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Biomedical subjects

A Saxena

Publications and source records attributed to A Saxena.

At least 145 records · Page 8Linked to original sources
PubMed1998

Total correction of tetralogy of Fallot in adults--surgical experience.

A total of 100 patients of tetralogy of Fallot aged 13 years and over were operated upon at the All India Institute of Medical Sciences, New Delhi, India between January 1991 and December 1996. There were 69 males (69%) and 31 females (31%). Age ranged from 13 years to 43 years (mean 19.66 years). Twenty % of patients had preoperative complications like haemoptysis, cerebrovascular accidents, brain abscess and infective endocarditis. Twenty-two patients had previous palliative shunts. Fifteen patients had coil embolisation of major collaterals prior to surgery. In hospital mortality rate was 4%. Follow-up ranged from 1 month to 5 years (mean 3.4 years). There was one late death due to infective endocarditis. Postoperatively 93.6% patients were in NYHA class I. Significant residual defects warranting re-operation were present in three patients. Total correction of tetralogy of Fallot in older patients can be performed with acceptable results.

Adolescent↗
PubMed1998

Allosteric control of acetylcholinesterase activity by monoclonal antibodies.

Previous studies showed that monoclonal antibodies raised against phosphorylated fetal bovine serum acetylcholinesterase appeared to modulate the catalytic activity of the enzyme by binding to a conformational epitope located at or near the region of the peripheral anionic site. The mechanism of inhibition of acetylcholinesterase by these monoclonal antibodies was further investigated by determining their effect on (i) substrate inhibition due to the binding of excess substrate to the peripheral anionic site and (ii) binding of peripheral anionic site ligands, such as propidium and fasciculin. Results of these experiments demonstrate that the accessibility of substrate to the peripheral anionic site in these complexes was restricted but not completely blocked, as none of the monoclonal antibodies eliminated the phenomenon of excess substrate inhibition. The results also show that propidium clearly slowed the inhibition of fetal bovine serum acetylcholinesterase by all six inhibitory monoclonal antibodies but to different levels. Complexation of fetal bovine serum acetylcholinesterase with monoclonal antibodies 25B1, 4E5, 6H9, and 5E8 interfered with the binding of fasciculin to the complexed enzyme, suggesting that part of their epitope overlapped with the fasciculin binding site. These monoclonal antibodies bind, in part, at the peripheral anionic site, since polyclonal anti-idiotypic antibodies generated against two monoclonal antibodies, 25B1 and 6H9, bound stoichiometric amounts of propidium. Like fasciculin, binding of these monoclonal antibodies in the vicinity of the peripheral anionic site at the rim of the active site gorge allosterically affects the orientation of W86 located at the base of the gorge, resulting in inhibition of enzyme activity.

Acetylcholinesterase↗
PubMed1998

Biologic and clinical significance of CD7 expression in acute myeloid leukemia.

CD7 antigen, a T-cell lineage associated antigen, is expressed in a minority of patients with acute myeloid leukemia (AML). The biologic and clinical significance of this finding is not clearly established. In this retrospective study of patients with de novo acute myeloid leukemia, we have identified CD7 expression and analyzed its association with markers expressed early in hemopoietic ontogeny and clinical parameters. Among 60 consecutive AML patients, we found six (10%) expressing CD7 on leukemic cells. There were five males and one female and the mean age was 59.6 years (age range: 32-76 years) with no demographic peculiarities. The FAB subtypes were: M0 (2), M1 (1), M2 (1), and M4 (2). CD7 expression was associated with immature antigens CD34, HLA-DR, and terminal deoxynucleotidyl transferase (TdT) and antigen receptor gene rearrangements (rearrangements of T-cell receptor gamma chain in 6/6 and immunoglobulin heavy chain in 2/6). Hepatomegaly was present in three and this was associated with splenomegaly with lymphadenopathy in one patient. Mediastinal or central nervous system involvement was absent. Complete remission was achieved in two patients with standard chemotherapy; one of these is in remission and alive (5 years later), while one died following relapse 9 months later. Three patients had significantly lower response to standard therapeutic regimen (two died during induction and one died 7 months later without ever achieving complete remission). One patient has been excluded in determining the prognostic significance of CD7 due to early death. Our results suggest origin of CD7+ AML from early hemopoietic precursors and indicate biologic aggressiveness in a significant proportion of patients. We suggest evaluation of CD7 in all patients with AML at the time of diagnosis in view of poor clinical outcome.

Acute Disease↗
PubMed1998

The relationship of vasogenic waves to ICP and cerebral perfusion pressure in head injured patients.

