonlinear pharmacokinetics which necessitate proper adjustment of the infusion schedule and/or dose to avoid any adverse consequences to the patient.

Adult↗
PubMed2001

Age of seizure onset in adults with Down's syndrome.

In a cohort of 68 adults (35 males and 33 females) with Down's syndrome aged 29-83 years, a history of seizures was found in 26.5%. The overall mean age of onset of seizures was 37 years, males (22 years) being significantly younger than females (51 years). The age of onset was bimodally distributed, with the first peak occurring in the first two decades, and a late-onset peak occurring in the fifth and sixth decades. A strong association between Alzheimer's disease and seizures was confirmed. Of those with a history of seizures, those aged over 45 years were significantly more likely to develop Alzheimer's disease than those younger than 45. It is suggested that late-onset epilepsy in Down's syndrome is associated with Alzheimer's disease, while early-onset epilepsy is associated with an absence of dementia.

Adult↗
PubMed2000

Asymmetric PTC C-alkylation catalyzed by chiral derivatives of tartaric acid and aminophenols. Synthesis Of (R)- and (S)-alpha-methyl amino acids

A new type of efficient chiral catalyst has been elaborated for asymmetric C-alkylation of CH acids under PTC conditions. Sodium alkoxides formed from chiral derivatives of tartaric acid and aminophenols (TADDOL's 2a-e and NOBIN's 3a-h) can be used as chiral catalysts in the enantioselective alkylation, as exemplified by the reaction of Schiff's bases 1a-e derived from alanine esters and benzaldehydes with active alkyl halides. Acid-catalyzed hydrolysis of the products formed in the reaction afforded (R)-alpha-methylphenylalanine, (R)-alpha-naphthylmethylalanine, and (R)-alpha-allylalanine in 61-93% yields and with ee 69-93%. The procedure could be successfully scaled up to 6 g of substrate 1b. When (S,S)-TADDOL or (R)-NOBIN are used, the (S)-amino acids are formed. A mechanism rationalizing the observed features of the reaction has been suggested.

Journal Article↗
PubMed2000

The characterization of phospholipase D in FRTL-5 thyroid cells.

We previously demonstrated that TSH activates phospholipase D (PLD) in Fischer rat thyroid line (FRTL)-5 cells. To date, two types of mammalian phosphatidylcholine-specific PLD cDNAs, designated as PLD-1 and PLD-2, have been cloned. The present study determined the PLD isoform composition in FRTL-5 thyroid cells and which isoform is regulated by TSH. PLD-1 is activated by small molecular weight G-proteins, such as ADP-ribosylation factor (ARF) and RhoA family members, while PLD-2 is relatively independent of such stimuli. We established the presence of PLD-1 and PLD-2 by Western blot analysis and compared PLD activity in cytosol, membranes and combined fractions in the presence and absence of GTPgammaS. The membrane fraction showed very little activity in the absence of GTPgammaS, but this activity increased approximately 5-fold (P<0.05, ANOVA) in the presence of GTPgammaS. Maximal PLD activity was seen with the combination of membrane plus cytosolic fractions (which contained ARF and RhoA) where the addition of GTPgammaS increased PLD activity approximately 8-fold (P<0.05, ANOVA). To determine the relative activities of PLD-1 and PLD-2 in FRTL-5 thyroid cells, cell-free PLD assays were performed in the presence of GTPgammaS or GDPbetaS with varying concentrations of phosphatidylinositol 4,5-bisphosphate (PIP(2)). PLD-2 contributed only approximately 19% of the total amount of PLD activity in the membranes and PLD-1 was the predominant PLD isoform. TSH stimulated PLD-1 activity by up to 2. 3-fold over control values (P<0.01, ANOVA). To establish the dependence of PLD-1 on small molecular weight G-proteins, the translocations of ARF and RhoA to the membrane fractions was determined after stimulation by TSH. Both ARF and RhoA were maximally translocated to the membrane fraction after 10 min incubation with 100 microU/ml TSH by approximately 1.7- and 2.3-fold over control values, respectively (P<0.02 and P<0.03, ANOVA). It is concluded that TSH stimulates PLD-1 activity in FRTL-5 thyroid cells and this is accompanied by the translocation of ARF and RhoA to the membrane fraction.