Slow vasogenic waves are characterised by sudden rises and falls in both the mean ICP and its cardiac pulsatile amplitude for periods of up to an hour. On reviewing the on-line computer records of a series of 200 consecutive head injured patients, some 650 waves with increases in mean ICP of at least 15 mm Hg were recognized. The mean ICP, pulsatile amplitude, perfusion pressure, arterial pressure and pulse rates which had been generated every minute were reviewed in each of a 100 randomly selected waves in the hopes of allocating them into defined groups according to precipitating factors. We had expected to find that the majority of waves were precipitated by a preceding fall in cerebral perfusion pressure as a result of a transient arterial hypotension. Only in 19 of the 100 waves did this sequence become apparent and in the remainder, no recognizable precipitating factors were found. In 21 of the records, there was a fall in ICP of at least 5 mm Hg before the onset of the pressure wave.

Blood Pressure↗
PubMed1998

Hepatitis G virus in multitransfused thalassaemics from India.

Hepatitis G virus (HGV)/GB virus-C (GBV-C) has been identified as a blood-borne agent with disputed pathogenicity. This virus belongs to the flaviviridae with a distant relationship to hepatitis C virus (HCV). Genetically divergent HGV isolates have been reported from different parts of the world. This study describes the prevalence of HGV in multitransfused thalassaemic children in India and genomic sequence variations in 11 HGV isolates from the same geographical location. Hepatitis G virus RNA was detected in 39.7% multitransfused thalassaemic children. The seroprevalence of hepatitis B virus (HBV) and HCV was 23.8% and 17.1%, respectively, and 11.4% had dual infection. The nucleotide sequence of a 166 bp HGV genomic segment from the putative capsid-envelope region (nucleotide; nt 578-743) from 11 Indian isolates was compared to the sequences available in the nucleotide databases. The isolates from India were 81.3-94.5% homologous to the isolates from other parts of the world. On phylogenetic analysis, it was observed that HGV isolates from India may belong to two genetically divergent types.

Amino Acid Sequence↗
PubMed1998

Aortic valve replacement with biological substitute.

In the quest for an ideal aortic valve substitute, homografts and autografts are well-established options. We reviewed our results with homografts and autografts for aortic valve replacement during the last 5 years. From March 1992 through July 1997, 189 patients (138 male and 51 female), age 8 months to 68 years (mean 31.0+/-4.2 years), underwent aortic valve replacement with a human biological substitute. Of these, 93 patients received a cryopreserved or antibiotic-preserved aortic/pulmonary homograft, whereas 96 patients underwent a Ross procedure. Etiology was rheumatic in 143 (75.6%) patients, bicuspid aortic valve in 40 (21.2%), Marfan's disease in 5 (2.6%), and myxomatous aortitis in 1 (0.5%). Among the homograft group, a scalloped subcoronary implantation technique was used in 54 patients, whereas 32 patients underwent root replacement. Five patients required aortic root and ascending aortia replacement for annuloaortic ectasia. In all patients undergoing the Ross procedure, a root replacement technique was used. Operative mortality was 7.4% (14 patients). Late mortality was 5.3% (10 patients). Follow-up ranged from 1 to 46 months postoperatively. In patients with homograft aortic valve replacement, 76 patients (91.5%) had trivial to mild aortic regurgitation, while 7 patients (8.4%) had important aortic regurgitation. In patients with the Ross procedure, 78 patients (89.6%) had trivial to mild regurgitation. Moderate to severe aortic regurgitation was present in 9 patients (10.3%), all of whom had rheumatic heart disease and were young (< 30 years at surgery). We conclude that homografts and autografts provide an excellent substitute for the diseased aortic valve. Young age (< 30 years) with rheumatic etiology is a major risk factor for early progressive aortic regurgitation in patients undergoing the Ross procedure.

Adult↗
PubMed1998

Role of oligosaccharides in the pharmacokinetics of tissue-derived and genetically engineered cholinesterases.

To understand the role of glycosylation in the circulation of cholinesterases, we compared the mean residence time of five tissue-derived and two recombinant cholinesterases (injected intravenously in mice) with their oligosaccharide profiles. Monosaccharide composition analysis revealed differences in the total carbohydrate, galactose, and sialic acid contents. The molar ratio of sialic acid to galactose residues on tetrameric human serum butyrylcholinesterase, recombinant human butyrylcholinesterase, and recombinant mouse acetylcholinesterase was found to be approximately 1.0. For Torpedo californica acetylcholinesterase, monomeric and tetrameric fetal bovine serum acetylcholinesterase, and equine serum butyrylcholinesterase, this ratio was approximately 0.5. However, the circulatory stability of cholinesterases could not be correlated with the sialic acid-to-galactose ratio. Fractionation of the total pool of oligosaccharides obtained after neuraminidase digestion revealed one major oligosaccharide for human serum butyrylcholinesterase and three or four major oligosaccharides in other cholinesterases. The glycans of tetrameric forms of plasma cholinesterases (human serum butyrylcholinesterase, fetal bovine serum acetylcholinesterase, and equine serum butyrylcholinesterase) clearly demonstrated a reduced heterogeneity and higher maturity compared with glycans of monomeric fetal bovine serum acetylcholinesterase, dimeric tissue-derived T. californica acetylcholinesterase, and recombinant cholinesterases. T. californica acetylcholinesterase, recombinant cholinesterases, and monomeric fetal bovine serum acetylcholinesterase showed a distinctive shorter mean residence time (44-304 min) compared with tetrameric forms of plasma cholinesterases (1902-3206 min). Differences in the pharmacokinetic parameters of cholinesterases seem to be due to the combined effect of the molecular weight and charge- and size-based heterogeneity in glycans.

Acetylcholinesterase↗
PubMed1998

Prostaglandin E1 in infants with congenital heart disease: Indian experience.

BACKGROUND: E-type prostaglandins (PGE1) can effectively maintain the patency of the ductus arteriosus in neonates. Its use, therefore and be life saving in infants born with ductus dependent congenital heart disease. Although PGE1 is available for over two decade in western world, it has been introduced in India only since April, 1995. OBJECTIVE: To assess the efficacy of PGE1 at our center. SETTING: Hospital based. METHOD: 65 infants with ductus dependent congenital heart disease were included. Age at time of starting PGE1 infusion ranged from 18 hours to 39 days. Forty two of these were more than a week of age, 19 were more than 14 days, and two were above one month. PGE1 was started in an initial dose of 0.05 microgram/kg/min, decreased to 0.005-0.01 microgram/kg/min for maintenance. The indications for use of PGE1 were to increase pulmonary blood flow in 33 cases with pulmonary atresia, tricuspid atresia or critical pulmonic stenosis (Group I); to increase systemic blood flow in 15 cases with coarctation of aorta, hypoplastic left heart and interruption of aortic arch (Group II); to improve mixing in 13 cases of transposition of great arteries (Group III) and for improving the left ventricular volumes by keeping the duct open in 4 cases of transposition of great arteries with intact ventricular septum (Group IV). The efficacy of the drug was assessed by a rise on PaO2 and SaO2% determined for Group I & III, and by appearance of lower limbs pulses in Group II. Left ventricular volumes were serially measured by echocardiography in Group IV cases. RESULTS: The drug was successful in 62 of the 65 cases. There were two failures. One was a 39 days old baby with Ebstein's anomaly of tricuspid valve and pulmonary atresia and other was an eight days old baby with coarctation of aorta and renal failure. In addition, PGE1 could not be continued in another baby due to development of a linear skin rash locally. Side effects included apnea in 5 (9%) of 56 spontaneously breathing patients. Necrotizing enterocolitis, hyperpyrexia and jitteriness was sent in one case each. Six patients died. Two were related to PGE1, one due to failure, another due to its side effects. Definitive procedure were performed in 51 cases electively. PGE1 was used upto 13 days with sustained benefit. CONCLUSIONS: PGE1 is an effective drug for keeping the ductus open in infants with ductus dependent congenital heart disease. It can be used for neonates beyond the first week of life with efficacy. Apnea is a major side effect and close monitoring is essential.

Age Factors↗
PubMed1998

Experience with homograft mitral valve replacement.

BACKGROUND AND AIMS OF THE STUDY: Homograft mitral valve replacement may offer a superior alternative to replacement with a prosthetic valve. The authors' early experience with this technique is reported. METHODS: Between May 1994 and May 1995, 24 patients (19 males, five females; age range 17 to 49 years) underwent homograft mitral valve replacement (HMVR) at the authors' institution. The etiology was rheumatic in all patients; 22 had severe calcific mitral stenosis (MS) and two had combined MS and severe mitral regurgitation (MR). RESULTS: There were three early deaths (12%) and two late deaths (8%). In three patients the homograft had to be explanted due to severe MR at six weeks, 10 weeks and 12 months, respectively. Mean follow up was 18 months (range: 12 to 25 months). Postoperative echocardiography showed trivial or mild MR in 12 patients and moderate MR in four. Mitral stenosis was absent in all patients (mean mitral valve area 2.5 cm2). Sixteen patients showed satisfactory homograft valve function at follow up. The valve explanted after six weeks showed normal cusp architecture, endothelial growth and incorporation of the pericardial strip and complete healing of the papillary muscle junction. Magnetic resonance imaging in 12 patients showed normal appearance and function of the homografts. CONCLUSIONS: The authors' experience suggests that homograft mitral valve replacement can be performed with good early results.