Animals↗
PubMed2000

Lipid phosphate phosphatase-1 and Ca2+ control lysophosphatidate signaling through EDG-2 receptors.

The serum-derived phospholipid growth factor, lysophosphatidate (LPA), activates cells through the EDG family of G protein-coupled receptors. The present study investigated mechanisms by which dephosphorylation of exogenous LPA by lipid phosphate phosphatase-1 (LPP-1) controls cell signaling. Overexpressing LPP-1 decreased the net specific cell association of LPA with Rat2 fibroblasts by approximately 50% at 37 degrees C when less than 10% of LPA was dephosphorylated. This attenuated cell activation as indicated by diminished responses, including cAMP, Ca(2+), activation of phospholipase D and ERK, DNA synthesis, and cell division. Conversely, decreasing LPP-1 expression increased net LPA association, ERK stimulation, and DNA synthesis. Whereas changing LPP-1 expression did not alter the apparent K(d) and B(max) for LPA binding at 4 degrees C, increasing Ca(2+) from 0 to 50 micrometer increased the K(d) from 40 to 900 nm. Decreasing extracellular Ca(2+) from 1.8 mm to 10 micrometer increased LPA binding by 20-fold, shifting the threshold for ERK activation to the nanomolar range. Hence the Ca(2+) dependence of the apparent K(d) values explains the long-standing discrepancy of why micromolar LPA is often needed to activate cells at physiological Ca(2+) levels. In addition, the work demonstrates that LPP-1 can regulate specific LPA association with cells without significantly depleting bulk LPA concentrations in the extracellular medium. This identifies a novel mechanism for controlling EDG-2 receptor activation.

Animals↗
PubMed2000

Marjolin's ulcer of the suprapubic cystostomy site infiltrating the urinary bladder: a rare occurrence.

We report a case of a 40-year-old man who had presented with a spontaneous suprapubic urinary leak from a well-healed suprapubic cystostomy tract scar, 20 years following a successful scrotal tube substitution urethroplasty done for a post-traumatic urethral stricture. Preoperative contrast studies suggested a recurrent bulbomembranous urethral stricture. Excision biopsy of the suprapubic fistulous tract revealed scar cancer infiltrating the bladder wall. Of 3 similar cases reported in the past, only 1 had bladder involvement. Ours is the second such case with bladder involvement.

Adult↗
PubMed2000

Rhinovirus-induced oxidative stress and interleukin-8 elaboration involves p47-phox but is independent of attachment to intercellular adhesion molecule-1 and viral replication.

Virus-induced elaboration of proinflammatory cytokines is mediated by virus-induced oxidative stress. The purpose of these studies was to determine the source of the virus-induced oxidative stress. Inhibition of viral replication with antibody to intercellular adhesion molecule-1 had no effect on virus-induced oxidative stress or interleukin-8 (IL-8) response (597+/-88 vs. 668+/-78 pg/mL in control cells). Treatment of cells with diphenylene iodonium inhibited virus-induced oxidative stress and IL-8 elaboration, but allopurinol, ibuprofen, and rotenone had no effect. Studies in cell lines produced from a patient with gp91-phox deficiency revealed normal responses. In contrast, the oxidative response was decreased and the IL-8 concentration was 227+/-36 pg/mL in cells from a patient with p47-phox deficiency, compared with 664+/-48 pg/mL in control cells. These studies suggest that the stimulation of reactive oxygen species by viral challenge occurs at the cell surface even in the absence of viral replication and involves a flavoprotein that may act in concert with p47-phox.

Allopurinol↗
PubMed2000

Primary malignant bladder carcinoid--a diagnostic and management dilemma.

A middle-aged man who presented with gross hematuria and irritative voiding symptoms was found to have an invasive infiltrating primary bladder carcinoid after radical cystoprostatectomy. Hurricane chest secondaries were prominent in the follow-up evaluation. The immunohistochemical markers for neuroendocrine differentiation were substantiated. The published reports of primary bladder carcinoid tumors are discussed.