Adolescent↗
PubMed1998

Studies on malaria during pregnancy in a tribal area of central India (Madhya Pradesh).

In tribal villages of central India where malaria is highly prevalent (mesoendemic), this preliminary study was undertaken to determine the effects of malaria infection in a group of 456 pregnant women with or without fever. Only 96 women were found infected with malaria, of which Plasmodium falciparum accounted for 64% of the detected parasites, while P. vivax for the remaining 36%. There were no instances of cerebral malaria or death however, one abortion and four still births were recorded among 38 primigravid women. Only one neonate was found infected with P. falciparum on day 21 though parasitemia was not high. Anemia was commonly present in most of the women (80%). Failure to clear P. falciparum parasitemia after a chloroquine regimen (25 mg/kg of body weight) was commonly observed. Persistent P. falciparum parasitemia was recorded in 8% cases. Poor response to chloroquine suggests the need to change the drug policy.

Adult↗
PubMed1998

[Significance of prenatal diagnosis in interdisciplinary treatment of sacrococcygeal teratoma].

The perinatal treatment of 23 infants with sacrococcygeal teratomas was recorded prospectively from 1990 to 1997, during which period 14 children (teratomas 6.9-18 cm) could be followed throughout the whole pregnancy at our own perinatal department. There were three prenatal deaths (21 h-27 week of gestation) and two peripartal deaths (1 hydrops and 1 ruptured teratoma). Prenatal Doppler sonography allows appropriate selection of high-risk fetuses. The vital prognostic sign was developing fetal hydrops with associated umbilical vein pulsations, increased aortal flow and an increasing pulsatility index in der venous duct.

Abortion, Induced↗
PubMed1997

Differences in active site gorge dimensions of cholinesterases revealed by binding of inhibitors to human butyrylcholinesterase.

Amino acid sequence alignments of cholinesterases revealed that 6 of 14 aromatic amino acid residues lining the active center gorge of acetylcholinesterase are replaced by aliphatic amino acid residues in butyrylcholinesterase. The Y337 (F330) in mammalian acetylcholinesterase, which is replaced by A328 in human butyrylcholinesterase, is implicated in the binding of ligands such as huperzine A, edrophonium, and acridines and one end of bisquaternary compounds such as BW284C51 and decamethonium. Y337 may sterically hinder the binding of phenothiazines such as ethopropazine, which contains a bulky exocyclic substitution. Inhibition studies of (-)-huperzine A with human butyrylcholinesterase mutants, where A328 (KI = 194.6 microM) was modified to either F (KI = 0.6 microM, as in Torpedo acetylcholinesterase) or Y (KI = 0.032 microM, as in mammalian acetylcholinesterase), confirmed previous observations made with acetylcholinesterase mutants that this residue is important for binding huperzine A. Inhibition studies of ethopropazine with butyrylcholinesterase mutants, where A328 (KI = 0.18 microM) was modified to either F (KI = 0.82 microM) or Y (KI = 0.28 microM), suggested that A328 was not solely responsible for the selectivity of ethopropazine. Volume calculations for the active site gorge showed that the poor inhibitory activity of ethopropazine toward acetylcholinesterase was due to the smaller dimension of the active site gorge which was unable to accommodate the bulky inhibitor molecule. The volume of the butyrylcholinesterase active site gorge is approximately 200 A3 larger than that of the acetylcholinesterase gorge, which allows the accommodation of ethopropazine in two different orientations as demonstrated by rigid-body refinement and molecular dynamics calculations.

Animals↗
PubMed1997

The headgroup orientation of dimyristoylphosphatidylinositol-4-phosphate in mixed lipid bilayers: a neutron diffraction study.