Adult↗
PubMed2000

Intraperoxisomal localization of very-long-chain fatty acyl-CoA synthetase: implication in X-adrenoleukodystrophy.

X-adrenoleukodystrophy (X-ALD) is a demyelinating disorder characterized by the accumulation of saturated very-long-chain (VLC) fatty acids (>C(22:0)) due to the impaired activity of VLC acyl-CoA synthetase (VLCAS). The gene responsible for X-ALD was found to code for a peroxisomal integral membrane protein (ALDP) that belongs to the ATP binding cassette superfamily of transporters. To understand the function of ALDP and how ALDP and VLCAS interrelate in the peroxisomal beta-oxidation of VLC fatty acids we investigated the peroxisomal topology of VLCAS protein. Antibodies raised against a peptide toward the C-terminus of VLCAS as well as against the N-terminus were used to define the intraperoxisomal localization and orientation of VLCAS in peroxisomes. Indirect immunofluorescent and electron microscopic studies show that peroxisomal VLCAS is localized on the matrix side. This finding was supported by protease protection assays and Western blot analysis of isolated peroxisomes. To further address the membrane topology of VLCAS, Western blot analysis of total membranes or integral membranes prepared from microsomes and peroxisomes indicates that VLCAS is a peripheral membrane-associated protein in peroxisomes, but an integral membrane in microsomes. Moreover, peroxisomes isolated from cultured skin fibroblasts from X-ALD patients with a mutation as well as a deletion in ALDP showed a normal amount of VLCAS. The consequence of VLCAS being localized to the luminal side of peroxisomes suggests that ALDP may be involved in stabilizing VLCAS activity, possibly through protein-protein interactions, and that loss or alterations in these interactions may account for the observed loss of peroxisomal VLCAS activity in X-ALD.

Adrenoleukodystrophy↗
PubMed2000

Endotoxin induces structure-function alterations of rat liver peroxisomes: Kupffer cells released factors as possible modulators.

We report that endotoxin treatment results in decreased amounts of peroxisomes as well as changes in structure and function of peroxisomal membranes. Peroxisomes isolated from the liver of control and treated animals showed a marked decrease in total protein, but no significant alteration in the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) protein profile. However, the Western blot study of the peroxisomal beta-oxidation enzymes and catalase showed an increase in those enzymes in the peroxisomal peak of normal density in endotoxin-treated rats. Disintegration of peroxisomal membranes by carbonate treatment from endotoxin-treated liver and change in the fluidity of peroxisomal membranes suggests alterations in peroxisomal membrane structure. No such alterations were found in mitochondrial or microsomal membranes of endotoxin-treated livers. The lipid analysis of these organelles showed that the only organelle affected was the peroxisome, with a significant decrease in the phospholipid and cholesterol concentrations. To understand the mechanism of endotoxin-mediated alterations in peroxisomes, we studied the possible role of Kupffer cell secreted soluble factors (tumor necrosis factor alpha [TNF-alpha]) on the peroxisomal structure/function. Inactivation/elimination of Kupffer cells by gadolinium chloride before endotoxin treatment did not normalize the overall peroxisomal protein amount and the lipid composition of isolated peroxisomes. However, the levels of individual protein amount in remaining peroxisomes were normalized. Endotoxin also decreased peroxisomal beta-oxidation, and this was partially restored with gadolinium treatment. These results clearly show that peroxisomes are severely affected by endotoxin treatment and suggest that the damage to this organelle may contribute, at least in part, to endotoxin-induced hepatic cytotoxicity.

Animals↗
PubMed2000

Lovastatin therapy for X-linked adrenoleukodystrophy: clinical and biochemical observations on 12 patients.

X-linked adrenoleukodystrophy (X-ALD) is a progressive demyelinating disorder whose neurological signs and symptoms can manifest in childhood as cerebral ALD or in adulthood in the form of a progressive myelopathy (AMN). The consistent metabolic abnormality in all forms of X-ALD is an inherited defect in the peroxisomal beta-oxidation of very long chain (VLC) fatty acids (>C(22:0)) which may in turn lead to a neuroinflammatory process associated with demyelination of the cerebral white matter. The current treatment for X-ALD with Lorenzo's oil aims to lower the excessive quantities of VLC fatty acids that accumulate in the patients' plasma and tissues, but does not directly address the inflammatory process in X-ALD. We have previously demonstrated that lovastatin and other 3-HMG-CoA reductase inhibitors are capable of normalizing VLC fatty acid levels in primary skin fibroblasts derived from X-ALD patients. Lovastatin can block the induction of inducible nitric oxide synthase and proinflammatory cytokines in astrocytes, microglia, and macrophages in vitro. In a preliminary report, we demonstrated that lovastatin therapy can normalize VLC fatty acids in the plasma of patients with X-ALD. Here we report our clinical and biochemical observations on 12 patients with X-ALD who were treated with lovastatin for up to 12 months. Our results show that the high plasma levels of hexacosanoic acid (C(26:0)) showed a decline from pretreatment values within 1 to 3 months of starting therapy with 40 mg of lovastatin per day and stabilized at various levels during a period of observation up to 12 months. The percentage decline from pretreatment values varied and did not correlate with the type of ALD gene mutation (point mutation versus gene deletion). In 6 patients, in whom red cell membrane fatty acid composition was studied, a mean correction of 50% of the excess C(26:0) was observed after 6 months of therapy suggesting sustained benefit. In a few patients who discontinued lovastatin therapy plasma C(26:0) levels reverted to pretreatment values suggesting a cause and effect relationship between these events. Two patients dropped out of the study claiming no clinical benefit, 1 was withdrawn due to adverse effects, and an adult patient with cerebral involvement died during the study. A 10-year-old boy with severe cerebral involvement showed worsening of his neurological status. All patients with AMN remained neurologically stable or showed modest subjective improvement. All patients who did not have Addison's disease at the time of enrollment maintained normal adrenal function throughout the study. The implications of our findings for developing an effective therapy for X-ALD are discussed.

Adrenoleukodystrophy↗
PubMed2000

Maternal and cord plasma selenium levels in full-term neonates.

Selenium is a part of the enzyme glutathione peroxidase and has an important role in the prevention of oxygen free radical injury. Hence good selenium nutrition is of special relevance to the neonate. The present study evaluated plasma selenium levels in cord plasma of 82 full term, appropriate for gestational age babies and their mothers at delivery. The plasma selenium levels in babies were 54.17 +/- 1.34 ppb which was significantly lower than 70.63 +/- 1.62 ppb seen in their mothers. Anemic mothers with a Hb < 8 g/dl had a plasma selenium level (60.74 +/- 4.57 ppb) which was lower than those with a Hb > 8 g/dl i.e. 74.19 +/- 2.17 ppb. Maternal age, parity, literacy and socio-economic status did not affect the plasma selenium levels.

Adult↗
PubMed2000

Identification of the pathway of alpha-oxidation of cerebronic acid in peroxisomes.

Cerebronic acid (2-hydroxytetracosanoic acid), an alpha-hydroxy very long-chain fatty acid (VLCFA) and a component of cerebrosides and sulfatides, is unique to nervous tissues. Studies were carried out to identify the pathway and the subcellular site involved in the oxidation of cerebronic acid. The results from these studies revealed that cerebronic acid was catabolized by alpha-oxidation to CO2 and tricosanoic acid (23:0). Studies with subcellular fractions indicated that cerebronic acid was alpha-oxidized in fractions having particulate bound catalase and enzyme systems for the beta-oxidation of VLCFA (e.g., lignoceric acid), suggesting peroxisomes as the subcellular organelle responsible for alpha-oxidation of cerebronic acid. Etomoxir, an inhibitor of mitochondrial fatty acid oxidation, had no effect on cerebronic acid alpha-oxidation. Further, cerebronic acid oxidation was found to be dependent on the presence of NAD+ but not FAD, NADPH, ATP, Mg2+, or CoASH. Intraorganellar localization studies indicated that the enzyme system for the alpha-oxidation of cerebronic acid was associated with the peroxisomal limiting membranes. Studies on cultured fibroblasts from normal subjects and patients with peroxisomal disorders indicated an impairment of alpha-oxidation of cerebronic acid in cell lines that lack peroxisomes [e.g., Zellweger syndrome (ZS)]. On the other hand, alpha-oxidation of cerebronic acid was found to be normal in cell lines from X-linked adrenoleukodystrophy, adult Refsum disease, and rhizomelic chondrodysplasia punctata. Our results clearly demonstrate that alpha-oxidation of alpha-hydroxy VLCFA (cerebronic acid) is a peroxisomal function and that this oxidation is impaired in ZS. Furthermore, this alpha-oxidation enzyme system is distinct from the one for the alpha-oxidation of beta-carbon branched-chain fatty acids (e.g., phytanic acid).