The trisodium salt of dimyristoylphosphatidylinositol-4-phosphate (DMPI-4P) has been synthesised specifically deuterated at particular sites in the headgroup. These materials have been used in neutron diffraction experiments, which successfully located the position (depth) of each of these deuterated sites to within +/- 0.5 A in a mixed model membrane (a 1:1 molar mixture of DMPI-4P with dimyristoyl-phosphatidylcholine, DMPC, in the L alpha phase, hydrated to the level of 28 water molecules per lipid molecule). The diffracted intensities were measured at four different D2O/H2O ratios and six orders of diffraction were obtained. These data sets, in conjunction with computer modelling, have been used to determine the orientation of the inositol ring of DMPI-4P, localising each vertical H-H distance to within approximately +/- 0.03 A. The orientation of the inositol ring is found to be one in which the C5 hydroxyl is extended out into the aqueous medium. This is, therefore, the most accessible site for water-borne reagents. This may be significant for the important pathway leading from PI-4P to PI-4,5P2. On the assumption that the P/ODAG bond is orientated parallel to the bilayer normal, these results are consistent with two possible conformations for the portion of the headgroup connecting the diacylglycerol to the inositol ring. Distinction between these two is difficult, but one may be favoured since the other involves close atom-atom contacts.

Computer Simulation↗
PubMed1997

Mutant acetylcholinesterases as potential detoxification agents for organophosphate poisoning.

It has been demonstrated that cholinesterases (ChEs) are an effective mode of pretreatment to prevent organophosphate (OP) toxicity in mice and rhesus monkeys. The efficacy of ChE as a bioscavenger of OP can be enhanced by combining enzyme pretreatment with oxime reactivation, since the scavenging capacity extends beyond a stoichiometric ratio of ChE to OP. Aging has proven to be a major barrier to achieving oxime reactivation of acetylcholinesterase (AChE) inhibited by the more potent OPs. To further increase the stoichiometry of OP to ChE required, we have sought AChE mutants that are more easily reactivated than wild-type enzyme. Substitution of glutamine for glutamate (E199) located at the amino-terminal to the active-site serine (S200) in Torpedo AChE generated an enzyme largely resistant to aging. Here we report the effect of the corresponding mutation on the rate of inhibition, reactivation by 1-(2-hydroxyiminomethyl-1-pyridinium)-1(4-carboxyaminopyridinium)- dimethyl ether hydrochloride (HI-6), and aging of mouse AChE inhibited by C(+)P(-)- and C(-)P(-)-epimers of soman. The E202 to Q mutation decreased the affinity of soman for AChE, slowed the reactivation of soman-inhibited AChE by HI-6, and decreased the aging of mutant AChE. These effects were more pronounced with C(-)P(-)-soman than with C(+)P(-)-soman. In vitro detoxification of soman and sarin by wild-type and E202Q AChE in the presence of 2 mM HI-6 showed that, E202Q AChE was 2-3 times more effective in detoxifying soman and sarin than wild-type AChE. These studies show that these recombinant DNA-derived AChEs are a great improvement over wild-type AChE as bioscavengers. They can be used to develop effective methods for the safe disposal of stored OP nerve agents and potential candidates for pre- or post-exposure treatment for OP toxicity.

Acetylcholinesterase↗
PubMed1997

Structure of glycan moieties responsible for the extended circulatory life time of fetal bovine serum acetylcholinesterase and equine serum butyrylcholinesterase.

Cholinesterases are serine hydrolases that can potentially be used as pretreatment drugs for organophosphate toxicity, as drugs to alleviate succinylcholine-induced apnea, and as detoxification agents for environmental toxins such as heroin and cocaine. The successful application of serum-derived cholinesterases as bioscavengers stems from their relatively long residence time in the circulation. To better understand the relationship between carbohydrate structure and the stability of cholinesterases in circulation, we determined the monosaccharide composition, the distribution of various oligosaccharides, and the structure of the major asparagine-linked oligosaccharides units present in fetal bovine serum acetylcholinesterase and equine serum butyrylcholinesterase. Our findings indicate that 70-80% of the oligosaccharides in both enzymes are negatively charged. This finding together with the molar ratio of galactose to sialic acid clearly suggests that the beta-galactose residues are only partially capped with sialic acid, yet they displayed a long duration in circulation. The structures of the two major oligosaccharides from fetal bovine serum acetylcholinesterase and one major oligosaccharide from equine serum butyrylcholinesterase were determined. The three carbohydrate structures were of the biantennary complex type, but only the ones from fetal bovine serum acetylcholinesterase were fucosylated on the innermost N-acetylglucosamine residue of the core. Pharmacokinetic studies with native, desialylated, and deglycosylated forms of both enzymes indicate that the microheterogeneity in carbohydrate structure may be responsible, in part, for the multiphasic clearance of cholinesterases from the circulation of mice.

Acetylcholinesterase↗