Animals↗
PubMed2000

Innate antiviral defenses in body fluids and tissues.

Innate, non-specific, resistance mechanisms are important barriers to pathogens, particularly delaying virus multiplication at the onset of infections. These innate defense mechanisms include a series of mechanical barriers, pre-existing inhibitory molecules, and cellular responses with antimicrobial activity. The antiviral activities of these innate inhibitors reside in a variety of partly characterized substances. This review presents the innate antiviral inhibitors in cell cultures, urine, serum, the gastrointestinal tract, the nervous system, tissues of crustaceans, and saliva. Medical adaptation of the innate antiviral defense mechanisms may be useful for prevention and treatment of viral infections.

Animals↗
PubMed2000

Quantitative structure-property relationships in pharmaceutical research - Part 1.

Quantitative structure-activity relationships (QSAR) have been applied for decades in the development of new drugs. Although a QSAR does not completely eliminate the trial and error factor involved in the development of a new drug, it certainly decreases the number of compounds synthesized by facilitating the selection of the most promising examples. The success of QSAR has tempted scientists, particularly in the pharmaceutical arena, to investigate relationships of molecular parameters with properties other than activity. The purpose of this two-part review is to provide a broad overview of the development of quantitative structure-property relationships (QSPR) and review the applications in pharmaceutical research. Part one discusses the advantages and limitations of QSPR, and various types of structural descriptors and properties, together with techniques to establish correlations between the two.

Journal Article↗
PubMed2000

Quantitative structure-property relationships in pharmaceutical research - Part 2.

Part one of this two-part review described the advantages and limitations of quantitative structure-property relationships (QSPR), and offered an overview of the components involved in the development of correlations1. Part two provides a discussion of a few notable examples of relationships with organoleptic, physicochemical and pharmaceutical properties.

Journal Article↗
PubMed2000

Characterization of fibroblast cytoplasmic proteins that bind to the 3' UTR of human catalase mRNA.

The excessive expression of catalase protein and its activity in cultured skin fibroblast from Zellweger Syndrome (ZS), a disorder of peroxisomal biogenesis, was found to be regulated at the translational level (J. Neurochem. 67: 2373-2378, 1996). Overall there is a considerable increase in the association of catalase mRNA with polysomes in ZS cell lines as compared to control indicating translational upregulation. To investigate the possibility that RNA-protein interactions are involved in the mediation of this increase in translation, the interaction between 3' untranslated region of human catalase mRNA and human fibroblast cytoplasmic proteins were investigated by RNA gel shift assay technique. Competition experiments demonstrated that all the 600 bases of 3' UTR (of human catalase gene) was required for efficient binding. Catalase RNA- protein interaction was sensitive to the altered redox state in these in vitro assays and this RNA-protein interaction could be enhanced by the addition of beta-mercaptoethanol in cytoplasm from control fibroblast but not in cytoplasm from ZS fibroblast. UV cross linked RNA-protein complexes on SDS polyacrylamide gel electrophoresis revealed the presence of at least four protein bands with approximate molecular masses of 38 kDa, 50 kDa, 66 kDa and 80 kDa. The potential role of these mRNA binding proteins in the regulation of catalase gene expression is discussed.

3' Untranslated Regions↗